Predictors of bleeding and thrombotic events among patients admitted to the hospital with COVID-19 and elevated D-dimer: insights from the ACTION randomized clinical trial.

Therapeutic anticoagulation showed inconsistent results in hospitalized patients with COVID-19 and selection of the best patients to use this strategy still a challenge balancing the risk of thrombotic and hemorrhagic outcomes. The present post-hoc analysis of the ACTION trial evaluated the variables independently associated with both bleeding events (major bleeding or clinically relevant non-major bleeding) and the composite outcomes thrombotic events (venous thromboembolism, myocardial infarction, stroke, systemic embolism, or major adverse limb events). Variables were assessed one by one with independent logistic regressions and final models were chosen based on Akaike information criteria. The model for bleeding events showed an area under the curve of 0.63 (95% confidence interval [CI] 0.53 to 0.73), while the model for thrombotic events had an area under the curve of 0.72 (95% CI 0.65 to 0.79). Non-invasive respiratory support was associated with thrombotic but not bleeding events, while invasive ventilation was associated with both outcomes (Odds Ratio of 7.03 [95 CI% 1.95 to 25.18] for thrombotic and 3.14 [95% CI 1.11 to 8.84] for bleeding events). Beyond respiratory support, creatinine level (Odds Ratio [OR] 1.01 95% CI 1.00 to 1.02 for every 1.0 mg/dL) and history of coronary disease (OR 3.67; 95% CI 1.32 to 10.29) were also independently associated to the risk of thrombotic events. Non-invasive respiratory support, history of coronary disease, and creatinine level may help to identify hospitalized COVID-19 patients at higher risk of thrombotic complications.ClinicalTrials.gov: NCT04394377.

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.

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.

BACKGROUND: Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited. METHODS: We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed. RESULTS: A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. CONCLUSIONS: Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.).

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).

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. METHODS: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3-0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. FINDINGS: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. INTERPRETATION: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. FUNDING: Coalition COVID-19 Brazil, Bayer SA.

Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.

BACKGROUND: The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19. METHODS: We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278. FINDINGS: 447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups. INTERPRETATION: In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. FUNDING: COALITION COVID-19 Brazil and EMS.

Randomized clinical trial to evaluate a routine full anticoagulation Strategy in Patients with Coronavirus Infection (SARS-CoV2) admitted to hospital: Rationale and design of the ACTION (AntiCoagulaTlon cOroNavirus)-Coalition IV trial.

BACKGROUND: Observational studies have suggested a higher risk of thrombotic events in patients with coronavirus disease 2019 (COVID-19). Moreover, elevated D-dimer levels have been identified as an important prognostic marker in COVID-19 directly associated with disease severity and progression. Prophylactic anticoagulation for hospitalized COVID-19 patients might not be enough to prevent thrombotic events; therefore, therapeutic anticoagulation regimens deserve clinical investigation. DESIGN: ACTION is an academic-led, pragmatic, multicenter, open-label, randomized, phase IV clinical trial that aims to enroll around 600 patients at 40 sites participating in the Coalition COVID-19 Brazil initiative. Eligible patients with a confirmed diagnosis of COVID-19 with symptoms up to 14 days and elevated D-dimer levels will be randomized to a strategy of full-dose anticoagulation for 30 days with rivaroxaban 20 mg once daily (or full-dose heparin if oral administration is not feasible) vs standard of care with any approved venous thromboembolism prophylaxis regimen during hospitalization. A confirmation of COVID-19 was mandatory for study entry, based on specific tests used in clinical practice (RT-PCR, antigen test, IgM test) collected before randomization, regardless of in the outpatient setting or not. Randomization will be stratified by clinical stability at presentation. The primary outcome is a hierarchical analysis of mortality, length of hospital stay, or duration of oxygen therapy at the end of 30 days. Secondary outcomes include the World Health Organization's 8-point ordinal scale at 30 days and the following efficacy outcomes: incidence of venous thromboembolism , acute myocardial infarction, stroke, systemic embolism, major adverse limb events, duration of oxygen therapy, disease progression, and biomarkers. The primary safety outcomes are major or clinically relevant non-major bleeding according to the International Society on Thrombosis and Haemostasis criteria. SUMMARY: The ACTION trial will evaluate whether in-hospital therapeutic anticoagulation with rivaroxaban for stable patients, or enoxaparin for unstable patients, followed by rivaroxaban through 30 days compared with standard prophylactic anticoagulation improves clinical outcomes in hospitalized patients with COVID-19 and elevated D-dimer levels.

Predictive Accuracy of the Quick Sepsis-related Organ Failure Assessment Score in Brazil. A Prospective Multicenter Study.

Rationale: Although proposed as a clinical prompt to sepsis based on predictive validity for mortality, the Quick Sepsis-related Organ Failure Assessment (qSOFA) score is often used as a screening tool, which requires high sensitivity.Objectives: To assess the predictive accuracy of qSOFA for mortality in Brazil, focusing on sensitivity.Methods: We prospectively collected data from two cohorts of emergency department and ward patients. Cohort 1 included patients with suspected infection but without organ dysfunction or sepsis (22 hospitals: 3 public and 19 private). Cohort 2 included patients with sepsis (54 hospitals: 24 public and 28 private). The primary outcome was in-hospital mortality. The predictive accuracy of qSOFA was examined considering only the worst values before the suspicion of infection or sepsis.Measurements and Main Results: Cohort 1 contained 5,460 patients (mortality rate, 14.0%; 95% confidence interval [CI], 13.1-15.0), among whom 78.3% had a qSOFA score less than or equal to 1 (mortality rate, 8.3%; 95% CI, 7.5-9.1). The sensitivity of a qSOFA score greater than or equal to 2 for predicting mortality was 53.9% and the 95% CI was 50.3 to 57.5. The sensitivity was higher for a qSOFA greater than or equal to 1 (84.9%; 95% CI, 82.1-87.3), a qSOFA score greater than or equal to 1 or lactate greater than 2 mmol/L (91.3%; 95% CI, 89.0-93.2), and systemic inflammatory response syndrome plus organ dysfunction (68.7%; 95% CI, 65.2-71.9). Cohort 2 contained 4,711 patients, among whom 62.3% had a qSOFA score less than or equal to 1 (mortality rate, 17.3%; 95% CI, 15.9-18.7), whereas in public hospitals the mortality rate was 39.3% (95% CI, 35.5-43.3).Conclusions: A qSOFA score greater than or equal to 2 has low sensitivity for predicting death in patients with suspected infection in a developing country. Using a qSOFA score greater than or equal to 2 as a screening tool for sepsis may miss patients who ultimately die. Using a qSOFA score greater than or equal to 1 or adding lactate to a qSOFA score greater than or equal to 1 may improve sensitivity.Clinical trial registered with www.clinicaltrials.gov (NCT03158493).

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.

Low- Versus High-Chloride Content Intravenous Solutions for Critically Ill and Perioperative Adult Patients: A Systematic Review and Meta-analysis.

BACKGROUND: To assess whether use of low-chloride solutions in unselected critically ill or perioperative adult patients for maintenance or resuscitation reduces mortality and renal replacement therapy (RRT) use when compared to high-chloride fluids. METHODS: Systematic review and meta-analysis with random-effects inverse variance model. PubMed, Cochrane library, EMBASE, LILACS, and Web of Science were searched from inception to October 2016. Published and unpublished randomized controlled trials in any language that enrolled critically ill and/or perioperative adult patients and compared a low- to a highchloride solution for volume maintenance or resuscitation. The primary outcomes were mortality and RRT use. We conducted trial sequential analyses and assessed risk of bias of individual trials and the overall quality of evidence. Fifteen trials with 4067 patients, most at low risk of bias, were identified. Of those, only 11 and 10 trials had data on mortality and RRT use, respectively. A total of 3710 patients were included in the mortality analysis and 3724 in the RRT analysis. RESULTS: No statistically significant impact on mortality (odds ratio, 0.90; 95% confidence interval, 0.69-1.17; P = .44; I = 0%) or RRT use (odds ratio, 1.12; 95% confidence interval, 0.80-1.58; P = .52; I = 0%) was found. Overall quality of evidence was low for both primary outcomes. Trial sequential analyses highlighted that the sample size needed was much larger than that available for properly powered outcome assessment. CONCLUSIONS: The current evidence on low- versus high-chloride solutions for unselected critically ill or perioperative adult patients demonstrates no benefit, but suffers from considerable imprecision. We noted a limited exposure volume for study fluids and a relatively low risk of the populations in each study. Together with the relatively small pooled sample size, these data leave us underpowered to detect potentially important differences. Results from well-conducted, adequately powered randomized controlled trials examining sufficiently large fluid exposure are necessary.

Estimation of Stroke Volume and Stroke Volume Changes by Electrical Impedance Tomography.

BACKGROUND: Electrical impedance tomography (EIT) is a noninvasive imaging method that identifies changes in air and blood volume based on thoracic impedance changes. Recently, there has been growing interest in EIT to measure stroke volume (SV). The objectives of this study are as follows: (1) to evaluate the ability of systolic impedance variations (ΔZsys) to track changes in SV in relation to a baseline condition; (2) to assess the relationship of ΔZsys and SV in experimental subjects; and (3) to identify the influence of body dimensions on the relationship between ΔZsys and SV. METHODS: Twelve Agroceres pigs were instrumented with transpulmonary thermodilution catheter and EIT and were mechanically ventilated in a random order using different settings of tidal volume (VT) and positive end-expiratory pressure (PEEP): VT 10 mL·kg and PEEP 10 cm H2O, VT 10 mL·kg and PEEP 5 cm H2O, VT 6 mL·kg and PEEP 10 cm H2O, and VT 6 mL·kg and PEEP 5 cm H2O. After baseline data collection, subjects were submitted to hemorrhagic shock and successive fluid challenges. RESULTS: A total of 204 paired measurements of SV and ΔZsys were obtained. The 4-quadrant plot showed acceptable trending ability with a concordance rate of 91.2%. Changes in ΔZsys after fluid challenges presented an area under the curve of 0.83 (95% confidence interval, 0.74-0.92) to evaluate SV changes. Conversely, the linear association between ΔZsys and SV was poor, with R from linear mixed model of 0.35. Adding information on body dimensions improved the linear association between ΔZsys and SV up to R from linear mixed model of 0.85. CONCLUSIONS: EIT showed good trending ability and is a promising hemodynamic monitoring tool. Measurements of absolute SV require that body dimensions be taken into account.

Quality Improvement Initiatives in Sepsis in an Emerging Country: Does the Institution's Main Source of Income Influence the Results? An Analysis of 21,103 Patients.

OBJECTIVE: We aimed to assess the results of a quality improvement initiative in sepsis in an emerging setting and to analyze it according to the institutions' main source of income (public or private). DESIGN: Retrospective analysis of the Latin American Sepsis Institute database from 2005 to 2014. SETTINGS: Brazilian public and private institutions. PATIENTS: Patients with sepsis admitted in the participant institutions. INTERVENTIONS: The quality improvement initiative was based on a multifaceted intervention. The institutions were instructed to collect data on 6-hour bundle compliance and outcomes in patients with sepsis in all hospital settings. Outcomes and compliance was measured for eight periods of 6 months each, starting at the time of the enrollment in the intervention. The primary outcomes were hospital mortality and compliance with 6-hour bundle. MEASUREMENTS AND MAIN RESULTS: We included 21,103 patients; 9,032 from public institutions and 12,071 from private institutions. Comparing the first period with the eigth period, compliance with the 6-hour bundle increased from 13.5% to 58.2% in the private institutions (p < 0.0001) and from 7.4% to 15.7% in the public institutions (p < 0.0001). Mortality rates significantly decreased throughout the program in private institutions, from 47.6% to 27.2% in the eighth period (adjusted odds ratio, 0.45; 95% CI, 0.32-0.64). However, in the public hospitals, mortality diminished significantly only in the first two periods. CONCLUSION: This quality improvement initiative in sepsis in an emerging country was associated with a reduction in mortality and with improved compliance with quality indicators. However, this reduction was sustained only in private institutions.

One-year survival and resource use after critical illness: impact of organ failure and residual organ dysfunction in a cohort study in Brazil.

INTRODUCTION: In this study, we evaluated the impacts of organ failure and residual dysfunction on 1-year survival and health care resource use using Intensive Care Unit (ICU) discharge as the starting point. METHODS: We conducted a historical cohort study, including all adult patients discharged alive after at least 72 h of ICU stay in a tertiary teaching hospital in Brazil. The starting point of follow-up was ICU discharge. Organ failure was defined as a value of 3 or 4 in its corresponding component of the Sequential Organ Failure Assessment score, and residual organ dysfunction was defined as a score of 1 or 2. We fit a multivariate flexible Cox model to predict 1-year survival. RESULTS: We analyzed 690 patients. Mortality at 1 year after discharge was 27%. Using multivariate modeling, age, chronic obstructive pulmonary disease, cancer, organ dysfunctions and albumin at ICU discharge were the main determinants of 1-year survival. Age and organ failure were non-linearly associated with survival, and the impact of organ failure diminished over time. We conducted a subset analysis with 561 patients (81%) discharged without organ failure within the previous 24 h of discharge, and the number of residual organs in dysfunction remained strongly associated with reduced 1-year survival. The use of health care resources among hospital survivors was substantial within 1 year: 40% of the patients were rehospitalized, 52% visited the emergency department, 90% were seen at the outpatient clinic, 14% attended rehabilitation outpatient services, 11% were followed by the psychological or psychiatric service and 7% used the day hospital facility. Use of health care resources up to 30 days after hospital discharge was associated with the number of organs in dysfunction at ICU discharge. CONCLUSIONS: Organ failure was an important determinant of 1-year outcome of critically ill survivors. Nevertheless, the impact of organ failure tended to diminish over time. Resource use after critical illness was elevated among ICU survivors, and a targeted action is needed to deliver appropriate care and to reduce the late critical illness burden.

Association Between Nighttime Discharge from the Intensive Care Unit and Hospital Mortality: A Multi-Center Retrospective Cohort Study.

BACKGROUND: We aimed to determine the impact of nighttime discharge from the intensive care unit (ICU) to the ward on hospital mortality and readmission rates in consecutive critically ill patients admitted to five Canadian ICUs. We hypothesized that hospital mortality and readmission rates would be higher for patients discharged after hours compared with discharge during the day. METHODS: A multi-center retrospective cohort study was carried out at five hospitals in Edmonton, Canada, between July 2002 and December 2009. Nighttime discharge was defined as discharge from the ICU occurring between 07:00 pm and 07:59 am. Logistic regression analysis was used to explore the associations between nighttime discharge and outcomes. RESULTS: Of 19,622 patients discharged alive from the ICU, 3,505 (17.9%) discharges occurred during nighttime. Nighttime discharge occurred more commonly among medical than surgical patients (19.9% vs. 13.8%, P < 0.001) and among those with more comorbid conditions, compared with daytime discharged patients. Crude hospital mortality (11.8% versus 8.8%, P < 0.001) was greater for nighttime discharged as compared to daytime discharged patients. In a multivariable analysis, after adjustment for comorbidities, diagnosis and source of admission, nighttime discharge remains associated with higher mortality (odds ratio [OR] 1.29; 95% CI, 1.14 to 1.46, P < 0.001). This finding was robust in two sensitivity analyses examining discharges occurring between 00:00 am and 04:59 am (OR 1.28; 1.12-1.47; P < 0.001) and for those who died within 48 h of ICU discharge without readmission (OR 1.24; 1.07-1.42, P = 0.002). There was no difference in ICU readmission for nighttime compared with daytime discharges (7.4% vs. 6.9 %, p = 0.26). However, rates were higher for nighttime discharges in community compared with tertiary hospitals (7.7% vs. 5.7%, P = 0.023). CONCLUSIONS: In a large integrated health region, 1 in 5 ICU patients are discharged at nighttime, a factor with increasing occurrence during our study and shown to be independently associated with higher hospital mortality.

Serum sodium shift in hyponatremic patients undergoing liver transplantation: a retrospective cohort study.

INTRODUCTION: We aimed to describe the pre-operative incidence of hyponatremia in patients undergoing liver transplantation (LTx), as well as the rate and consequences of rapid peri-operative sodium rises in these patients. METHODS: This was a retrospective before and after observational study performed at a University-affiliated LTx center between January 2007 and June 2013. The primary exposure was pre-operative hyponatremia, defined as a serum sodium (SNa) <133 mmol/L. The primary outcome was occurrence of a rapid SNa shift, defined as ≥10 mmol/L in the first 24 h following LTx. The rates of rapid peri-operative SNa shift were compared before and after a focused quality assurance (QA) initiative performed in July 2009. RESULTS: Of 366 LTx, 69 (18.9%) had pre-operative hyponatremia, 6 (8.7%) of whom had a rapid rise in serum sodium (SNa). Rapid rise was associated with a greater intra-operative positive fluid balance (p < 0.001) and use of intra-operative continuous renal replacement therapy (CRRT) (p = 0.017). A rapid rise in SNa was associated with more neurological investigations in the post-transplant period (brain computed tomography, electroencephalogram, swallow studies), increased neurological deficits (p = 0.006), more abnormal swallowing assessments (p = 0.003), a tendency for more neurology consultations (p = 0.058), increased discharge to a rehabilitation or long-term care facility (p < 0.001), and increased 6-month mortality (p < 0.001). Following a QA initiative, rapid peri-operative rises in SNa among hyponatremic patients was significantly reduced (20% vs. 0%, p < 0.003). CONCLUSION: Pre-operative hyponatremia and rapid peri-operative SNa shifts are associated with a more complicated post-operative course and worse outcomes following LTx. Increased education and awareness, along with process changes, such as standardizing CRRT prescription, can reduce iatrogenic rapid peri-operative shifts in SNa.

Sepsis-related deaths in Brazil: an analysis of the national mortality registry from 2002 to 2010.

INTRODUCTION: Limited population-based epidemiologic information about sepsis' demography, including its mortality and temporal changes is available from developing countries. We investigated the epidemiology of sepsis deaths in Brazil using secondary data from the Brazilian Mortality Information System. METHODS: Retrospective descriptive analysis of Brazilian multiple-cause-of-death data between 2002 and 2010, with sepsis-associated International Classification of Diseases, 10th Revision (ICD-10) code indicated as the cause of death. Population-based sepsis associated mortality rates and trends were estimated. Annual population-based mortality rates were calculated using age-stratified population estimates from the 2010 census provided by the Brazilian Institute of Geography and Statistics as denominators. RESULTS: The total number of annual deaths recorded in Brazil increased over the decade, from 982,294 deaths reported in 2002 to 1,133,761 deaths reported in 2010. The number of sepsis associated deaths also increased both in absolute numbers and proportions from 95,972 (9.77% of total deaths) in 2002 to 186,712 deaths (16.46%) in 2010. The age-adjusted rate of sepsis-associated mortality increased from 69.5 deaths per 100,000 to 97.8 deaths per 100,000 population from 2002 to 2010 (P < 0.001). Sepsis-associated mortality was higher in individuals older than 60 years of age as compared to subjects aged 0 to 20 years (adjusted rate ratio 15.7 (95% confidence interval (CI) 15.6 to 15.8)) and in male subjects (1.15 (95% CI 1.15 to 1.16)). CONCLUSIONS: Between 2002 and 2010 the contribution of sepsis to all cause mortality as reported in multiple-cause-of-death forms increased significantly in Brazil. Age-adjusted mortality rates by sepsis also increased in the last decade. Our results confirm the importance of sepsis as a significant healthcare issue in Brazil.