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Despite several studies designed to evaluate the efficacy of chloroquine and hydroxychloroquine in the treatment of coronavirus disease 2019 (COVID-19), there is still doubt about the effects of these drugs, especially in patients with severe forms of the disease. This randomized, open-label, controlled, phase III trial assessed the efficacy of chloroquine or hydroxychloroquine for five days in combination with standard care compared to standard care alone in patients hospitalized with severe COVID-19. Chloroquine 450 mg BID on day 1 and 450 mg once daily from days 2 to 5 or hydroxychloroquine 400 mg BID on day 1 and 400 mg once daily from days 2 to 5 were administered in the intervention group. Patients were enrolled from April 16 to August 06, 2020, in 6 hospitals in southern Brazil. The primary outcome was the clinical status measured on day 14 after randomization with a 9-point ordinal scale. The main secondary outcomes were all-cause mortality; invasive mechanical ventilation use; the incidence of acute renal dysfunction in 28 days; and the clinical status of patients on days 5, 7, 10 and 28. All patients with a positive RT-PCR result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were analyzed (modified intention to treat (mITT) population). Arrythmias and cardiovascular complications were assessed as safety outcomes. A total of 105 patients were enrolled and followed for 28 days. The trial was stopped before reaching the planned sample size due to harmful effects. Patients in the intervention group had a worse clinical outcome on the 14th day (odds ratio (OR) 2.45 [1.17 to 4.93], p = 0.016) and on the 28th day (OR 2.47 [1.15 to 5.30], p = 0.020). Moreover, the intervention group had higher incidences of invasive mechanical ventilation use (risk ratio (RR) 2.15 [1.05 to 4.40], p = 0.030) and severe renal dysfunction (KDIGO stage 3) (RR 2.24 [1.01 to 4.99], p = 0.042) until the 28th day of follow-up. No significant arrythmia was noted. In patients with severe COVID-19, the use of chloroquine/hydroxychloroquine added to standard treatment resulted in a significant worsening of clinical status, an increased risk of renal dysfunction and an increased need for invasive mechanical ventilation. Trial Registration: ClinicalTrials.gov, NCT04420247. Registered 09 June 2020—Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/study/NCT04420247 .

Background Ceftolozane/tazobactam is approved for treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) at double the dose approved for other infection sites. Among nosocomial pneumonia subtypes, ventilated HABP (vHABP) is associated with the lowest survival. In the ASPECT-NP randomized, controlled trial, participants with vHABP treated with ceftolozane/tazobactam had lower 28-day all-cause mortality (ACM) than those receiving meropenem. We conducted a series of post hoc analyses to explore the clinical significance of this finding. Methods ASPECT-NP was a multinational, phase 3, noninferiority trial comparing ceftolozane/tazobactam with meropenem for treating vHABP and VABP; study design, efficacy, and safety results have been reported previously. The primary endpoint was 28-day ACM. The key secondary endpoint was clinical response at test-of-cure. Participants with vHABP were a prospectively defined subgroup, but subgroup analyses were not powered for noninferiority testing. We compared baseline and treatment factors, efficacy, and safety between ceftolozane/tazobactam and meropenem in participants with vHABP. We also conducted a retrospective multivariable logistic regression analysis in this subgroup to determine the impact of treatment arm on mortality when adjusted for significant prognostic factors. Results Overall, 99 participants in the ceftolozane/tazobactam and 108 in the meropenem arm had vHABP. 28-day ACM was 24.2% and 37.0%, respectively, in the intention-to-treat population (95% confidence interval [CI] for difference: 0.2, 24.8) and 18.2% and 36.6%, respectively, in the microbiologic intention-to-treat population (95% CI 2.5, 32.5). Clinical cure rates in the intention-to-treat population were 50.5% and 44.4%, respectively (95% CI − 7.4, 19.3). Baseline clinical, baseline microbiologic, and treatment factors were comparable between treatment arms. Multivariable regression identified concomitant vasopressor use and baseline bacteremia as significantly impacting ACM in ASPECT-NP; adjusting for these two factors, the odds of dying by day 28 were 2.3-fold greater when participants received meropenem instead of ceftolozane/tazobactam. Conclusions There were no underlying differences between treatment arms expected to have biased the observed survival advantage with ceftolozane/tazobactam in the vHABP subgroup. After adjusting for clinically relevant factors found to impact ACM significantly in this trial, the mortality risk in participants with vHABP was over twice as high when treated with meropenem compared with ceftolozane/tazobactam. Trial registration clinicaltrials.gov, NCT02070757. Registered 25 February, 2014, clinicaltrials.gov/ct2/show/NCT02070757.

Evaluate current recommendation for the use of noninvasive ventilation (Bi-level positive airway pressure- BiPAP modality) in hypoxemic acute respiratory failure, excluding chronic obstructive pulmonary disease. Electronic searches in MEDLINE, Web of Science, Clinical Trials, and The Cochrane Central Register of Controlled Clinical Trials. We searched for randomized controlled trials comparing BiPAP to a control group in patients with hypoxemic acute respiratory failure. Endotracheal intubation and death were the assessed outcomes. Of the 563 studies found, nine met the inclusion criteria for this systematic review. The pooled RR (95% CI) for intubation in patients with acute pulmonary edema (APE)/community acquired pneumonia (CAP) and in immunosuppressed patients (cancer and transplants) were 0.61 (0.39–0.84) and 0.77 (0.60–0.93), respectively. For Intensive Care Units (ICU) mortality, the RR (95% CI) in patients with APE/CAP was 0.51 (0.22–0.79). The heterogeneity was low in all comparisons. NIV showed a significant protective effect for intubation in immunosuppressed patients (cancer and transplants) and in patients with APE/CAP. However, the benefits of NIV for other etiologies are not clear and more trials are needed to prove these effects. •Noninvasive ventilation reduces the risk of intubation in subgroups of acute hypoxemic patients.•Immunosuppressed, acute pulmonary edema and pneumonia patients may benefit most from NIV.•Well designed randomized clinical trials are required to address the benefit in other populations.

Background The gold-standard method for establishing a microbiological diagnosis of COVID-19 is reverse-transcriptase polymerase chain reaction (RT-PCR). This study aimed to evaluate the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a set of clinical-radiological criteria for COVID-19 screening in patients with severe acute respiratory failure (SARF) admitted to intensive care units (ICUs), using reverse-transcriptase polymerase chain reaction (RT-PCR) as the reference standard. Methods Diagnostic accuracy study including a historical cohort of 1009 patients consecutively admitted to ICUs across six hospitals in Curitiba (Brazil) from March to September, 2020. The sample was stratified into groups by the strength of suspicion for COVID-19 (strong versus weak) using parameters based on three clinical and radiological (chest computed tomography) criteria. The diagnosis of COVID-19 was confirmed by RT-PCR (referent). Results With respect to RT-PCR, the proposed criteria had 98.5% (95% confidence interval [95% CI] 97.5–99.5%) sensitivity, 70% (95% CI 65.8–74.2%) specificity, 85.5% (95% CI 83.4–87.7%) accuracy, PPV of 79.7% (95% CI 76.6–82.7%) and NPV of 97.6% (95% CI 95.9–99.2%). Similar performance was observed when evaluated in the subgroups of patients admitted with mild/moderate respiratory disfunction, and severe respiratory disfunction. Conclusion The proposed set of clinical-radiological criteria were accurate in identifying patients with strong versus weak suspicion for COVID-19 and had high sensitivity and considerable specificity with respect to RT-PCR. These criteria may be useful for screening COVID-19 in patients presenting with SARF.

Frailty is a critical factor influencing outcomes in intensive care units (ICUs). A retrospective cohort study involving 8041 adult ICU patients in Curitiba (May 2023-April 2024) evaluated the role of the Clinical Frailty Scale (CFS) as a mortality risk and functional dependence at ICU discharge. Patients were classified according to their CFS score at admission, with higher scores indicating greater frailty. The primary outcomes were ICU mortality and transition to a higher level of functional dependence at discharge. Multivariable models were adjusted for age, sex, number of comorbidities, type of hospitalization, presence of limitations on life-sustaining therapies, and SOFA score within the first 24 h. The cohort had a mean age of 66 years (51.4% women), with a median SOFA score of 2. Most patients were classified as “managing well” (33.5%), “vulnerable” (21%), or “mildly frail” (10.1%). Overall ICU mortality was 11.5%, and more than 40% of patients were discharged with some degree of functional dependence. Higher frailty at admission was independently associated with worse outcomes, including increased mortality and greater functional dependence. These findings reinforce the value of frailty assessment by using the CFS to support prognostic decision-making in critically ill patients.

Background Dysglycemias have been associated with worse prognosis in critically ill patients with COVID-19, but data on the association of dysglycemia with COVID-19 in comparison with other forms of severe acute respiratory syndrome are lacking. This study aimed to compare the occurrence of different glycemic abnormalities in patients with severe acute respiratory syndrome and COVID-19 admitted to intensive care units versus glycemic abnormalities in patients with severe acute respiratory syndrome from other causes, to evaluate the adjusted attributable risk associated with COVID-19 and dysglycemia and to assess the influence of these dysglycemias on mortality. Methods We conducted a retrospective cohort of consecutive patients with severe acute respiratory syndrome and suspected COVID-19 hospitalized in intensive care units between March 11 and September 13, 2020, across eight hospitals in Curitiba-Brazil. The primary outcome was the influence of COVID-19 on the variation of the following parameters of dysglycemia: highest glucose level at admission, mean and highest glucose levels during ICU stay, mean glucose variability, percentage of days with hyperglycemia, and hypoglycemia during ICU stay. The secondary outcome was the influence of COVID-19 and each of the six parameters of dysglycemia on hospital mortality within 30 days from ICU admission. Results The sample consisted of 841 patients, of whom 703 with and 138 without COVID-19. Comparing patients with and without COVID-19, those with COVID-19 had significantly higher glucose peaks at admission (165 mg/dL vs. 146 mg/dL; p = 0.002) and during ICU stay (242 mg/dL vs. 187md/dL; p < 0.001); higher mean daily glucose (149.7 mg/dL vs. 132.6 mg/dL; p < 0.001); higher percentage of days with hyperglycemia during ICU stay (42.9% vs. 11.1%; p < 0.001); and greater mean glucose variability (28.1 mg/dL vs. 25.0 mg/dL; p = 0.013). However, these associations were no longer statistically significant after adjustment for Acute Physiology and Chronic Health Evaluation II scores, Sequential Organ Failure Assessment scores, and C-reactive protein level, corticosteroid use and nosocomial infection. Dysglycemia and COVID-19 were each independent risk factors for mortality. The occurrence of hypoglycemia (< 70 mg/dL) during ICU stay was not associated with COVID-19. Conclusion Patients with severe acute respiratory syndrome due to COVID-19 had higher mortality and more frequent dysglycemia than patients with severe acute respiratory syndrome due to other causes. However, this association did not seem to be directly related to the SARS-CoV-2 infection.

Background Traumatic brain injury (TBI) has substantial physical, psychological, social and economic impacts, with high rates of morbidity and mortality. Considering its high incidence, the aim of this study was to identify epidemiological and clinical characteristics that predict mortality in patients hospitalized for TBI in intensive care units (ICUs). Methods A retrospective cohort study was carried out with patients over 18 years old with TBI admitted to an ICU of a Brazilian trauma referral hospital between January 2012 and August 2019. TBI was compared with other traumas in terms of clinical characteristics of ICU admission and outcome. Univariate and multivariate analyses were used to estimate the odds ratio for mortality. Results Of the 4816 patients included, 1114 had TBI, with a predominance of males (85.1%). Compared with patients with other traumas, patients with TBI had a lower mean age (45.3 ± 19.1 versus 57.1 ± 24.1 years, p < 0.001), higher median APACHE II (19 versus 15, p < 0.001) and SOFA (6 versus 3, p < 0.001) scores, lower median Glasgow Coma Scale (GCS) score (10 versus 15, p < 0.001), higher median length of stay (7 days versus 4 days, p < 0.001) and higher mortality (27.6% versus 13.3%, p < 0.001). In the multivariate analysis, the predictors of mortality were older age (OR: 1.008 [1.002–1.015], p = 0.016), higher APACHE II score (OR: 1.180 [1.155–1.204], p < 0.001), lower GCS score for the first 24 h (OR: 0.730 [0.700–0.760], p < 0.001), greater number of brain injuries and presence of associated chest trauma (OR: 1.727 [1.192–2.501], p < 0.001). Conclusion Patients admitted to the ICU for TBI were younger and had worse prognostic scores, longer hospital stays and higher mortality than those admitted to the ICU for other traumas. The independent predictors of mortality were older age, high APACHE II score, low GCS score, number of brain injuries and association with chest trauma.

Nosocomial pneumonia due to antimicrobial-resistant pathogens is associated with high mortality. We assessed the efficacy and safety of the combination antibacterial drug ceftolozane–tazobactam versus meropenem for treatment of Gram-negative nosocomial pneumonia. We conducted a randomised, controlled, double-blind, non-inferiority trial at 263 hospitals in 34 countries. Eligible patients were aged 18 years or older, were undergoing mechanical ventilation, and had nosocomial pneumonia (either ventilator-associated pneumonia or ventilated hospital-acquired pneumonia). Patients were randomly assigned (1:1) with block randomisation (block size four), stratified by type of nosocomial pneumonia and age (<65 years vs ≥65 years), to receive either 3 g ceftolozane–tazobactam or 1 g meropenem intravenously every 8 h for 8–14 days. The primary endpoint was 28-day all-cause mortality (at a 10% non-inferiority margin). The key secondary endpoint was clinical response at the test-of-cure visit (7–14 days after the end of therapy; 12·5% non-inferiority margin). Both endpoints were assessed in the intention-to-treat population. Investigators, study staff, patients, and patients' representatives were masked to treatment assignment. Safety was assessed in all randomly assigned patients who received study treatment. This trial was registered with ClinicalTrials.gov, NCT02070757. Between Jan 16, 2015, and April 27, 2018, 726 patients were enrolled and randomly assigned, 362 to the ceftolozane–tazobactam group and 364 to the meropenem group. Overall, 519 (71%) patients had ventilator-associated pneumonia, 239 (33%) had Acute Physiology and Chronic Health Evaluation II scores of at least 20, and 668 (92%) were in the intensive care unit. At 28 days, 87 (24·0%) patients in the ceftolozane–tazobactam group and 92 (25·3%) in the meropenem group had died (weighted treatment difference 1·1% [95% CI −5·1 to 7·4]). At the test-of-cure visit 197 (54%) patients in the ceftolozane–tazobactam group and 194 (53%) in the meropenem group were clinically cured (weighted treatment difference 1·1% [95% CI −6·2 to 8·3]). Ceftolozane–tazobactam was thus non-inferior to meropenem in terms of both 28-day all-cause mortality and clinical cure at test of cure. Treatment-related adverse events occurred in 38 (11%) of 361 patients in the ceftolozane–tazobactam group and 27 (8%) of 359 in the meropenem group. Eight (2%) patients in the ceftolozane–tazobactam group and two (1%) in the meropenem group had serious treatment-related adverse events. There were no treatment-related deaths. High-dose ceftolozane–tazobactam is an efficacious and well tolerated treatment for Gram-negative nosocomial pneumonia in mechanically ventilated patients, a high-risk, critically ill population. Merck & Co.

ABSTRACT Objective: Doripenem is a new carbapenem that has broad-spectrum activity against bacterial pathogens commonly responsible for nosocomial pneumonia (NP). It has several advantages over currently available carbapenems and other classes of drugs used in this indication. This prospective, randomized, open-label, multicenter study was designed to establish whether doripenem was noninferior to piperacillin/tazobactam in NP. Methods: Adults (n = 448) with signs and symptoms of NP, including non-ventilated patients and those ventilated for <5 days, were stratified by ventilation mode, illness severity (Acute Physiology and Chronic Health Evaluation II score), and geographic region and then randomly allocated to treatment with doripenem 500 mg every 8 h by a 1-h intravenous (IV) infusion or piperacillin/tazobactam 4.5 g every 6 h by 30-min IV infusion. After receiving IV study drug for at least 72 h, eligible patients could be switched to oral levofloxacin 750 mg once daily. Antibiotic therapy was continued for a total of 7–14 days. The primary endpoint was the clinical cure rate, assessed 7–14 days after treatment completion, in clinically evaluable patients and in the clinical modified intent-to-treat population (cMITT). Trial registration: ClinicalTrials.gov, NCT00211003. Results: Doripenem was noninferior to piperacillin/tazobactam. Clinical cure rates in clinically evaluable patients (n = 253) were 81.3% in the doripenem arm and 79.8% in the piperacillin/tazobactam arm (between-treatment difference: 1.5%; 95% confidence interval [CI], −9.1 to 12.1%) and in the cMITT population 69.5% and 64.1%, respectively, (between-treatment difference: 5.4%; 95% CI, −4.1 to 14.8%). Baseline resistance of Klebsiella pneumoniae and Pseudomonas aeruginosa to piperacillin/tazobactam was 44% and 26.9%, respectively; a doripenem minimum inhibitory concentration (MIC) >8 µg/mL occurred in 0% and 7.7%, respectively. Favorable microbiological outcome rates against Gram-negative pathogens were numerically higher with doripenem than with piperacillin/tazobactam, but the difference was not statistically significant. Both study drugs were generally well tolerated, as only 16.1% and 17.6% of patients receiving doripenem and piperacillin/tazobactam, respectively, had a drug-related adverse event. Study limitations included the open-label design, the low rate of monotherapy (adjunctive use of aminoglycoside was required when P. aeruginosa was suspected), and the exclusion of the most critically ill and immunocompromized patients. Conclusions: Doripenem was clinically and microbiologically effective in patents with NP, including those with early-onset ventilator-associated pneumonia, and was therapeutically noninferior to piperacillin/tazobactam.