Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Importance: The effects of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remain uncertain. Objective: To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate to severe ARDS compared with a conventional low-PEEP strategy. Design, Setting, and Participants: Multicenter, randomized trial conducted at 120 intensive care units (ICUs) from 9 countries from November 17, 2011, through April 25, 2017, enrolling adults with moderate to severe ARDS. Interventions: An experimental strategy with a lung recruitment maneuver and PEEP titration according to the best respiratory-system compliance (n = 501; experimental group) or a control strategy of low PEEP (n = 509). All patients received volume-assist control mode until weaning. Main Outcomes and Measures: The primary outcome was all-cause mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days through day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality. Results: A total of 1010 patients (37.5% female; mean [SD] age, 50.9 [17.4] years) were enrolled and followed up. At 28 days, 277 of 501 patients (55.3%) in the experimental group and 251 of 509 patients (49.3%) in the control group had died (hazard ratio [HR], 1.20; 95% CI, 1.01 to 1.42; P = .041). Compared with the control group, the experimental group strategy increased 6-month mortality (65.3% vs 59.9%; HR, 1.18; 95% CI, 1.01 to 1.38; P = .04), decreased the number of mean ventilator-free days (5.3 vs 6.4; difference, -1.1; 95% CI, -2.1 to -0.1; P = .03), increased the risk of pneumothorax requiring drainage (3.2% vs 1.2%; difference, 2.0%; 95% CI, 0.0% to 4.0%; P = .03), and the risk of barotrauma (5.6% vs 1.6%; difference, 4.0%; 95% CI, 1.5% to 6.5%; P = .001). There were no significant differences in the length of ICU stay, length of hospital stay, ICU mortality, and in-hospital mortality. Conclusions and Relevance: In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients. Trial Registration: clinicaltrials.gov Identifier: NCT01374022.

The respiratory oxygenation index for identifying the risk of orotracheal intubation in COVID-19 patients receiving high-flow nasal cannula oxygen.

OBJECTIVE: To assess whether the respiratory oxygenation index (ROX index) measured after the start of high-flow nasal cannula oxygen therapy can help identify the need for intubation in patients with acute respiratory failure due to coronavirus disease 2019. METHODS: This retrospective, observational, multicenter study was conducted at the intensive care units of six Brazilian hospitals from March to December 2020. The primary outcome was the need for intubation up to 7 days after starting the high-flow nasal cannula. RESULTS: A total of 444 patients were included in the study, and 261 (58.7%) were subjected to intubation. An analysis of the area under the receiver operating characteristic curve (AUROC) showed that the ability to discriminate between successful and failed high-flow nasal cannula oxygen therapy within 7 days was greater for the ROX index measured at 24 hours (AUROC 0.80; 95%CI 0.76 - 0.84). The median interval between high-flow nasal cannula initiation and intubation was 24 hours (24 - 72), and the most accurate predictor of intubation obtained before 24 hours was the ROX index measured at 12 hours (AUROC 0.75; 95%CI 0.70 - 0.79). Kaplan-Meier curves revealed a greater probability of intubation within 7 days in patients with a ROX index ≤ 5.54 at 12 hours (hazard ratio 3.07; 95%CI 2.24 - 4.20) and ≤ 5.96 at 24 hours (hazard ratio 5.15; 95%CI 3.65 - 7.27). CONCLUSION: The ROX index can aid in the early identification of patients with acute respiratory failure due to COVID-19 who will progress to the failure of high-flow nasal cannula supportive therapy and the need for intubation.

Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults in the intensive care unit with suspected hypoxic ischaemic encephalopathy following a cardiac arrest (Mega-ROX HIE).

Background: The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with hypoxic ischaemic encephalopathy (HIE) following a cardiac arrest who are receiving invasive mechanical ventilation in the intensive care unit (ICU) is uncertain. Objective: To summarise the protocol and statistical analysis plan for the Mega-ROX HIE trial. Design setting and participants: Mega-ROX HIE is an international randomised clinical trial that will be conducted within an overarching 40,000-participant registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We expect to enrol approximately 4000 participants with suspected HIE following a cardiac arrest who are receiving invasive mechanical ventilation in the ICU. Main outcome measures: The primary outcome is in-hospital all-cause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of participants discharged home. Results and conclusions: Mega-ROX HIE will compare the effect of conservative vs. liberal oxygen therapy regimens on day-90 in-hospital mortality in adults in the ICU with suspected HIE following a cardiac arrest. The protocol and planned analyses are reported here to mitigate analysis bias. Trial registration: Australian and New Zealand Clinical Trials Registry (ACTRN 12620000391976).

Adherence to low tidal volume in the transition to spontaneous ventilation in patients with acute respiratory failure in intensive care units in Latin America (SPIRAL): a study protocol.

OBJECTIVE: Patients with acute respiratory failure often require mechanical ventilation to reduce the work of breathing and improve gas exchange; however, this may exacerbate lung injury. Protective ventilation strategies, characterized by low tidal volumes (≤ 8mL/kg of predicted body weight) and limited plateau pressure below 30cmH2O, have shown improved outcomes in patients with acute respiratory distress syndrome. However, in the transition to spontaneous ventilation, it can be challenging to maintain tidal volume within protective levels, and it is unclear whether low tidal volumes during spontaneous ventilation impact patient outcomes. We developed a study protocol to estimate the prevalence of low tidal volume ventilation in the first 24 hours of spontaneous ventilation in patients with hypoxemic acute respiratory failure and its association with ventilator-free days and survival. METHODS: We designed a multicenter, multinational, cohort study with a 28-day follow-up that will include patients with acute respiratory failure, defined as a partial oxygen pressure/fraction of inspired oxygen ratio < 300mmHg, in transition to spontaneous ventilation in intensive care units in Latin America. RESULTS: We plan to include 422 patients in ten countries. The primary outcomes are the prevalence of low tidal volume in the first 24 hours of spontaneous ventilation and ventilator-free days on day 28. The secondary outcomes are intensive care unit and hospital mortality, incidence of asynchrony and return to controlled ventilation and sedation. CONCLUSION: In this study, we will assess the prevalence of low tidal volume during spontaneous ventilation and its association with clinical outcomes, which can inform clinical practice and future clinical trials.

Prospective, randomized, controlled trial assessing the effects of a driving pressure-limiting strategy for patients with acute respiratory distress syndrome due to community-acquired pneumonia (STAMINA trial): protocol and statistical analysis plan.

BACKGROUND: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear. OBJECTIVE: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia. METHODS: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance. OUTCOMES: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide. CONCLUSION: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.

Parafoveal chondral lesion of the femoral head in patients with femoroacetabular impingement.

Objective: To describe cases of parafoveal chondral lesion of the femoral head in patients with femoroacetabular impingement, correlating the clinical and imaging data. Materials and Methods: This was a retrospective descriptive case series of parafoveal chondral lesion of the femoral head in 21 patients who underwent computed tomography and magnetic resonance arthrography scans of the hip, having then received an imaging-based diagnosis of femoroacetabular impingement. Results: Of the 21 patients evaluated, 15 (71%) had cam-type femoroacetabular impingement, whereas five (24%) had mixed-type impingement, and one (5%) had pincer-type impingement. Twelve patients (57%) had a low frequency of physical activity, which was significantly associated with the presence of cam-type impingement (p = 0.015). Although the extent of the lesion correlated significantly with the acetabular coverage angle (p = 0.04), it did not correlate significantly with the alpha angle or femoral head-neck offset value (p = 0.08 and p = 0.06, respectively). We also found no correlation between the extent of the lesion and the other main parameters that define the femoroacetabular impingement types. Conclusion: This was one of the largest case series of parafoveal chondral lesion of the femoral head in patients with imaging findings of femoroacetabular impingement. The extent of such lesions does not appear to correlate with the parameters of femoroacetabular impingement, with the exception of the acetabular coverage angle.

Objetivo: Descrever casos de lesão condral parafoveal da cabeça femoral em pacientes com impacto femoroacetabular, correlacionando dados clínicos e de imagem. Materiais e Métodos: Esta foi uma série de casos descritiva retrospectiva de lesão condral parafoveal da cabeça femoral em 21 pacientes submetidos a tomografia computadorizada e artrorressonância magnética do quadril e que receberam diagnóstico por imagem de impacto femoroacetabular. Resultados: Dos 21 pacientes avaliados, 15 (71%) tiveram impacto femoroacetabular do tipo cam, enquanto cinco (24%) tiveram impacto do tipo misto e um (5%) teve impacto do tipo pincer. Doze pacientes (57%) apresentaram baixa frequência de atividade física, sendo esta significativamente associada a impacto do tipo cam (p = 0,015). Houve correlação significativa entre a extensão da lesão e o ângulo de cobertura acetabular (p = 0,04), porém, não se correlacionou significativamente com o ângulo alfa ou com o valor do deslocamento cabeça-colo femoral (p = 0,08 e p = 0,06, respectivamente). Também não encontramos correlação entre a extensão da lesão e os outros principais parâmetros que definem os tipos de impacto femoroacetabular. Conclusão: Esta foi uma das maiores casuísticas de lesão condral parafoveal da cabeça femoral em pacientes com achados de imagem de impacto femoroacetabular. A extensão dessas lesões não parece se correlacionar com os parâmetros do impacto femoroacetabular, com exceção do ângulo de cobertura acetabular.

Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults with sepsis in the intensive care unit (Mega-ROX Sepsis).

Background: The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis receiving unplanned invasive mechanical ventilation in the intensive care unit (ICU) is uncertain. Objective: The objective of this study was to summarise the protocol and statistical analysis plan for the Mega-ROX Sepsis trial. Design setting and participants: The Mega-ROX Sepsis trial is an international randomised clinical trial that will be conducted within an overarching 40,000-patient registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We anticipate that between 10,000 and 13,000 patients with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU will be enrolled in this trial. Main outcome measures: The primary outcome is in-hospital all-cause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of patients discharged home. Results and conclusions: Mega-ROX Sepsis will compare the effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU. The protocol and a prespecified approach to analyses are reported here to mitigate analysis bias.

Evaluation of the characteristics of infection prevention and control programs and infection control committees in Brazilian hospitals: A countrywide cross-sectional study.

Objective: Data are scarce regarding hospital infection control committees and compliance with infection prevention and control (IPC) recommendations in Brazil, a country of continental dimensions. We assessed the main characteristics of infection control committees (ICCs) on healthcare-associated infections (HAIs) in Brazilian hospitals. Methods: This cross-sectional study was conducted in ICCs of public and private hospitals distributed across all Brazilian regions. Data were collected directly from the ICC staff by completing an online questionnaire and during on-site visits through face-to-face interviews. Results: In total, 53 Brazilian hospitals were evaluated from October 2019 to December 2020. All hospitals had implemented the IPC core components in their programs. All centers had protocols for the prevention and control of ventilator-associated pneumonia as well as bloodstream, surgical site, and catheter-associated urinary tract infections. Most hospitals (80%) had no budget specifically allocated to the IPC program; 34% of the laundry staff had received specific IPC training; and only 7.5% of hospitals reported occupational infections in healthcare workers. Conclusions: In this sample, most ICCs complied with the minimum requirements for IPC programs. The main limitation regarding ICCs was the lack of financial support. The findings of this survey support the development of strategic plans to improve IPCs in Brazilian hospitals.

Erratum: Evaluation of the characteristics of infection prevention and control programs and infection control committees in Brazilian hospitals: A countrywide cross-sectional study - CORRIGENDUM.

[This corrects the article DOI: 10.1017/ash.2023.136.].

Is there an association of genetic polymorphisms of the catechol-O-methyltransferase gene (rs165656 and rs174675) and the 5-hydroxytryptamine receptor 2A gene (rs4941573 and rs6313) with sleep bruxism in individuals with obstructive sleep apnea?

OBJECTIVE: To evaluate the association of single-nucleotide polymorphisms within the catechol-O-methyltransferase and 5-hydroxytryptamine receptor 2A genes with sleep bruxism in individuals diagnosed with obstructive sleep apnea. DESIGN: Sixty-nine individuals with suspected sleep-related problems were evaluated by polysomnography, following the recommendations of the American Academy of Sleep Medicine. Deoxyribonucleic acid (DNA) samples were collected only from 48 of the study participants because of missing polysomnographic data. DNA samples were collected and two single-nucleotide polymorphisms in the 5-hydroxytryptamine receptor 2A encoding HTR2A gene (rs4941573 and rs6313) and two in the catechol-O-methyltransferase gene (rs165656 and rs174675) were selected to be genotyped using real-time polymerase chain reaction. The association between sleep bruxism and genetic polymorphisms was investigated by recessive and dominant models. Association analyses were performed using a 95% confidence interval and the level of statistical significance was p < 0.05. RESULTS: From the 69 study participants, 48 were included in the polymorphism analysis and sleep bruxism was present in 35.4%. No significant differences were observed in the dominant and recessive models (p > 0.05). Haplotype and diplotype analyses revealed the predicted four haplotypes and two diplotypes were not associated with sleep bruxism. CONCLUSION: Polymorphisms rs174675 and rs165656 in the catechol-O-methyltransferase gene and rs4941573 and rs6313 in the 5-hydroxytryptamine receptor 2A gene were not significantly associated with sleep bruxism in individuals with obstructive sleep apnea.

Association between genetic polymorphisms in the melatonin receptor type 1 A gene and sleep bruxism.

OBJECTIVE: This study evaluated whether single nucleotide polymorphisms in the melatonin receptor type 1 A gene are associated with sleep bruxism in a Brazilian population. DESIGN: Individuals with suspected sleep-related problems were evaluated using polysomnography, following the recommendations proposed by the American Academy of Sleep Medicine and the Research Diagnostic Criteria for Temporomandibular Disorders. Deoxyribonucleic acid (DNA) samples were collected, and three single nucleotide polymorphisms in the melatonin receptor type 1 A gene (rs13140012, rs6553010, and rs6847693) were selected and genotyped using real-time polymerase chain reaction (RT-PCR). Chi-square and odds ratio tests were used to analyze genotypes and alleles individually, while using the plink software for haplotypes. A confidence interval of 95% was considered, and statistical significance was set at p < 0.05. RESULTS: This study included 48 individuals aged between 21 and 80 years, with 27 males and 21 females. From this sample, 17 individuals were diagnosed with sleep bruxism and 31 without bruxism. No associations were found between sleep bruxism and single nucleotide polymorphisms in either the genotypic, allelic, dominant, or recessive models (p > 0.05). Haplotype genetic analysis also did not reveal any association between single nucleotide polymorphisms and sleep bruxism (p > 0.05). CONCLUSION: The genetic polymorphisms rs6553010, rs13140012, and rs6847693 were not associated with sleep bruxism in the studied population.

Clinical outcomes and lung mechanics characteristics between COVID-19 and non-COVID-19-associated acute respiratory distress syndrome: a propensity score analysis of two major randomized trials. / Desfechos clínicos e características da mecânica pulmonar entre a síndrome do desconforto respiratório agudo associada à COVID-19 e a não associada à COVID-19: uma análise de escore de propensão de dois importantes ensaios randomizados.

OBJECTIVE: To compare the lung mechanics and outcomes between COVID-19-associated acute respiratory distress syndrome and non-COVID-19-associated acute respiratory distress syndrome. METHODS: We combined data from two randomized trials in acute respiratory distress syndrome, one including only COVID-19 patients and the other including only patients without COVID-19, to determine whether COVID-19-associated acute respiratory distress syndrome is associated with higher 28-day mortality than non-COVID-19 acute respiratory distress syndrome and to examine the differences in lung mechanics between these two types of acute respiratory distress syndrome. RESULTS: A total of 299 patients with COVID-19-associated acute respiratory distress syndrome and 1,010 patients with non-COVID-19-associated acute respiratory distress syndrome were included in the main analysis. The results showed that non-COVID-19 patients used higher positive end-expiratory pressure (12.5cmH2O; SD 3.2 versus 11.7cmH2O SD 2.8; p < 0.001), were ventilated with lower tidal volumes (5.8mL/kg; SD 1.0 versus 6.5mL/kg; SD 1.2; p < 0.001) and had lower static respiratory compliance adjusted for ideal body weight (0.5mL/cmH2O/kg; SD 0.3 versus 0.6mL/cmH2O/kg; SD 0.3; p = 0.01). There was no difference between groups in 28-day mortality (52.3% versus 58.9%; p = 0.52) or mechanical ventilation duration in the first 28 days among survivors (13 [IQR 5 - 22] versus 12 [IQR 6 - 26], p = 0.46). CONCLUSION: This analysis showed that patients with non-COVID-19-associated acute respiratory distress syndrome have different lung mechanics but similar outcomes to COVID-19-associated acute respiratory distress syndrome patients. After propensity score matching, there was no difference in lung mechanics or outcomes between groups.

OBJETIVO: Comparar a mecânica pulmonar e os desfechos entre a síndrome do desconforto respiratório agudo associada à COVID-19 e a síndrome do desconforto respiratório agudo não associada à COVID-19. MÉTODOS: Combinamos dados de dois ensaios randomizados sobre a síndrome do desconforto respiratório agudo, um incluindo apenas pacientes com COVID-19 e o outro incluindo apenas pacientes sem COVID-19, para determinar se a síndrome do desconforto respiratório agudo associada à COVID-19 está associada à maior mortalidade aos 28 dias do que a síndrome do desconforto respiratório agudo não associada à COVID-19 e também examinar as diferenças na mecânica pulmonar entre esses dois tipos de síndrome do desconforto respiratório agudo. RESULTADOS: Foram incluídos na análise principal 299 pacientes com síndrome do desconforto respiratório agudo associada à COVID-19 e 1.010 pacientes com síndrome do desconforto respiratório agudo não associada à COVID-19. Os resultados mostraram que os pacientes sem COVID-19 utilizaram pressão positiva expiratória final mais alta (12,5cmH2O; DP 3,2 versus 11,7cmH2O; DP 2,8; p < 0,001), foram ventilados com volumes correntes mais baixos (5,8mL/kg; DP 1,0 versus 6,5mL/kg; DP 1,2; p < 0,001) e apresentaram menor complacência respiratória estática ajustada para o peso ideal (0,5mL/cmH2O/kg; DP 0,3 versus 0,6mL/cmH2O/kg; DP 0,3; p = 0,01). Não houve diferença entre os grupos quanto à mortalidade aos 28 dias (52,3% versus 58,9%; p = 0,52) ou à duração da ventilação mecânica nos primeiros 28 dias entre os sobreviventes (13 [IQ 5 - 22] dias versus 12 [IQ 6 - 26] dias; p = 0,46). CONCLUSÃO: Esta análise mostrou que os pacientes com síndrome do desconforto respiratório agudo não associada à COVID-19 têm mecânica pulmonar diferente, mas desfechos semelhantes aos dos pacientes com síndrome do desconforto respiratório agudo associada à COVID-19. Após pareamento por escore de propensão, não houve diferença na mecânica pulmonar e nem nos desfechos entre os grupos.

Antivirals for adult patients hospitalized with SARS-CoV-2 infection: A randomized, Phase II/III, multicenter, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocol and statistical analysis plan. / Antivirais para pacientes adultos hospitalizados com infecção por SARS-CoV-2: Um estudo de Fase II/III, randomizado, multicêntrico, controlado por placebo, adaptativo, com múltiplos braços e estágios. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocolo e plano de análise estatística.

Repurposed drugs are important in resource-limited settings because the interventions are more rapidly available, have already been tested safely in other populations and are inexpensive. Repurposed drugs are an effective solution, especially for emerging diseases such as COVID-19. The REVOLUTIOn trial has the objective of evaluating three repurposed antiviral drugs, atazanavir, daclatasvir and sofosbuvir, already used for HIV- and hepatitis C virus-infected patients in a randomized, placebo-controlled, adaptive, multiarm, multistage study. The drugs will be tested simultaneously in a Phase II trial to first identify whether any of these drugs alone or in combination reduce the viral load. If they do, a Phase III trial will be initiated to investigate if these medications are capable of increasing the number of days free respiratory support. Participants must be hospitalized adults aged ≥ 18 years with initiation of symptoms ≤ 9 days and SpO2 ≤ 94% in room air or a need for supplemental oxygen to maintain an SpO2 > 94%. The expected total sample size ranges from 252 to 1,005 participants, depending on the number of stages that will be completed in the study. Hence, the protocol is described here in detail together with the statistical analysis plan. In conclusion, the REVOLUTIOn trial is designed to provide evidence on whether atazanavir, daclatasvir or sofosbuvir decrease the SARS-CoV-2 load in patients with COVID-19 and increase the number of days patients are free of respiratory support. In this protocol paper, we describe the rationale, design, and status of the trial. ClinicalTrials.gov identifier: NCT04468087.

Os medicamentos reaproveitados são importantes em contextos de recursos limitados porque as intervenções estão mais rapidamente disponíveis, já foram testadas com segurança em outras populações e são, em geral, mais baratas. Os medicamentos reaproveitados são uma solução eficaz, especialmente para doenças emergentes, como a COVID-19. O estudo REVOLUTIOn visa avaliar três medicamentos antivirais reaproveitados: atazanavir, daclatasvir e sofosbuvir, já utilizados em pacientes infectados pelo HIV ou pelo vírus da hepatite C, em um estudo randomizado, controlado por placebo, adaptativo, multibraço e em múltiplos estágios. Os medicamentos serão testados simultaneamente em um ensaio de Fase II para primeiro identificar se algum deles, isoladamente ou em combinação, reduz a carga viral. Se reduzirem, será iniciado um estudo de Fase III para investigar se tais medicamentos são capazes de aumentar o número de dias sem suporte respiratório. Os participantes devem ser adultos hospitalizados com idade ≥ 18 anos com início dos sintomas ≤ 9 dias e saturação de oxigênio ≤ 94% em ar ambiente ou necessidade de oxigênio suplementar para manter saturação de oxigênio > 94%. O tamanho total esperado da amostra varia entre 252 e 1.005 participantes, dependendo do número de estágios que serão concluídos no estudo. Assim, o protocolo é aqui descrito em detalhes, juntamente do plano de análise estatística. Em conclusão, o estudo REVOLUTIOn foi concebido para fornecer evidências se o atazanavir, o daclatasvir ou o sofosbuvir reduzem a carga viral de SARS-CoV-2 em pacientes com COVID-19 e aumentam o número de dias em que os pacientes ficam sem suporte respiratório. Neste artigo de protocolo, descrevem-se a fundamentação, o desenho e a situação do ensaio. Identificador do ClinicalTrials.gov: NCT04468087.

Driving Pressure-limited Strategy for Patients with Acute Respiratory Distress Syndrome. A Pilot Randomized Clinical Trial.

Rationale: Evidence from observational studies suggests that driving pressure is strongly associated with pulmonary injury and mortality, regardless of positive end-expiratory pressure (PEEP) levels, tidal volume, or plateau pressure. Therefore, it is possible that targeting driving pressure may improve the safety of ventilation strategies for patients with acute respiratory distress syndrome (ARDS). However, the clinical effects of a driving pressure-limited strategy for ARDS has not been assessed in randomized controlled trials.Objectives: To evaluate the feasibility of testing a driving pressure-limited strategy in comparison with a conventional lung-protective ventilation strategy in patients with ARDS and a baseline driving pressure of ≥13 cm H2O.Methods: This was a randomized, controlled, nonblinded trial that included 31 patients with ARDS who were on invasive mechanical ventilation and had a driving pressure of ≥13 cm H2O. Patients allocated to the driving pressure-limited strategy were ventilated with volume-controlled or pressure-support ventilation modes, with tidal volume titrated to 4-8 ml/kg of predicted body weight (PBW), aiming at a driving pressure of 10 cm H2O, or the lowest possible. Patients in the control group were ventilated according to the ARDSNet (Acute Respiratory Distress Syndrome Network) protocol, using a tidal volume of 6 ml/kg PBW, which was allowed to be set down to 4 ml/kg PBW if the plateau pressure was >30 cm H2O. The primary endpoint was the driving pressure on Days 1-3.Results: Sixteen patients were randomized to the driving pressure-limited group and 15 were randomized to the conventional strategy group. All patients were considered in analyses. Most of the patients had mild ARDS with a mean arterial oxygen tension/fraction of inspired oxygen ratio of 215 (standard deviation [SD] = 95). The baseline driving pressure was 15.0 cm H2O (SD = 2.6) in both groups. In comparison with the conventional strategy, driving pressure from the first hour to the third day was 4.6 cm H2O lower in the driving pressure-limited group (95% confidence interval [CI], 6.5 to 2.8; P < 0.001). From the first hour up to the third day, tidal volume in the driving pressure-limited strategy group was kept lower than in the control group (mean difference [ml/kg of PBW], 1.3; 95% CI, 1.7 to 0.9; P < 0.001). We did not find statistically significant differences in the incidence of severe acidosis (pH < 7.10) within 7 days (absolute difference -12.1; 95% CI, -41.5 to -17.3) or any clinical secondary endpoint.Conclusions: In patients with ARDS, a trial assessing the effects of a driving pressure-limited strategy using very low tidal volumes versus a conventional ventilation strategy on clinical outcomes is feasible.Clinical trial registered with ClinicalTrials.gov (NCT02365038).

COVID-19-associated ARDS treated with DEXamethasone (CoDEX): study design and rationale for a randomized trial. / Síndrome do desconforto respiratório agudo associada à COVID-19 tratada com DEXametasona (CoDEX): delineamento e justificativa de um estudo randomizado.

OBJECTIVE: The infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads worldwide and is considered a pandemic. The most common manifestation of SARS-CoV-2 infection (coronavirus disease 2019 - COVID-19) is viral pneumonia with varying degrees of respiratory compromise and up to 40% of hospitalized patients might develop acute respiratory distress syndrome. Several clinical trials evaluated the role of corticosteroids in non-COVID-19 acute respiratory distress syndrome with conflicting results. We designed a trial to evaluate the effectiveness of early intravenous dexamethasone administration on the number of days alive and free of mechanical ventilation within 28 days after randomization in adult patients with moderate or severe acute respiratory distress syndrome due to confirmed or probable COVID-19. METHODS: This is a pragmatic, prospective, randomized, stratified, multicenter, open-label, controlled trial including 350 patients with early-onset (less than 48 hours before randomization) moderate or severe acute respiratory distress syndrome, defined by the Berlin criteria, due to COVID-19. Eligible patients will be randomly allocated to either standard treatment plus dexamethasone (Intervention Group) or standard treatment without dexamethasone (Control Group). Patients in the intervention group will receive dexamethasone 20mg intravenous once daily for 5 days, followed by dexamethasone 10mg IV once daily for additional 5 days or until intensive care unit discharge, whichever occurs first. The primary outcome is ventilator-free days within 28 days after randomization, defined as days alive and free from invasive mechanical ventilation. Secondary outcomes are all-cause mortality rates at day 28, evaluation of the clinical status at day 15 assessed with a 6-level ordinal scale, mechanical ventilation duration from randomization to day 28, Sequential Organ Failure Assessment Score evaluation at 48 hours, 72 hours and 7 days and intensive care unit -free days within 28.

OBJETIVO: A infecção causada pelo coronavírus da síndrome respiratória aguda grave 2 (SARS-CoV-2) disseminou-se por todo o mundo e foi categorizada como pandemia. As manifestações mais comuns da infecção pelo SARS-CoV-2 (doença pelo coronavírus 2019 - COVID-19) se referem a uma pneumonia viral com graus variáveis de comprometimento respiratório e até 40% dos pacientes hospitalizados, que podem desenvolver uma síndrome do desconforto respiratório agudo. Diferentes ensaios clínicos avaliaram o papel dos corticosteroides na síndrome do desconforto respiratório agudo não relacionada com COVID-19, obtendo resultados conflitantes. Delineamos o presente estudo para avaliar a eficácia da administração endovenosa precoce de dexametasona no número de dias vivo e sem ventilação mecânica nos 28 dias após a randomização, em pacientes adultos com quadro moderado ou grave de síndrome do desconforto respiratório agudo causada por COVID-19 provável ou confirmada. MÉTODOS: Este é um ensaio pragmático, prospectivo, randomizado, estratificado, multicêntrico, aberto e controlado que incluirá 350 pacientes com quadro inicial (menos de 48 horas antes da randomização) de síndrome do desconforto respiratório agudo moderada ou grave, definida segundo os critérios de Berlim, causada por COVID-19. Os pacientes elegíveis serão alocados de forma aleatória para tratamento padrão mais dexametasona (Grupo Intervenção) ou tratamento padrão sem dexametasona (Grupo Controle). Os pacientes no Grupo Intervenção receberão dexametasona 20mg por via endovenosa uma vez ao dia, por 5 dias, e, a seguir, dexametasona por via endovenosa 10mg ao dia por mais 5 dias, ou até receber alta da unidade de terapia intensiva, o que ocorrer antes. O desfecho primário será o número de dias livres de ventilação mecânica nos 28 dias após a randomização, definido como o número de dias vivo e livres de ventilação mecânica invasiva. Os desfechos secundários serão a taxa de mortalidade por todas as causas no dia 28, a condição clínica no dia 15 avaliada com utilização de uma escala ordinal de seis níveis, a duração da ventilação mecânica desde a randomização até o dia 28, a avaliação com o Sequential Organ Failure Assessment Score após 48 horas, 72 horas e 7 dias, e o número de dias fora da unidade de terapia intensiva nos 28 dias após a randomização.

Statistical analysis plan for the Balanced Solution versus Saline in Intensive Care Study (BaSICS). / Plano de análise estatística para o estudo Balanced Solution versus Saline in Intensive Care Study (BaSICS).

OBJECTIVE: To report the statistical analysis plan (first version) for the Balanced Solutions versus Saline in Intensive Care Study (BaSICS). METHODS: BaSICS is a multicenter factorial randomized controlled trial that will assess the effects of Plasma-Lyte 148 versus 0.9% saline as the fluid of choice in critically ill patients, as well as the effects of a slow (333mL/h) versus rapid (999mL/h) infusion speed during fluid challenges, on important patient outcomes. The fluid type will be blinded for investigators, patients and the analyses. No blinding will be possible for the infusion speed for the investigators, but all analyses will be kept blinded during the analysis procedure. RESULTS: BaSICS will have 90-day mortality as its primary endpoint, which will be tested using mixed-effects Cox proportional hazard models, considering sites as a random variable (frailty models) adjusted for age, organ dysfunction and admission type. Important secondary endpoints include renal replacement therapy up to 90 days, acute renal failure, organ dysfunction at days 3 and 7, and mechanical ventilation-free days within 28 days. CONCLUSION: This manuscript provides details on the first version of the statistical analysis plan for the BaSICS trial and will guide the study's analysis when follow-up is finished.

OBJETIVO: Relatar o plano de análise estatística (primeira versão) para o estudo Balanced Solutions versus Saline in Intensive Care Study (BaSICS). MÉTODOS: O estudo BaSICS é um ensaio multicêntrico fatorial e randomizado que avaliará os efeitos da administração dos fluidos Plasma-Lyte 148 em comparação com solução salina 0,9% como fluido de escolha em pacientes críticos, assim como os efeitos de uma velocidade de infusão lenta (333mL/hora) em comparação com uma velocidade de infusão rápida (999mL/hora) durante desafios com volume, em importantes desfechos do paciente. O tipo de fluido será mantido cego para os investigadores, pacientes e nas análises. Não será possível, entretanto, ocultar dos investigadores a velocidade de infusão, mas os procedimentos de análise serão mantidos cegos quanto a esse aspecto. RESULTADOS: O estudo BaSICS terá como parâmetro primário a mortalidade em 90 dias, que será testada com utilização de modelos de risco proporcional de Cox de efeitos mistos, considerando os centros de estudo como variável randômica (modelos de fragilidade) ajustada por idade, disfunção de órgãos e tipo de admissão. Os parâmetros secundários importantes incluem terapia de substituição renal até 90 dias, insuficiência renal aguda, disfunção de órgãos nos dias 3 e 7 e dias sem ventilação mecânica em 28 dias. CONCLUSÃO: Este artigo fornece detalhes referentes à primeira versão do plano de análise estatística para o estudo BaSICS e orientará a análise do estudo após a conclusão do seguimento.

The respiratory oxygenation index for identifying the risk of orotracheal intubation in COVID-19 patients receiving high-flow nasal cannula oxygen / Índice de oxigenação respiratória para identificar risco de intubação orotraqueal em pacientes com COVID-19 que recebem oxigênio por cânula nasal de alto fluxo

ABSTRACT Objective: To assess whether the respiratory oxygenation index (ROX index) measured after the start of high-flow nasal cannula oxygen therapy can help identify the need for intubation in patients with acute respiratory failure due to coronavirus disease 2019. Methods: This retrospective, observational, multicenter study was conducted at the intensive care units of six Brazilian hospitals from March to December 2020. The primary outcome was the need for intubation up to 7 days after starting the high-flow nasal cannula. Results: A total of 444 patients were included in the study, and 261 (58.7%) were subjected to intubation. An analysis of the area under the receiver operating characteristic curve (AUROC) showed that the ability to discriminate between successful and failed high-flow nasal cannula oxygen therapy within 7 days was greater for the ROX index measured at 24 hours (AUROC 0.80; 95%CI 0.76 - 0.84). The median interval between high-flow nasal cannula initiation and intubation was 24 hours (24 - 72), and the most accurate predictor of intubation obtained before 24 hours was the ROX index measured at 12 hours (AUROC 0.75; 95%CI 0.70 - 0.79). Kaplan-Meier curves revealed a greater probability of intubation within 7 days in patients with a ROX index ≤ 5.54 at 12 hours (hazard ratio 3.07; 95%CI 2.24 - 4.20) and ≤ 5.96 at 24 hours (hazard ratio 5.15; 95%CI 3.65 - 7.27). Conclusion: The ROX index can aid in the early identification of patients with acute respiratory failure due to COVID-19 who will progress to the failure of high-flow nasal cannula supportive therapy and the need for intubation.

RESUMO Objetivo: Avaliar se o índice de oxigenação respiratória medido após o início da terapia de oxigênio com cânula nasal de alto fluxo pode ajudar a identificar a necessidade de intubação em pacientes com insuficiência respiratória aguda devido à COVID-19. Métodos: Este estudo retrospectivo, observacional e multicêntrico foi realizado nas unidades de terapia intensiva de seis hospitais brasileiros, de março a dezembro de 2020. O desfecho primário foi a necessidade de intubação até 7 dias após o início da cânula nasal de alto fluxo. Resultados: O estudo incluiu 444 pacientes; 261 (58,7%) foram submetidos à intubação. Uma análise da área sob a curva receiver operating characteristic (ASC ROC) mostrou que a capacidade de discriminar entre o sucesso e o fracasso da oxigenoterapia com cânula nasal de alto fluxo dentro de 7 dias foi maior para o índice de oxigenação respiratória medido em 24 horas (ASC ROC 0,80; IC95% 0,76 - 0,84). O intervalo médio entre o início da cânula nasal de alto fluxo e a intubação foi de 24 horas (24 - 72), e o preditor mais preciso de intubação obtido antes de 24 horas foi o índice de oxigenação respiratória medido em 12 horas (ASC ROC 0,75; IC95% 0,70 - 0,79). As curvas de Kaplan-Meier revelaram maior probabilidade de intubação em 7 dias em pacientes com índice de oxigenação respiratória ≤ 5,54 em 12 horas (razão de risco 3,07; IC95% 2,24 - 4,20) e ≤ 5,96 em 24 horas (razão de risco 5,15; IC95% 3,65 - 7,27). Conclusões: O índice de oxigenação respiratória pode ajudar na identificação precoce de pacientes com insuficiência respiratória aguda devido à COVID-19 que evoluirão para o fracasso da terapia de suporte com cânula nasal de alto fluxo e a necessidade de intubação.

Prospective, randomized, controlled trial assessing the effects of a driving pressure-limiting strategy for patients with acute respiratory distress syndrome due to community-acquired pneumonia (STAMINA trial): protocol and statistical analysis plan / Estudo randomizado prospectivo e controlado de avaliação dos efeitos de uma estratégia de limitação da driving pressure em pacientes com síndrome do desconforto respiratório agudo devido à pneumonia adquirida na comunidade (estudo STAMINA): protocolo e plano de análise estatística

ABSTRACT Background: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear. Objective: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia. Methods: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance. Outcomes: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide. Conclusion: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.

RESUMO Contexto: Em estudos observacionais sobre a síndrome do desconforto respiratório agudo, sugeriu-se que a driving pressure é o principal fator de lesão pulmonar induzida por ventilador e de mortalidade. Não está claro se uma estratégia de limitação da driving pressure pode melhorar os desfechos clínicos. Objetivo: Descrever o protocolo e o plano de análise estatística que serão usados para testar se uma estratégia de limitação da driving pressure envolvendo a titulação da pressão positiva expiratória final de acordo com a melhor complacência respiratória e a redução do volume corrente é superior a uma estratégia padrão envolvendo o uso da tabela de pressão positiva expiratória final baixa do protocolo ARDSNet, em termos de aumento do número de dias sem ventilador em pacientes com síndrome do desconforto respiratório agudo devido à pneumonia adquirida na comunidade. Métodos: O estudo STAMINA (ventilator STrAtegy for coMmunIty acquired pNeumoniA) é randomizado, multicêntrico e aberto e compara uma estratégia de limitação da driving pressure com a tabela de pressão positiva expiratória final baixa do protocolo ARDSnet em pacientes com síndrome do desconforto respiratório agudo moderada a grave devido à pneumonia adquirida na comunidade internados em unidades de terapia intensiva. Esperamos recrutar 500 pacientes de 20 unidades de terapia intensiva brasileiras e duas colombianas. Eles serão randomizados para um grupo da estratégia de limitação da driving pressure ou para um grupo de estratégia padrão usando a tabela de pressão positiva expiratória final baixa do protocolo ARDSnet. No grupo da estratégia de limitação da driving pressure, a pressão positiva expiratória final será titulada de acordo com a melhor complacência do sistema respiratório. Desfechos: O desfecho primário é o número de dias sem ventilador em 28 dias. Os desfechos secundários são a mortalidade hospitalar e na unidade de terapia intensiva e a necessidade de terapias de resgate, como suporte de vida extracorpóreo, manobras de recrutamento e óxido nítrico inalado. Conclusão: O STAMINA foi projetado para fornecer evidências sobre se uma estratégia de limitação da driving pressure é superior à estratégia da tabela de pressão positiva expiratória final baixa do protocolo ARDSnet para aumentar o número de dias sem ventilador em 28 dias em pacientes com síndrome do desconforto respiratório agudo moderada a grave. Aqui, descrevemos a justificativa, o desenho e o status do estudo.

Effect of antibiotics administered via the respiratory tract in the prevention of ventilator-associated pneumonia: A systematic review and meta-analysis.

PURPOSE: We evaluated the effect of antibiotics administered via the respiratory tract to prevent the ventilator-associated pneumonia (VAP) in mechanically ventilated (MV) patients. METHODS: We searched relevant articles for trials that evaluated the impact of prophylactic antibiotics administered through the respiratory tract on the occurrence of VAP. The end-point was the occurrence of VAP in MV patients. RESULTS: We included 6 comparative trials involving 1158 patients (632 received prophylactic antibiotic). Our meta-analysis revealed that prophylactic antibiotics administered through the respiratory tract reduced the occurrence of VAP when compared to placebo or no treatment (OR 0.53; 95% CI 0.34-0.84). This effect was seen when the antibiotics were given by nebulization (OR 0.46; 95% CI 0.22-0.97), but not when they were administered by intratracheal instillation (OR 0.57; 95% CI 0.28-1.15). We did not find a significant difference between the compared groups in the intensive care unit (ICU) mortality (OR 0.89; 95% CI 0.64-1.25). Antibiotic prophylaxis did not impact occurrence of VAP due to multidrug resistant (MDR) pathogens (OR 0.67; 95% CI 0.17-2.62). CONCLUSIONS: Prophylactic antibiotics administered through the respiratory tract by nebulization reduce the occurrence of VAP, without a significant effect on either the ICU mortality or occurrence of VAP due to MDR pathogens.

Parafoveal chondral lesion of the femoral head in patients with femoroacetabular impingement / Lesão condral parafoveal da cabeça femoral em pacientes com impacto femoroacetabular

Abstract Objective: To describe cases of parafoveal chondral lesion of the femoral head in patients with femoroacetabular impingement, correlating the clinical and imaging data. Materials and Methods: This was a retrospective descriptive case series of parafoveal chondral lesion of the femoral head in 21 patients who underwent computed tomography and magnetic resonance arthrography scans of the hip, having then received an imaging-based diagnosis of femoroacetabular impingement. Results: Of the 21 patients evaluated, 15 (71%) had cam-type femoroacetabular impingement, whereas five (24%) had mixed-type impingement, and one (5%) had pincer-type impingement. Twelve patients (57%) had a low frequency of physical activity, which was significantly associated with the presence of cam-type impingement (p = 0.015). Although the extent of the lesion correlated significantly with the acetabular coverage angle (p = 0.04), it did not correlate significantly with the alpha angle or femoral head-neck offset value (p = 0.08 and p = 0.06, respectively). We also found no correlation between the extent of the lesion and the other main parameters that define the femoroacetabular impingement types. Conclusion: This was one of the largest case series of parafoveal chondral lesion of the femoral head in patients with imaging findings of femoroacetabular impingement. The extent of such lesions does not appear to correlate with the parameters of femoroacetabular impingement, with the exception of the acetabular coverage angle.

Resumo Objetivo: Descrever casos de lesão condral parafoveal da cabeça femoral em pacientes com impacto femoroacetabular, correlacionando dados clínicos e de imagem. Materiais e Métodos: Esta foi uma série de casos descritiva retrospectiva de lesão condral parafoveal da cabeça femoral em 21 pacientes submetidos a tomografia computadorizada e artrorressonância magnética do quadril e que receberam diagnóstico por imagem de impacto femoroacetabular. Resultados: Dos 21 pacientes avaliados, 15 (71%) tiveram impacto femoroacetabular do tipo cam, enquanto cinco (24%) tiveram impacto do tipo misto e um (5%) teve impacto do tipo pincer. Doze pacientes (57%) apresentaram baixa frequência de atividade física, sendo esta significativamente associada a impacto do tipo cam (p = 0,015). Houve correlação significativa entre a extensão da lesão e o ângulo de cobertura acetabular (p = 0,04), porém, não se correlacionou significativamente com o ângulo alfa ou com o valor do deslocamento cabeça-colo femoral (p = 0,08 e p = 0,06, respectivamente). Também não encontramos correlação entre a extensão da lesão e os outros principais parâmetros que definem os tipos de impacto femoroacetabular. Conclusão: Esta foi uma das maiores casuísticas de lesão condral parafoveal da cabeça femoral em pacientes com achados de imagem de impacto femoroacetabular. A extensão dessas lesões não parece se correlacionar com os parâmetros do impacto femoroacetabular, com exceção do ângulo de cobertura acetabular.