Differential Effect of Positive End-Expiratory Pressure Strategies in Patients With ARDS: A Bayesian Analysis of Clinical Subphenotypes.

BACKGROUND: ARDS is a heterogeneous condition with two subphenotypes identified by different methodologies. Our group similarly identified two ARDS subphenotypes using nine routinely available clinical variables. However, whether these are associated with differential response to treatment has yet to be explored. RESEARCH QUESTION: Are there differential responses to positive end-expiratory pressure (PEEP) strategies on 28-day mortality according to subphenotypes in adult patients with ARDS? STUDY DESIGN AND METHODS: We evaluated data from two prior ARDS trials (Higher vs Lower Positive End-Expiratory Pressures in Patients With the ARDS [ALVEOLI] and ARDS Trial [ART]) that compared different PEEP strategies. We classified patients into one of two subphenotypes as described previously. We assessed the differential effect of PEEP with a Bayesian hierarchical logistic model for the primary outcome of 28-day mortality. RESULTS: We analyzed data from 1,559 patients with ARDS. Compared with lower PEEP, a higher PEEP strategy resulted in higher 28-day mortality in patients with subphenotype A disease in the ALVEOLI study (OR, 1.61; 95% credible interval [CrI], 0.90-2.94) and ART (OR, 1.73; 95% CrI, 1.01-2.98), with a probability of harm resulting from higher PEEP in this subphenotype of 94.3% and 97.7% in the ALVEOLI and ART studies, respectively. Higher PEEP was not associated with mortality in patients with subphenotype B disease in each trial (OR, 0.95 [95% CrI, 0.51-1.73] and 1.00 [95% CrI, 0.63-1.55], respectively), with probability of benefit of 56.4% and 50.7% in the ALVEOLI and ART studies, respectively. These effects were not modified by Pao2 to Fio2 ratio, driving pressure, or the severity of illness for the cohorts. INTERPRETATION: We found evidence of differential response to PEEP strategies across two ARDS subphenotypes, suggesting possible harm with a higher PEEP strategy in one subphenotype. These observations may assist with predictive enrichment in future clinical trials.

Identification of acute respiratory distress syndrome subphenotypes de novo using routine clinical data: a retrospective analysis of ARDS clinical trials.

OBJECTIVES: The acute respiratory distress syndrome (ARDS) is a heterogeneous condition, and identification of subphenotypes may help in better risk stratification. Our study objective is to identify ARDS subphenotypes using new simpler methodology and readily available clinical variables. SETTING: This is a retrospective Cohort Study of ARDS trials. Data from the US ARDSNet trials and from the international ART trial. PARTICIPANTS: 3763 patients from ARDSNet data sets and 1010 patients from the ART data set. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was 60-day or 28-day mortality, depending on what was reported in the original trial. K-means cluster analysis was performed to identify subgroups. Sets of candidate variables were tested to assess their ability to produce different probabilities for mortality in each cluster. Clusters were compared with biomarker data, allowing identification of subphenotypes. RESULTS: Data from 4773 patients were analysed. Two subphenotypes (A and B) resulted in optimal separation in the final model, which included nine routinely collected clinical variables, namely heart rate, mean arterial pressure, respiratory rate, bilirubin, bicarbonate, creatinine, PaO2, arterial pH and FiO2. Participants in subphenotype B showed increased levels of proinflammatory markers, had consistently higher mortality, lower number of ventilator-free days at day 28 and longer duration of ventilation compared with patients in the subphenotype A. CONCLUSIONS: Routinely available clinical data can successfully identify two distinct subphenotypes in adult ARDS patients. This work may facilitate implementation of precision therapy in ARDS clinical trials.

High flow nasal catheter therapy versus non-invasive positive pressure ventilation in acute respiratory failure (RENOVATE trial): protocol and statistical analysis plan.

Background: The best way to offer non-invasive respiratory support across several aetiologies of acute respiratory failure (ARF) is presently unclear. Both high flow nasal catheter (HFNC) therapy and non-invasive positive pressure ventilation (NIPPV) may improve outcomes in critically ill patients by avoiding the need for invasive mechanical ventilation (IMV). Objective: Describe the details of the protocol and statistical analysis plan designed to test whether HFNC therapy is non-inferior or even superior to NIPPV in patients with ARF due to different aetiologies. Methods: RENOVATE is a multicentre adaptive randomised controlled trial that is recruiting patients from adult emergency departments, wards and intensive care units (ICUs). It takes advantage of an adaptive Bayesian framework to assess the effectiveness of HFNC therapy versus NIPPV in four subgroups of ARF (hypoxaemic non-immunocompromised, hypoxaemic immunocompromised, chronic obstructive pulmonary disease exacerbations, and acute cardiogenic pulmonary oedema). The study will report the posterior probabilities of non-inferiority, superiority or futility for the comparison between HFNC therapy and NIPPV. The study assumes neutral priors and the final sample size is not fixed. The final sample size will be determined by a priori determined stopping rules for non-inferiority, superiority and futility for each subgroup or by reaching the maximum of 2000 patients. Outcomes: The primary endpoint is endotracheal intubation or death within 7 days. Secondary outcomes are 28-day and 90-day mortality, and ICU-free and IMV-free days in the first 28 days. Results and conclusions: RENOVATE is designed to provide evidence on whether HFNC therapy improves, compared with NIPPV, important patient-centred outcomes in different aetiologies of ARF. Here, we describe the rationale, design and status of the trial. Trial registration:ClinicalTrials.gov NCT03643939.

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.

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).

Ticagrelor Versus Clopidogrel in Patients With STEMI Treated With Fibrinolysis: TREAT Trial.

BACKGROUND: The efficacy of ticagrelor in the long-term post-ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remains uncertain. OBJECTIVES: The purpose of this study was to evaluate the efficacy of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. METHODS: This international, multicenter, randomized, open-label with blinded endpoint adjudication trial enrolled 3,799 patients (age <75 years) with STEMI receiving fibrinolytic therapy. Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). The key outcomes were cardiovascular mortality, myocardial infarction, or stroke, and the same composite outcome with the addition of severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events at 12 months. RESULTS: The combined outcome of cardiovascular mortality, myocardial infarction, or stroke occurred in 129 of 1,913 patients (6.7%) receiving ticagrelor and in 137 of 1,886 patients (7.3%) receiving clopidogrel (hazard ratio: 0.93; 95% confidence interval: 0.73 to 1.18; p = 0.53). The composite of cardiovascular mortality, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events occurred in 153 of 1,913 patients (8.0%) treated with ticagrelor and in 171 of 1,886 patients (9.1%) receiving clopidogrel (hazard ratio: 0.88; 95% confidence interval: 0.71 to 1.09; p = 0.25). The rates of major, fatal, and intracranial bleeding were similar between the ticagrelor and clopidogrel groups. CONCLUSION: Among patients age <75 years with STEMI, administration of ticagrelor after fibrinolytic therapy did not significantly reduce the frequency of cardiovascular events when compared with clopidogrel. (Ticagrelor in Patients With ST Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis [TREAT]; NCT02298088).

Ticagrelor versus clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: Rationale and design of the ticagrelor in patients with ST elevation myocardial infarction treated with thrombolysis (TREAT) trial.

BACKGROUND: The safety and efficacy of ticagrelor in patients with ST-elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remain uncertain. OBJECTIVES: The primary objective of the TicagRElor in pAtients with ST elevation myocardial infarction treated with Thrombolysis (TREAT) trial is to evaluate the short-term safety of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. Key secondary objectives are to assess the safety and efficacy of ticagrelor compared with clopidogrel at 12-months. DESIGN: The TREAT trial is a multicenter, randomized, phase III, Prospective randomized open blinded end-point (PROBE) study that enrolled 3,799 patients in 152 sites from 10 countries. Following administration of fibrinolytic therapy patients were randomized to a loading dose of ticagrelor 180 mg or clopidogrel 300 mg followed by a maintenance dose of ticagrelor 90 mg twice daily or clopidogrel 75 mg/day for 12-months. The primary outcome is the rate of TIMI major bleeding at 30-days and will be assessed for non-inferiority using an intention-to-treat analysis. Co-treatments include aspirin and anticoagulants. Other evidence based therapies are also recommended. Secondary efficacy outcome include a composite of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack or other arterial thrombotic event. All-cause mortality as well as individual components of the combined efficacy endpoint will also be ascertained. SUMMARY: TREAT is an international randomized controlled trial comparing ticagrelor with clopidogrel in STEMI patients treated with fibrinolytic therapy. The results of this trial will inform clinical practice and international guidelines.

Ticagrelor vs Clopidogrel After Fibrinolytic Therapy in Patients With ST-Elevation Myocardial Infarction: A Randomized Clinical Trial.

Importance: The bleeding safety of ticagrelor in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy remains uncertain. Objective: To evaluate the short-term safety of ticagrelor when compared with clopidogrel in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy. Design, Setting and Participants: We conducted a multicenter, randomized, open-label with blinded end point adjudication trial that enrolled 3799 patients (younger than 75 years) with ST-segment elevation myocardial infarction receiving fibrinolytic therapy in 152 sites from 10 countries from November 2015 through November 2017. The prespecified upper boundary for noninferiority for bleeding was an absolute margin of 1.0%. Interventions: Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter). Patients were randomized with a median of 11.4 hours after fibrinolysis, and 90% were pretreated with clopidogrel. Main Outcomes and Measures: The primary outcome was thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days. Results: The mean (SD) age was 58.0 (9.5) years, 2928 of 3799 patients (77.1%) were men, and 2177 of 3799 patients (57.3%) were white. At 30 days, TIMI major bleeding had occurred in 14 of 1913 patients (0.73%) receiving ticagrelor and in 13 of 1886 patients (0.69%) receiving clopidogrel (absolute difference, 0.04%; 95% CI, -0.49% to 0.58%; P < .001 for noninferiority). Major bleeding defined by the Platelet Inhibition and Patient Outcomes criteria and by the Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 23 patients (1.20%) in the ticagrelor group and in 26 patients (1.38%) in the clopidogrel group (absolute difference, -0.18%; 95% CI, -0.89% to 0.54; P = .001 for noninferiority). The rates of fatal (0.16% vs 0.11%; P = .67) and intracranial bleeding (0.42% vs 0.37%; P = .82) were similar between the ticagrelor and clopidogrel groups, respectively. Minor and minimal bleeding were more common with ticagrelor than with clopidogrel. The composite of death from vascular causes, myocardial infarction, or stroke occurred in 76 patients (4.0%) treated with ticagrelor and in 82 patients (4.3%) receiving clopidogrel (hazard ratio, 0.91; 95% CI, 0.67-1.25; P = .57). Conclusions and Relevance: In patients younger than 75 years with ST-segment elevation myocardial infarction, delayed administration of ticagrelor after fibrinolytic therapy was noninferior to clopidogrel for TIMI major bleeding at 30 days. Trial Registration: clinicaltrials.gov Identifier: NCT02298088.

Impact of an early physiotherapy program after kidney transplant during hospital stay: a randomized controlled trial / Impacto de um programa precoce de fisioterapia após transplante renal durante a internação: um estudo clínico randomizado controlado

Abstract Introduction: Cardiorespiratory and musculoskeletal dysfunctions are common in the postoperative period of kidney transplant patients and are often accompanied by low exercise tolerance. Objective: The purpose of this study was to evaluate the impact of an early physiotherapy program during hospital stay on functional capacity and peripheral and respiratory muscle strength after kidney transplant. Methods: An open, randomized clinical trial was conducted in patients undergoing living donor kidney transplant. Sixty-three patients were included (intervention group-IG: n = 30; control group-CG: n = 33). IG received an early physiotherapy program from first postoperative day until hospital discharge and CG received standard care. The variables of interest were measured preoperatively and at discharge except for respiratory muscle strength and vital capacity (VC), which were also measured on the first postoperative day. Functional capacity was evaluated through six-minute walk test (6MWT); peripheral and respiratory muscle strength using a dynamometer and manovacuometer, respectively; and VC through spirometer. Results: After surgery, there was a reduction in functional walking capacity and peripheral muscle strength without different between groups (p > 0.05); however, respiratory muscle strength was significantly higher in IG (p < 0.001) at hospital discharge, when comparing with CG. Conclusions: An early physiotherapy program during hospitalization for patients undergoing living donor kidney transplant caused a lower reduction in respiratory muscle strength and without additional benefits in the functional capacity, when compared to a control group, although the clinical relevance of this finding is uncertain.

Resumo Introdução: Distúrbios cardiorrespiratórios e musculoesqueléticos são comuns no período pós-operatório de pacientes de transplante renal, e são frequentemente acompanhados por baixa tolerância a exercícios. Objetivo: O presente estudo pretendeu avaliar o impacto de um programa precoce de fisioterapia durante a internação sobre a capacidade funcional e força muscular periférica e respiratória após transplante renal. Métodos: Foi realizado um estudo clínico randomizado aberto com pacientes submetidos a transplantes renais com doadores vivos. Sessenta e três pacientes foram incluídos (grupo de intervenção GI: n = 30; grupo de controle - GC: n = 33). O GI recebeu o programa precoce de fisioterapia a partir do primeiro dia de pós-operatório até a alta hospitalar e o GC recebeu tratamento padrão. As variáveis de interesse foram medidas no pré-operatório e na alta, exceto por força muscular respiratória e capacidade vital (CV), que foram medidas no primeiro dia de pós-operatório. A capacidade funcional foi avaliada através do teste da caminhada dos seis minutos (TC6); força muscular periférica e respiratória com o uso de um dinamômetro e um manovacuômetro, respectivamente; e a CV por meio de um espirômetro. Resultados: Após a cirurgia houve reduções na capacidade funcional de caminhar e na força muscular respiratória sem diferenças entre os grupos (p > 0,05); contudo, a força muscular respiratória foi significativamente mais elevada no GI (p < 0,001) no momento da alta hospitalar em comparação ao GC. Conclusões: O programa precoce de fisioterapia oferecido durante a internação dos pacientes submetidos a transplantes renais com doadores vivos produziu uma menor redução da força muscular respiratória e não resultou em benefícios adicionais na capacidade funcional, apesar da relevância clínica desse achado ser incerta.

Statistical analysis plan for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART). A randomized controlled trial. / Plano de análise estatística para o Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART). Ensaio controlado randomizado.

BACKGROUND: The Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) is an international multicenter randomized pragmatic controlled trial with allocation concealment involving 120 intensive care units in Brazil, Argentina, Colombia, Italy, Poland, Portugal, Malaysia, Spain, and Uruguay. The primary objective of ART is to determine whether maximum stepwise alveolar recruitment associated with PEEP titration, adjusted according to the static compliance of the respiratory system (ART strategy), is able to increase 28-day survival in patients with acute respiratory distress syndrome compared to conventional treatment (ARDSNet strategy). OBJECTIVE: To describe the data management process and statistical analysis plan. METHODS: The statistical analysis plan was designed by the trial executive committee and reviewed and approved by the trial steering committee. We provide an overview of the trial design with a special focus on describing the primary (28-day survival) and secondary outcomes. We describe our data management process, data monitoring committee, interim analyses, and sample size calculation. We describe our planned statistical analyses for primary and secondary outcomes as well as pre-specified subgroup analyses. We also provide details for presenting results, including mock tables for baseline characteristics, adherence to the protocol and effect on clinical outcomes. CONCLUSION: According to best trial practice, we report our statistical analysis plan and data management plan prior to locking the database and beginning analyses. We anticipate that this document will prevent analysis bias and enhance the utility of the reported results. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01374022.

FUNDAMENTAÇÃO: O estudo Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) é um ensaio clínico internacional, multicêntrico, randomizado, pragmático e controlado com ocultação da alocação que envolve 120 unidades de terapia intensiva no Brasil, Argentina, Colômbia, Espanha, Itália, Polônia, Portugal, Malásia e Uruguai, com o objetivo primário de determinar se o recrutamento alveolar gradual máximo associado com titulação da pressão positiva expiratória final, ajustada segundo a complacência estática do sistema respiratório (estratégia ART), é capaz de aumentar, quando comparada aos resultados do tratamento convencional (estratégia ARDSNet), a sobrevivência em 28 dias de pacientes com síndrome do desconforto respiratório agudo. OBJETIVO: Descrever o processo de gerenciamento dos dados e o plano de análise estatística em um ensaio clínico internacional. MÉTODOS: O plano de análise estatística foi delineado pelo comitê executivo e revisado pelo comitê diretivo do ART. Foi oferecida uma visão geral do delineamento do estudo, com foco especial na descrição de desfechos primário (sobrevivência aos 28 dias) e secundários. Foram descritos o processo de gerenciamento dos dados, o comitê de monitoramento de dados, a análise interina e o cálculo do tamanho da amostra. Também foram registrados o plano de análise estatística para os desfechos primário e secundários, e os subgrupos de análise pré-especificados. Detalhes para apresentação dos resultados, inclusive modelos de tabelas para as características basais, adesão ao protocolo e efeito nos desfechos clínicos, foram fornecidos. CONCLUSÃO: Em acordo com as melhores práticas em ensaios clínicos, submetemos nossos planos de análise estatística e de gerenciamento de dados para publicação antes do fechamento da base de dados e início das análises. Antecipamos que este documento deve prevenir viés em análises e incrementar a utilidade dos resultados a serem relatados. REGISTRO DO ESTUDO: Número no registro ClinicalTrials.gov NCT01374022.

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.

Plano de análise estatística para o Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART). Ensaio controlado randomizado / Statistical analysis plan for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART). A randomized controlled trial

RESUMO Fundamentação: O estudo Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) é um ensaio clínico internacional, multicêntrico, randomizado, pragmático e controlado com ocultação da alocação que envolve 120 unidades de terapia intensiva no Brasil, Argentina, Colômbia, Espanha, Itália, Polônia, Portugal, Malásia e Uruguai, com o objetivo primário de determinar se o recrutamento alveolar gradual máximo associado com titulação da pressão positiva expiratória final, ajustada segundo a complacência estática do sistema respiratório (estratégia ART), é capaz de aumentar, quando comparada aos resultados do tratamento convencional (estratégia ARDSNet), a sobrevivência em 28 dias de pacientes com síndrome do desconforto respiratório agudo. Objetivo: Descrever o processo de gerenciamento dos dados e o plano de análise estatística em um ensaio clínico internacional. Métodos: O plano de análise estatística foi delineado pelo comitê executivo e revisado pelo comitê diretivo do ART. Foi oferecida uma visão geral do delineamento do estudo, com foco especial na descrição de desfechos primário (sobrevivência aos 28 dias) e secundários. Foram descritos o processo de gerenciamento dos dados, o comitê de monitoramento de dados, a análise interina e o cálculo do tamanho da amostra. Também foram registrados o plano de análise estatística para os desfechos primário e secundários, e os subgrupos de análise pré-especificados. Detalhes para apresentação dos resultados, inclusive modelos de tabelas para as características basais, adesão ao protocolo e efeito nos desfechos clínicos, foram fornecidos. Conclusão: Em acordo com as melhores práticas em ensaios clínicos, submetemos nossos planos de análise estatística e de gerenciamento de dados para publicação antes do fechamento da base de dados e início das análises. Antecipamos que este documento deve prevenir viés em análises e incrementar a utilidade dos resultados a serem relatados. Registro do estudo: Número no registro ClinicalTrials.gov NCT01374022.

ABSTRACT Background: The Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) is an international multicenter randomized pragmatic controlled trial with allocation concealment involving 120 intensive care units in Brazil, Argentina, Colombia, Italy, Poland, Portugal, Malaysia, Spain, and Uruguay. The primary objective of ART is to determine whether maximum stepwise alveolar recruitment associated with PEEP titration, adjusted according to the static compliance of the respiratory system (ART strategy), is able to increase 28-day survival in patients with acute respiratory distress syndrome compared to conventional treatment (ARDSNet strategy). Objective: To describe the data management process and statistical analysis plan. Methods: The statistical analysis plan was designed by the trial executive committee and reviewed and approved by the trial steering committee. We provide an overview of the trial design with a special focus on describing the primary (28-day survival) and secondary outcomes. We describe our data management process, data monitoring committee, interim analyses, and sample size calculation. We describe our planned statistical analyses for primary and secondary outcomes as well as pre-specified subgroup analyses. We also provide details for presenting results, including mock tables for baseline characteristics, adherence to the protocol and effect on clinical outcomes. Conclusion: According to best trial practice, we report our statistical analysis plan and data management plan prior to locking the database and beginning analyses. We anticipate that this document will prevent analysis bias and enhance the utility of the reported results. Trial registration: ClinicalTrials.gov number, NCT01374022.

Comparison between the phase angle and phase shift parameters to assess thoracoabdominal asynchrony in COPD patients.

Determining the presence of thoracoabdominal asynchrony in chronic obstructive pulmonary disease (COPD) patients is clinically relevant, but there is no consensus on the optimal parameters for performing this analysis. We assessed 22 COPD patients (FEV1 40 ± 10% predicted) and 13 healthy controls during rest and exercise with optoelectronic plethysmography (70% maximum workload) on a cycle ergometer. Thoracoabdominal asynchrony was calculated by using phase angle and phase shift parameters following a three-compartment model involving the upper and lower rib cages and abdomen. Patients were classified as having thoracoabdominal asynchrony (TAA+) or not (TAA-) based on control values (mean ± 2 SDs). The chest wall volume and compartmental contribution were also measured. Thoracoabdominal asynchrony was observed in the lower rib cage. The phase angle detected more TAA+ patients at rest (15 vs. 7 patients) and during exercise (14 vs. 8 patients) compared with the phase shift. TAA+ patients also presented a lower chest wall volume, lower rib cage contribution, and higher abdominal contribution to chest wall volume compared with the control and TAA- patients. Thoracoabdominal asynchrony was more detectable during rest and exercise using the phase angle parameter, and it was observed in the lower rib cage compartment, reducing the chest wall volume during exercise in patients with COPD.NEW & NOTEWORTHY This study contributes to advance the knowledge over the previous lack of consensus on the assessment of thoracoabdominal asynchrony. We rigorously evaluated the related features that interfere in the measurement of the asynchrony (measurement tool, chest wall model and calculation parameter). Our results suggest that phase angle detects more suitably thoracoabdominal asynchrony that occurs on the lower ribcage and leads to a reduction in the chest wall volume during exercise in COPD patients.

Impact of an early physiotherapy program after kidney transplant during hospital stay: a randomized controlled trial.

INTRODUCTION: Cardiorespiratory and musculoskeletal dysfunctions are common in the postoperative period of kidney transplant patients and are often accompanied by low exercise tolerance. OBJECTIVE: The purpose of this study was to evaluate the impact of an early physiotherapy program during hospital stay on functional capacity and peripheral and respiratory muscle strength after kidney transplant. METHODS: An open, randomized clinical trial was conducted in patients undergoing living donor kidney transplant. Sixty-three patients were included (intervention group-IG: n = 30; control group-CG: n = 33). IG received an early physiotherapy program from first postoperative day until hospital discharge and CG received standard care. The variables of interest were measured preoperatively and at discharge except for respiratory muscle strength and vital capacity (VC), which were also measured on the first postoperative day. Functional capacity was evaluated through six-minute walk test (6MWT); peripheral and respiratory muscle strength using a dynamometer and manovacuometer, respectively; and VC through spirometer. RESULTS: After surgery, there was a reduction in functional walking capacity and peripheral muscle strength without different between groups (p > 0.05); however, respiratory muscle strength was significantly higher in IG (p < 0.001) at hospital discharge, when comparing with CG. CONCLUSIONS: An early physiotherapy program during hospitalization for patients undergoing living donor kidney transplant caused a lower reduction in respiratory muscle strength and without additional benefits in the functional capacity, when compared to a control group, although the clinical relevance of this finding is uncertain.

Atorvastatin for high-risk statin-naïve patients undergoing noncardiac surgery: The Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose (LOAD) randomized trial.

Preliminary evidence suggests that statins may prevent major perioperative vascular complications. METHODS: We randomized 648 statin-naïve patients who were scheduled for noncardiac surgery and were at risk for a major vascular complication. Patients were randomized to a loading dose of atorvastatin or placebo (80 mg anytime within 18hours before surgery), followed by a maintenance dose of 40 mg (or placebo), started at least 12hours after the surgery, and then 40 mg/d (or placebo) for 7days. The primary outcome was a composite of all-cause mortality, nonfatal myocardial injury after noncardiac surgery, and stroke at 30days. RESULTS: The primary outcome was observed in 54 (16.6%) of 326 patients in the atorvastatin group and 59 (18.7%) of 316 patients in the placebo group (hazard ratio [HR] 0.87, 95% CI 0.60-1.26, P=.46). No significant effect was observed on the 30-day secondary outcomes of all-cause mortality (4.3% vs 4.1%, respectively; HR 1.14, 95% CI 0.53-2.47, P=.74), nonfatal myocardial infarction (3.4% vs 4.4%, respectively; HR 0.76, 95% CI 0.35-1.68, P=.50), myocardial injury after noncardiac surgery (13.2% vs 16.5%; HR 0.79, 95% CI 0.53-1.19, P=.26), and stroke (0.9% vs 0%, P=.25). CONCLUSION: In contrast to the prior observational and trial data, the LOAD trial has neutral results and did not demonstrate a reduction in major cardiovascular complications after a short-term perioperative course of statin in statin-naïve patients undergoing noncardiac surgery. We demonstrated, however, that a large multicenter blinded perioperative statin trial for high-risk statin-naïve patients is feasible and should be done to definitely establish the efficacy and safety of statin in this patient population.

Effects of aerobic training combined with respiratory muscle stretching on the functional exercise capacity and thoracoabdominal kinematics in patients with COPD: a randomized and controlled trial.

BACKGROUND: Patients with COPD present a major recruitment of the inspiratory muscles, predisposing to chest incoordination, increasing the degree of dyspnea and impairing their exercise capacity. Stretching techniques could decrease the respiratory muscle activity and improve their contractile capacity; however, the systemic effects of stretching remain unknown. OBJECTIVE: The aim of this study was to evaluate the effects of aerobic training combined with respiratory muscle stretching on functional exercise capacity and thoracoabdominal kinematics in patients with COPD. DESIGN: This study was a randomized and controlled trial. PARTICIPANTS: A total of 30 patients were allocated to a treatment group (TG) or a control group (CG; n=15, each group). INTERVENTION: The TG was engaged in respiratory muscle stretching and the CG in upper and lower limb muscle stretching. Both groups performed 24 sessions (twice a week, 12 weeks) of aerobic training. EVALUATIONS: Functional exercise capacity (6-minute walk test), thoracoabdominal kinematics (optoelectronic plethysmography), and respiratory muscle activity (surface electromyography) were evaluated during exercise. Analysis of covariance was used to compare the groups at a significance level of 5%. RESULTS: After the intervention, the TG showed improved abdominal (ABD) contribution, compartmental volume, mobility, and functional exercise capacity with decreased dyspnea when compared with the CG (P<0.01). The TG also showed a decreased respiratory muscle effort required to obtain the same pulmonary volume compared to the CG (P<0.001). CONCLUSION: Our results suggest that aerobic training combined with respiratory muscle stretching increases the functional exercise capacity with decreased dyspnea in patients with COPD. These effects are associated with an increased efficacy of the respiratory muscles and participation of the ABD compartment.

Effectiveness of an early mobilization program on functional capacity after coronary artery bypass surgery: A randomized controlled trial protocol.

BACKGROUND: Muscle atrophy and prolonged inactivity are associated with an increased sensation of fatigue and reduced functional capacity in the postoperative period in patients undergoing coronary artery bypass grafting. Cardiac rehabilitation after hospital discharge is highly recommended and contributes to improvement in functional capacity and quality of life. However, few studies have evaluated the effectiveness of early mobilization protocols during hospitalization on the patterns of physical activity and functional capacity after coronary artery bypass grafting. OBJECTIVE: To investigate the effectiveness of an early mobilization program on the functional capacity of patients undergoing coronary artery bypass grafting in the short and long term. METHODS: This is a prospective, randomized, controlled, single-blind trial protocol that will evaluate 66 consecutive patients undergoing coronary artery bypass grafting. Patients will be randomized into two training groups: the control group (N = 33), which will perform breathing exercises and the intervention group (N = 33), which will perform breathing exercises and aerobic exercises. The groups will receive treatment from first to the seventh postoperative day, twice daily. In the preoperative period, the following outcomes will be assessed: physical activity level (Baecke Questionnaire), Functional Independence Measure, and functional capacity (6-min walking test). Functional capacity will be reassessed after the 7th and 60th postoperative day. Pulmonary complications and length of hospital stay will also be evaluated. Statistical analysis will be calculated using linear mixed models and will be based on intention-to-treat. The level of significance will be set at α = 5%.

Effects of nephrectomy on respiratory function and quality of life of living donors: a longitudinal study.

BACKGROUND: A living donor transplant improves the survival and quality of life of a transplant patient. However, the impact of transplantation on postoperative lung function and respiratory muscular strength in kidney donors remains unknown. OBJECTIVE: To evaluate pulmonary function, respiratory muscle strength, quality of life and the incidence of postoperative pulmonary complications (PPCs) in kidney donors undergoing nephrectomy. METHOD: This prospective cohort enrolled 110 consecutive kidney donors undergoing nephrectomy. Subjects underwent pulmonary function (using spirometry) and respiratory muscular strength (using manovacuometry) assessments on the day prior to surgery and 1, 2, 3 and 5 days postoperatively. Quality of life (measured by the SF-36) was evaluated preoperatively and 30 days postoperatively. PPCs were assessed daily by a blinded assessor. RESULTS: Donors exhibited a decrease of 27% in forced vital capacity, 58% in maximum inspiratory capacity and 51% in maximum expiratory pressure on the 1stpostoperative day (p<0.001) but this improved over days 2, 3 and 5 but had not returned to preoperative levels. Patient quality of life was still impaired at 30 days with regards to functional capacity, physical role, pain, vitality and social functioning (p<0.05) but these parameters improved slowly. None of the patients developed PPCs. CONCLUSION: Kidney donors submitted to nephrectomy exhibited a reduction in pulmonary function, respiratory muscular strength and quality of life, most of which were improving toward pre-surgical levels.

Effects of nephrectomy on respiratory function and quality of life of living donors: a longitudinal study

BACKGROUND: A living donor transplant improves the survival and quality of life of a transplant patient. However, the impact of transplantation on postoperative lung function and respiratory muscular strength in kidney donors remains unknown.OBJECTIVE: To evaluate pulmonary function, respiratory muscle strength, quality of life and the incidence of postoperative pulmonary complications (PPCs) in kidney donors undergoing nephrectomy.METHOD: This prospective cohort enrolled 110 consecutive kidney donors undergoing nephrectomy. Subjects underwent pulmonary function (using spirometry) and respiratory muscular strength (using manovacuometry) assessments on the day prior to surgery and 1, 2, 3 and 5 days postoperatively. Quality of life (measured by the SF-36) was evaluated preoperatively and 30 days postoperatively. PPCs were assessed daily by a blinded assessor.RESULTS: Donors exhibited a decrease of 27% in forced vital capacity, 58% in maximum inspiratory capacity and 51% in maximum expiratory pressure on the 1stpostoperative day (p<0.001) but this improved over days 2, 3 and 5 but had not returned to preoperative levels. Patient quality of life was still impaired at 30 days with regards to functional capacity, physical role, pain, vitality and social functioning (p<0.05) but these parameters improved slowly. None of the patients developed PPCs.CONCLUSION: Kidney donors submitted to nephrectomy exhibited a reduction in pulmonary function, respiratory muscular strength and quality of life, most of which were improving toward pre-surgical levels.

Comparison of lung expansion techniques on thoracoabdominal mechanics and incidence of pulmonary complications after upper abdominal surgery: a randomized and controlled trial.

OBJECTIVE: Lung expansion techniques (LETs) are widely used to prevent postoperative pulmonary complications (PPCs). However, the effects of each of these techniques on thoracoabdominal mechanics and PPC incidence after abdominal surgery remain unclear. The objective of this study was to compare the effects of LET on pulmonary volumes, respiratory muscle activation, and PPC incidence after major, elective upper abdominal surgery. METHODS: This randomized controlled trial enrolled 137 patients who were randomly assigned into four groups: control (n = 35), flow incentive spirometry (n = 33), deep breathing (n = 35), and volume incentive spirometry (n = 34). Each intervention was performed tid during 5 consecutive days. Subsequently, PPCs (pneumonia, atelectasis, or severe hypoxemia) were analyzed by a blinded assessor until hospital discharge. Lung volumes (optoelectronic plethysmography) and inspiratory muscular activation (surface electromyography) were assessed before and 3 days after surgery. Intention-to-treat analysis was performed. RESULTS: Before surgery, all groups were homogenous for age, sex, BMI, lung function, and thoracoabdominal mechanics. After surgery, no difference was observed in the lung volumes and inspiratory muscular activation during the lung expansion technique (P > .05). The PPC incidence was higher in the deep breathing group (P < .05). Higher American Society of Anesthesiologists scores and surgery duration were the only predictors of PPC (n = 14, 11.2%). CONCLUSIONS: LETs do not modify the changes on thoracoabdominal mechanics or prevent PPCs after abdominal surgery. The indiscriminate use of LETs should not be routinely prescribed to prevent PPCs; however, more studies are required to confirm our results and to change the standard practice. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01993602; URL: www.clinicaltrials.gov.