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Author(s): Fernando G. Zampieri [sup.1], Nazir I. Lone [sup.2], Sean M. Bagshaw [sup.3] Author Affiliations: (1) grid.477370.0, 0000 0004 0454 243X, HCor Research Institute, , São Paulo, SP, Brazil (2) [...]

Randomised clinical trials (RCTs) are the gold standard for providing unbiased evidence of intervention effects. Here, we provide an overview of the history of RCTs and discuss the major challenges and limitations of current critical care RCTs, including overly optimistic effect sizes; unnuanced conclusions based on dichotomization of results; limited focus on patient-centred outcomes other than mortality; lack of flexibility and ability to adapt, increasing the risk of inconclusive results and limiting knowledge gains before trial completion; and inefficiency due to lack of re-use of trial infrastructure. We discuss recent developments in critical care RCTs and novel methods that may provide solutions to some of these challenges, including a research programme approach (consecutive, complementary studies of multiple types rather than individual, independent studies), and novel design and analysis methods. These include standardization of trial protocols; alternative outcome choices and use of core outcome sets; increased acceptance of uncertainty, probabilistic interpretations and use of Bayesian statistics; novel approaches to assessing heterogeneity of treatment effects; adaptation and platform trials; and increased integration between clinical trials and clinical practice. We outline the advantages and discuss the potential methodological and practical disadvantages with these approaches. With this review, we aim to inform clinicians and researchers about conventional and novel RCTs, including the rationale for choosing one or the other methodological approach based on a thorough discussion of pros and cons. Importantly, the most central feature remains the randomisation, which provides unparalleled restriction of confounding compared to non-randomised designs by reducing confounding to chance., Author(s): Anders Granholm [sup.1], Waleed Alhazzani [sup.2] [sup.3], Lennie P. G. Derde [sup.4] [sup.5], Derek C. Angus [sup.6], Fernando G. Zampieri [sup.7], Naomi E. Hammond [sup.8] [sup.9], Rob Mac Sweeney [...]

Purpose To assess whether intensive care unit (ICU) outcomes for patients not affected by coronavirus disease 2019 (COVID-19) worsened during the COVID-19 pandemic. Methods Retrospective cohort study including prospectively collected information of patients admitted to 165 ICUs in a hospital network in Brazil between 2011 and 2020. Association between admission in 2020 and worse hospital outcomes was performed using different techniques, including assessment of changes in illness severity of admitted patients, a variable life-adjusted display of mortality during 2020, a multivariate mixed regression model with admission year as both fixed effect and random slope adjusted for SAPS 3 score, an analysis of trends in performance using standardized mortality ratio (SMR) and standardized resource use (SRU), and perturbation analysis. Results A total of 644,644 admissions were considered. After excluding readmissions and patients with COVID-19, 514,219 patients were available for analysis. Non-COVID-19 patients admitted in 2020 had slightly lower age and SAPS 3 score but a higher mortality (6.4%) when compared with previous years (2019: 5.6%; 2018: 6.1%). Variable-adjusted life display (VLAD) in 2020 increased but started to decrease as the number of COVID-19 cases increased; this trend reversed as number of COVID cases reduced but recurred on the second wave. After logistic regression, being admitted in 2020 was associated with higher mortality when compared to previous years from 2016 and 2019. Individual ICUs standardized mortality ratio also increased during 2020 (higher SMR) while resource use remained constant, suggesting worsening performance. A perturbation analysis further confirmed changes in ICU outcomes for non-COVID-19 patients. Conclusion Hospital outcomes of non-COVID-19 critically ill patients worsened during the pandemic in 2020, possibly resulting in an increased number of deaths in critically ill non-COVID patients., Author(s): Fernando G. Zampieri [sup.1] [sup.2], Leonardo S. L. Bastos [sup.1] [sup.3], Marcio Soares [sup.1], Jorge I. Salluh [sup.1], Fernando A. Bozza [sup.1] Author Affiliations: (1) D'Or Research and Educational [...]

Purpose Clinical characteristics and management of COVID-19 patients have evolved during the pandemic, potentially changing their outcomes. We analyzed the associations of changes in mortality rates with clinical profiles and respiratory support strategies in COVID-19 critically ill patients. Methods A multicenter cohort of RT-PCR-confirmed COVID-19 patients admitted at 126 Brazilian intensive care units between February 27.sup.th and October 28.sup.th, 2020. Assessing temporal changes in deaths, we identified distinct time periods. We evaluated the association of characteristics and respiratory support strategies with 60-day in-hospital mortality using random-effects multivariable Cox regression with inverse probability weighting. Results Among the 13,301 confirmed-COVID-19 patients, 60-day in-hospital mortality was 13%. Across four time periods identified, younger patients were progressively more common, non-invasive respiratory support was increasingly used, and the 60-day in-hospital mortality decreased in the last two periods. 4188 patients received advanced respiratory support (non-invasive or invasive), from which 42% underwent only invasive mechanical ventilation, 37% only non-invasive respiratory support and 21% failed non-invasive support and were intubated. After adjusting for organ dysfunction scores and premorbid conditions, we found that younger age, absence of frailty and the use of non-invasive respiratory support (NIRS) as first support strategy were independently associated with improved survival (hazard ratio for NIRS first [95% confidence interval], 0.59 [0.54-0.65], p < 0.001). Conclusion Age and mortality rates have declined over the first 8 months of the pandemic. The use of NIRS as the first respiratory support measure was associated with survival, but causal inference is limited by the observational nature of our data., Author(s): Pedro Kurtz [sup.1] [sup.2] [sup.3], Leonardo S. L. Bastos [sup.4], Leila F. Dantas [sup.4], Fernando G. Zampieri [sup.1] [sup.5] [sup.6], Marcio Soares [sup.1], Silvio Hamacher [sup.4], Jorge I. F. [...]

Purpose To describe trends in outcomes of cancer patients with unplanned admissions to intensive-care units (ICU) according to cancer type, organ support use, and performance status (PS) over an 8-year period. Methods We retrospectively analyzed prospectively collected data from all cancer patients admitted to 92 medical-surgical ICUs from July/2011 to June/2019. We assessed trends in mortality through a Bayesian hierarchical model adjusted for relevant clinical confounders and whether there was a reduction in ICU length-of-stay (LOS) over time using a competing risk model. Results 32,096 patients (8.7% of all ICU admissions; solid tumors, 90%; hematological malignancies, 10%) were studied. Bed/days use by cancer patients increased up to more than 30% during the period. Overall adjusted mortality decreased by 9.2% [95% credible interval (CI), 13.1-5.6%]. The largest reductions in mortality occurred in patients without need for organ support (9.6%) and in those with need for mechanical ventilation (MV) only (11%). Smallest reductions occurred in patients requiring MV, vasopressors, and dialysis (3.9%) simultaneously. Survival gains over time decreased as PS worsened. Lung cancer patients had the lowest decrease in mortality. Each year was associated with a lower sub-hazard for ICU death [SHR 0.93 (0.91-0.94)] and a higher chance of being discharged alive from the ICU earlier [SHR 1.01 (1-1.01)]. Conclusion Outcomes in critically ill cancer patients improved in the past 8 years, with reductions in both mortality and ICU LOS, suggesting improvements in overall care. However, outcomes remained poor in patients with lung cancer, requiring multiple organ support and compromised PS., Author(s): Fernando G. Zampieri [sup.1] [sup.2] [sup.3], Thiago G. Romano [sup.4] [sup.5] [sup.9], Jorge I. F. Salluh [sup.6], Leandro U. Taniguchi [sup.7] [sup.8], Pedro V. Mendes [sup.4] [sup.8] [sup.9], Antonio [...]

The aim of this Intensive Care Medicine Rapid Practice Guideline (ICM‐RPG) was to provide evidence‐based clinical guidance about the use of higher versus lower oxygenation targets for adult patients in the intensive care unit (ICU). The guideline panel comprised 27 international panelists, including content experts, ICU clinicians, methodologists, and patient representatives. We adhered to the methodology for trustworthy clinical practice guidelines, including the use of the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence, and used the Evidence‐to‐Decision framework to generate recommendations. A recently published updated systematic review and meta‐analysis constituted the evidence base. Through teleconferences and web‐based discussions, the panel provided input on the balance and magnitude of the desirable and undesirable effects, the certainty of evidence, patients' values and preferences, costs and resources, equity, feasibility, acceptability, and research priorities. The updated systematic review and meta‐analysis included data from 17 randomized clinical trials with 10,248 participants. There was little to no difference between the use of higher versus lower oxygenation targets for all outcomes with available data, including all‐cause mortality, serious adverse events, stroke, functional outcomes, cognition, and health‐related quality of life (very low certainty of evidence). The panel felt that values and preferences, costs and resources, and equity favored the use of lower oxygenation targets. The ICM‐RPG panel issued one conditional recommendation against the use of higher oxygenation targets: "We suggest against the routine use of higher oxygenation targets in adult ICU patients (conditional recommendation, very low certainty of evidence). Remark: an oxygenation target of SpO2 88%–92% or PaO2 8 kPa/60 mmHg is relevant and safe for most adult ICU patients." [ABSTRACT FROM AUTHOR]

Purpose The Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial compared prophylactic pantoprazole with placebo in 3291 adult ICU patients at risk of clinically important gastrointestinal bleeding (CIB). As a predefined subgroup analysis suggested increased 90-day mortality with pantoprazole in the most severely ill patients, we aimed to further explore whether heterogenous treatment effects (HTE) were present. Methods We assessed HTE in subgroups defined according to illness severity by SAPS II quintiles and the total number of risk factors for CIB using Bayesian hierarchical models, and on the continuous scale using Bayesian logistic regression models with interactions. Estimates were presented as posterior probability distributions of odds ratios (ORs), probabilities of different effect sizes, and marginal effects plots. Results We observed potential HTE for 90-day mortality according to illness severity (median subgroup OR range 0.90-1.09) with higher risk in the most severely ill, but not with different numbers of risk factors (1.00-1.02). We observed potential HTE of pantoprazole for clinically important events (0.86-1.18) and infectious adverse events (0.88-1.27) with higher risk in patients with greater illness severity and in those with more risk factors for CIB. Pantoprazole substantially and consistently reduced the risk of CIB with no indications of HTE (0.53-0.63). Conclusions In this post hoc analysis of the SUP-ICU trial, we found indications of HTE with increased risks of serious adverse events in patients with greater illness severity or more risk factors for CIB allocated to pantoprazole. These findings are hypothesis-generating and warrant further prospective investigation. ClinicalTrials.gov identifier NCT02467621, Author(s): Anders Granholm [sup.1], Søren Marker [sup.1] [sup.2], Mette Krag [sup.1] [sup.2], Fernando G. Zampieri [sup.3] [sup.4], Hans-Christian Thorsen-Meyer [sup.1] [sup.5], Benjamin Skov Kaas-Hansen [sup.5] [sup.6], Iwan C. C. van [...]

Purpose Ventilator associated-lower respiratory tract infections (VA-LRTIs), either ventilator-associated pneumonia (VAP) or tracheobronchitis (VAT), accounts for most nosocomial infections in intensive care units (ICU) including. Our aim was to determine if appropriate antibiotic treatment in patients with VA-LRTI will effectively reduce mortality in patients who had cardiovascular failure. Methods This was a pre-planned subanalysis of a large prospective cohort of mechanically ventilated patients for at least 48 h in eight countries in two continents. Patients with a modified Sequential Organ Failure Assessment (mSOFA) cardiovascular score of 4 (at the time of VA-LRTI diagnosis and needed be present for at least 12 h) were defined as having cardiovascular failure. Results VA-LRTI occurred in 689 (23.2%) out of 2960 patients and 174 (25.3%) developed cardiovascular failure. Patients with cardiovascular failure had significantly higher ICU mortality than those without (58% vs. 26.8%; p < 0.001; OR 3.7; 95% CI 2.6-5.4). A propensity score analysis found that the presence of inappropriate antibiotic treatment was an independent risk factor for ICU mortality in patients without cardiovascular failure, but not in those with cardiovascular failure. When the propensity score analysis was conducted in patients with VA-LRTI, the use of appropriate antibiotic treatment conferred a survival benefit for patients without cardiovascular failure who had only VAP. Conclusions Patients with VA-LRTI and cardiovascular failure did not show an association to a higher ICU survival with appropriate antibiotic treatment. Additionally, we found that in patients without cardiovascular failure, appropriate antibiotic treatment conferred a survival benefit for patients only with VAP. Trial registry ClinicalTrials.gov, number NCT01791530., Author(s): Ignacio Martin-Loeches [sup.1] [sup.2] [sup.3], Antoni Torres [sup.3], Pedro Povoa [sup.4] [sup.5] [sup.6], Fernando G. Zampieri [sup.7], Jorge Salluh [sup.8], Saad Nseir [sup.9], Miquel Ferrer [sup.3], Alejandro Rodriguez [sup.10], [...]

Purpose To study whether ICU staffing features are associated with improved hospital mortality, ICU length of stay (LOS) and duration of mechanical ventilation (MV) using cluster analysis directed by machine learning. Methods The following variables were included in the analysis: average bed to nurse, physiotherapist and physician ratios, presence of 24/7 board-certified intensivists and dedicated pharmacists in the ICU, and nurse and physiotherapist autonomy scores. Clusters were defined using the partition around medoids method. We assessed the association between clusters and hospital mortality using logistic regression and with ICU LOS and MV duration using competing risk regression. Results Analysis included data from 129,680 patients admitted to 93 ICUs (2014-2015). Three clusters were identified. The features distinguishing between the clusters were: the presence of board-certified intensivists in the ICU 24/7 (present in Cluster 3), dedicated pharmacists (present in Clusters 2 and 3) and the extent of nurse autonomy (which increased from Clusters 1 to 3). The patients in Cluster 3 exhibited the best outcomes, with lower adjusted hospital mortality [odds ratio 0.92 (95% confidence interval (CI), 0.87-0.98)], shorter ICU LOS [subhazard ratio (SHR) for patients surviving to ICU discharge 1.24 (95% CI 1.22-1.26)] and shorter durations of MV [SHR for undergoing extubation 1.61(95% CI 1.54-1.69)]. Cluster 1 had the worst outcomes. Conclusion Patients treated in ICUs combining 24/7 expert intensivist coverage, a dedicated pharmacist and nurses with greater autonomy had the best outcomes. All of these features represent achievable targets that should be considered by policy makers with an interest in promoting equal and optimal ICU care., Author(s): Fernando G. Zampieri [sup.1] [sup.2], Jorge I. F. Salluh [sup.1] [sup.3], Luciano C. P. Azevedo [sup.4], Jeremy M. Kahn [sup.5] [sup.6], Lucas P. Damiani [sup.2], Lunna P. Borges [sup.3], [...]

Author(s): Fernando G. Zampieri [sup.1] , Sharon Einav [sup.2] Author Affiliations: (1) grid.477370.0, 0000 0004 0454 243X, Research Institute, HCor-Hospital do Coração, , São Paulo, Brazil (2) grid.9619.7, 0000 0004 [...]

Author(s): Fernando G. Zampieri [sup.1], Matt P. G. Morgan [sup.2], Morten Hylander Møller [sup.3] [sup.4] Author Affiliations: (1) 0000 0004 0454 243X, grid.477370.0, Research Institute, HCor-Hospital Do Coração, , São [...]

Purpose Frail patients are known to experience poor outcomes. Nevertheless, we know less about how frailty manifests itself in patients' physiology during critical illness and how it affects resource use in intensive care units (ICU). We aimed to assess the association of frailty with short-term outcomes and organ support used by critically ill patients. Methods Retrospective analysis of prospective collected data from 93 ICUs in Brazil from 2014 to 2015. We assessed frailty using the modified frailty index (MFI). The primary outcome was in-hospital mortality. Secondary outcomes were discharge home without need for nursing care, ICU and hospital length of stay (LOS), and utilization of ICU organ support and transfusion. We used mixed logistic regression and competing risk models accounting for relevant confounders in outcome analyses. Results The analysis consisted of 129,680 eligible patients. There were 40,779 (31.4%) non-frail (MFI = 0), 64,407 (49.7%) pre-frail (MFI = 1-2) and 24,494 (18.9%) frail (MFI [greater than or equal to] 3) patients. After adjusted analysis, frailty was associated with higher in-hospital mortality (OR 2.42, 95% CI 1.89-3.08), particularly in patients admitted with lower SOFA scores. Frail patients were less likely to be discharged home (OR 0.36, 95% CI 0.54-0.79) and had higher hospital and ICU LOS than non-frail patients. Use of all forms of organ support (mechanical ventilation, non-invasive ventilation, vasopressors, dialysis and transfusions) were more common in frail patients and increased as MFI increased. Conclusions Frailty, as assessed by MFI, was associated with several patient-centered endpoints including not only survival, but also ICU LOS and organ support., Author(s): Fernando G. Zampieri [sup.1] [sup.18], Theodore J. Iwashyna [sup.2] [sup.3], Elizabeth M. Viglianti [sup.2], Leandro U. Taniguchi [sup.4] [sup.5], William N. Viana [sup.6], Roberto Costa [sup.7], Thiago D. Corrêa [...]