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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.

Purpose To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06448-5.

Purpose To survey healthcare workers (HCW) on availability and use of personal protective equipment (PPE) caring for COVID-19 patients in the intensive care unit (ICU). Materials and method A web-based survey distributed worldwide in April 2020. Results We received 2711 responses from 1797 (67%) physicians, 744 (27%) nurses, and 170 (6%) Allied HCW. For routine care, most (1557, 58%) reportedly used FFP2/N95 masks, waterproof long sleeve gowns (1623; 67%), and face shields/visors (1574; 62%). Powered Air-Purifying Respirators were used routinely and for intubation only by 184 (7%) and 254 (13%) respondents, respectively. Surgical masks were used for routine care by 289 (15%) and 47 (2%) for intubations. At least one piece of standard PPE was unavailable for 1402 (52%), and 817 (30%) reported reusing single-use PPE. PPE was worn for a median of 4 h (IQR 2, 5). Adverse effects of PPE were associated with longer shift durations and included heat (1266, 51%), thirst (1174, 47%), pressure areas (1088, 44%), headaches (696, 28%), Inability to use the bathroom (661, 27%) and extreme exhaustion (492, 20%). Conclusions HCWs reported widespread shortages, frequent reuse of, and adverse effects related to PPE. Urgent action by healthcare administrators, policymakers, governments and industry is warranted., Graphical abstract Unlabelled Image, Highlights • Wide variability in what PPE is available for ICU staff caring for COVID-19 patients. • More than half report at least one PPE item missing or out of stock. • Adverse effects of wearing PPE reported by 80% of health care workers. • Adverse effects related to duration of a shift wearing PPE without taking a break.

Supplemental Digital Content is available in the text., Background: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. Methods: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. Results: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which four are best practice statements, nine are strong recommendations, and 35 are weak recommendations. No recommendation was provided for six questions. The topics were: 1) infection control, 2) laboratory diagnosis and specimens, 3) hemodynamic support, 4) ventilatory support, and 5) COVID-19 therapy. Conclusion: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new evidence in further releases of these guidelines.

The authors regret errors were present in the published article. Counts of some of the adverse events were erroneous. Changes to the text include. Last sentence of the abstract should read. Adverse effects of PPE included heat (1266, 51%), thirst (1174, 47%), pressure areas (1088, 44%), headaches (696, 28%), Inability to use the bathroom (661, 27%) and extreme exhaustion (492, 20%). All but pressure areas were associated with longer shift durations. Last sentence of the results section of the manuscript should read. All but pressure areas were associated with longer duration of shifts wearing PPE (Table 4). Table 1 the total number of community/urban type of hospital should read 740 instead of 741. Updated Tables 3 and 4 should read as below: The authors would like to apologise for any inconvenience caused.

BACKGROUND: The coronavirus disease 2019 pandemic continues to affect millions worldwide. Given the rapidly growing evidence base, we implemented a living guideline model to provide guidance on the management of patients with severe or critical coronavirus disease 2019 in the ICU. METHODS: The Surviving Sepsis Campaign Coronavirus Disease 2019 panel has expanded to include 43 experts from 14 countries; all panel members completed an electronic conflict-of-interest disclosure form. In this update, the panel addressed nine questions relevant to managing severe or critical coronavirus disease 2019 in the ICU. We used the World Health Organization's definition of severe and critical coronavirus disease 2019. The systematic reviews team searched the literature for relevant evidence, aiming to identify systematic reviews and clinical trials. When appropriate, we performed a random-effects meta-analysis to summarize treatment effects. We assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach, then used the evidence-to-decision framework to generate recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. RESULTS: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued nine statements (three new and six updated) related to ICU patients with severe or critical coronavirus disease 2019. For severe or critical coronavirus disease 2019, the panel strongly recommends using systemic corticosteroids and venous thromboprophylaxis but strongly recommends against using hydroxychloroquine. In addition, the panel suggests using dexamethasone (compared with other corticosteroids) and suggests against using convalescent plasma and therapeutic anticoagulation outside clinical trials. The Surviving Sepsis Campaign Coronavirus Diease 2019 panel suggests using remdesivir in nonventilated patients with severe coronavirus disease 2019 and suggests against starting remdesivir in patients with critical coronavirus disease 2019 outside clinical trials. Because of insufficient evidence, the panel did not issue a recommendation on the use of awake prone positioning. CONCLUSION: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued several recommendations to guide healthcare professionals caring for adults with critical or severe coronavirus disease 2019 in the ICU. Based on a living guideline model the recommendations will be updated as new evidence becomes available.

Although the Surviving Sepsis Campaign bundle recommends obtaining blood cultures within 1 hour of sepsis recognition, adherence is suboptimal in many settings. We, therefore, implemented routine blood culture collection for all nonelective ICU admissions (regardless of infection suspicion) and evaluated its diagnostic yield.A before-after analysis.A mixed-ICU of a tertiary care hospital in the Netherlands.Patients acutely admitted to the ICU between January 2015 and December 2018.Automatic orders for collecting a single set of blood cultures immediately upon ICU admission were implemented on January 1, 2017. Blood culture results and the impact of contaminated blood cultures were compared for 2015-2016 (before period) and 2017-2018 (after period). Positive blood cultures were categorized as bloodstream infection or contamination. Blood cultures were obtained in 573 of 1,775 patients (32.3%) and in 1,582 of 1,871 patients (84.5%) in the before and after periods, respectively (p0.0001), and bloodstream infection was diagnosed in 95 patients (5.4%) and 154 patients (8.2%) in both study periods (relative risk 1.5; 95% CI 1.2-2.0; p = 0.0006). The estimated number needed to culture for one additional patient with bloodstream infection was 17. Blood culture contamination occurred in 40 patients (2.3%) and 180 patients (9.6%) in the before period and after period, respectively (relative risk 4.3; 95% CI 3.0-6.0; p0.0001). Rate of vancomycin use or presumed episodes of catheter-related bloodstream infections treated with antibiotics did not differ between both study periods.Implementation of routine blood cultures was associated with a 1.5-fold increase of detected bloodstream infection. The 4.3-fold increase in contaminated blood cultures was not associated with an increase in vancomycin use in the ICU.

Objectives: Infections caused by carbapenemase-producing Enterobacteriaceae are increasing worldwide, especially in ICUs, and have been associated with high mortality rates. However, unequivocally demonstrating causality of such infections to death is difficult in critically ill patients because of potential confounding and competing events. Here, we quantified the effects of carbapenemase-producing Enterobacteriaceae carriage on patient outcome in two Greek ICUs with carbapenemase-producing Enterobacteriaceae endemicity. Design: Observational cohort study. Setting: Two ICUs with carbapenemase-producing Enterobacteriaceae endemicity. Patients: Patients admitted to the ICU with an expected length of ICU stay of at least 3 days were included. Interventions: None. Measurements and Main Results: Carbapenemase-producing Enterobacteriaceae colonization was established through screening in perineum swabs obtained at admission and twice weekly and inoculated on chromogenic plates. Detection of carbapenemases was performed phenotypically, with confirmation by polymerase chain reaction. Risk factors for ICU mortality were evaluated using cause-specific hazard ratios and subdistribution hazard ratios, with carbapenemase-producing Enterobacteriaceae colonization as time-varying covariate. One thousand seven patients were included, 36 (3.6%) were colonized at admission, and 96 (9.5%) acquired carbapenemase-producing Enterobacteriaceae colonization during ICU stay, and 301 (29.9%) died in ICU. Of 132 carbapenemase-producing Enterobacteriaceae isolates, 125 (94.7%) were Klebsiella pneumoniae and 74 harbored K. pneumoniae carbapenemase (56.1%), 54 metallo-beta-lactamase (40.9%), and four both (3.0%). Carbapenemase-producing Enterobacteriaceae colonization was associated with a statistically significant increase of the subdistribution hazard ratio for ICU mortality (subdistribution hazard ratio = 1.79; 95% CI, 1.31-2.43), not explained by an increased daily hazard of dying (cause-specific hazard ratio for death = 1.02; 95% CI, 0.74-1.41), but by an increased length of stay (cause-specific hazard ratio for discharge alive = 0.73; 95% CI, 0.51-0.94). Other risk factors in the subdistribution hazard model were Acute Physiology and Chronic Health Evaluation II score (subdistribution hazard ratio = 1.13; 95% CI, 1.11-1.15), female gender (subdistribution hazard ratio = 1.29; 95% CI, 1.02-1.62), presence of solid tumor (subdistribution hazard ratio = 1.54; 95% CI, 1.15-2.06), hematopoietic malignancy (subdistribution hazard ratio = 1.61; 95% CI, 1.04-2.51), and immunodeficiency (subdistribution hazard ratio = 1.59; 95% CI, 1.11-2.27). Conclusions: Patients colonized with carbapenemase-producing Enterobacteriaceae have on average a 1.79 times higher hazard of dying in ICU than noncolonized patients, primarily because of an increased length of stay.

The changed epidemiology of extended spectrum beta-lactamases (ESBL), the spread to the community and the need for prudent use of carbapenems require updated knowledge of risk factors for colonization with ESBL-producing enterobacteriaceae (ESBL-PE). An 8-month prospective study in the medical ICU of an 850-bed general and university-affiliated hospital. Of 610 patients admitted, 531 (87 %) had a rectal swab obtained at admission, showing a 15 % (82 patients) ESBL-PE carriage rate, mostly of E. coli (n = 51, 62 %); ESBL-PE caused 9 (3 %) infections on admission. By multivariable analysis, transfer from another ICU (OR = 2.56 [1, 22]), hospital admission in another country [OR = 5.28 (1.56–17.8)], surgery within the past year [OR = 2.28 (1.34–3.86)], prior neurologic disease [OR = 2.09 (1.1–4.0)], and prior administration of third generation cephalosporin (within 3–12 months before ICU admission) [OR = 3.05 (1.21–7.68)] were independent predictive factors of colonization by ESBL-PE upon ICU admission. Twenty-eight patients (13 % of those staying for more than 5 days) acquired ESBL carriage in ICU, mostly with E. cloacae (n = 13, 46 %) and K. pneumoniae (n = 10, 36 %). In carriers, ESBL-PE caused 10 and 27 % of first and second episodes of ICU-acquired infections, respectively. We found a high prevalence of ESBLE-PE colonization on admission to our ICU, even in the subgroup admitted from the community, but few first infections. Identifying risk factors for ESBL-PE colonization may help identifying which patients may warrant empiric ESBL-targeted antimicrobial drug therapy as a means to limit carbapenem use.

Ventilator-associated pneumonia (VAP) is a common cause of morbidity, antibiotic use, increased length of stay and, possibly, increased mortality in ICU patients. Colonization of the oropharyngeal cavity with potentially pathogenic micro-organisms is instrumental in the pathogenesis of VAP, and selective oropharyngeal decontamination (SOD) with antibiotics (AB-SOD) or antiseptics, such as chlorhexidine gluconate (CHX-SOD), has been associated with reduced incidences of VAP. In a recent issue of Critical Care Scannapieco and colleagues investigated differences in oropharyngeal colonization between mechanically ventilated patients receiving oropharyngeal decontamination with 0.12% CHX-SOD either once or twice daily compared to placebo. CHX-SOD was associated with a reduction in Staphylococcus aureus colonization, but the study was underpowered to demonstrate a reduction in VAP incidence. We urgently need well-designed and adequately powered studies to evaluate the potential benefits of CHX-SOD on patient outcome in ICUs.

Purpose Infections caused by antimicrobial-resistant bacteria (AMRB) are increasing worldwide, especially in intensive care units (ICUs). Chlorhexidine body washing (CHG-BW) has been proposed as a measure to limit the spread of AMRB. We have systematically assessed the evidence on the effectiveness of CHG-BW in reducing colonization and infection with AMRB in adult ICU patients. Methods PubMed, Embase, CINAHL, and OpenSigle databases were searched using synonyms for “intensive care unit,” “hospital,” and “chlorhexidine.” All potentially relevant articles were examined by two independent reviewers. Inclusion was limited to studies with ICU patients as domain, providing outcomes related to colonization or infection with AMRB. Data from 16 studies were extracted; 9 were excluded because of assessed high risk of bias or inadequate analyses. The remaining studies differed markedly in (co-)interventions and case mix, which precluded pooling of data in a formal meta-analysis. Results Incidences of MRSA acquisition were reduced significantly in three studies in which this was the primary endpoint. Significant reduction in MRSA infection rates was observed in only one of five studies. Carriage and bacteremia rates of VRE were assessed in one study, and both significantly declined. There were hardly any data on the effects of CHG-BW on antibiotic-resistant gram-negative bacteria (ARGNB). Conclusions CHG-BW may be effective in preventing carriage, and possibly bloodstream infections, with MRSA and VRE in different ICU settings. As CHG-BW protocols, co-interventions and case mix varied widely, attribution of these effects to CHG-BW alone should be done with care. Evidence that CHG-BW reduces carriage of or infections with ARGNB is lacking.