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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.

IDH2 R172 mutations occur in sinonasal undifferentiated carcinoma (SNUC), large-cell neuroendocrine carcinoma (LCNEC), sinonasal adenocarcinomas, and olfactory neuroblastoma (ONB). We performed a clinical, pathologic, and genetic/epigenetic analysis of a large IDH2-mutated sinonasal tumor cohort to explore their distinct features. A total 165 sinonasal/skull base tumors included 40 IDH2 mutants studied by light microscopy, immunohistochemistry, and genome-wide DNA methylation, and 125 IDH2 wild-type tumors used for comparison. Methylation profiles were analyzed by unsupervised hierarchical clustering, t-distributed stochastic neighbor embedding dimensionality reduction and assessed for copy number alterations (CNA). Thirty-nine histologically assessable cases included 25 (64.1%) SNUC, 8 (20.5%) LCNEC, 2 (5.1%) poorly differentiated adenocarcinomas, 1 (2.7%) ONB, and 3 (7.7%) IDH2-mutated tumors with ONB features. All cases were high-grade showing necrosis (82.4%), prominent nucleoli (88.9%), and median 21 mitoses/10 HPFs. AE1/AE3 and/or CAM 5.2 were positive in all and insulinoma-associated protein 1 (INSM1) in 80% cases. All IDH2 mutants formed one distinct group by t-distributed stochastic neighbor embedding dimensionality reduction separating from all IDH2 wild-type tumors. There was no correlation between methylation clusters and histopathologic diagnoses. Recurrent CNA included 1q gain (79.3%), 17p loss (75.9%), and 17q gain (58.6%). No CNA differences were observed between SNUC and LCNEC. IDH2 mutants showed better disease-specific survival than SMARCB1-deficient (P=0.027) and IDH2 wild-type carcinomas overall (P=0.042). IDH2-mutated sinonasal tumors are remarkably homogeneous at the molecular level and distinct from IDH2 wild-type sinonasal malignancies. Biology of IDH2-mutated sinonasal tumors might be primarily defined by their unique molecular fingerprint rather than by their respective histopathologic diagnoses.

Objective: To develop and validate Clinical Diversity In Meta-analyses (CDIM), a new tool for assessing clinical diversity between trials in meta-analyses of interventions. Study design and setting: The development of CDIM was based on consensus work informed by empirical literature and expertise. We drafted the CDIM tool, refined it, and validated CDIM for interrater scale reliability and agreement in three groups. Results: CDIM measures clinical diversity on a scale that includes four domains with 11 items overall: setting (time of conduct/country development status/units type); population (age, sex, patient inclusion criteria/baseline disease severity, comorbidities); interventions (intervention intensity/strength/duration of intervention, timing, control intervention, cointerventions); and outcome (definition of outcome, timing of outcome assessment). The CDIM is completed in two steps: first two authors independently assess clinical diversity in the four domains. Second, after agreeing upon scores of individual items a consensus score is achieved. Interrater scale reliability and agreement ranged from moderate to almost perfect depending on the type of raters. Conclusion: CDIM is the first tool developed for assessing clinical diversity in meta-analyses of interventions. We found CDIM to be a reliable tool for assessing clinical diversity among trials in meta-analysis. (c) 2021 Elsevier Inc. All rights reserved.

BACKGROUND: Randomised clinical trials (RCTs) conducted in intensive care units (ICUs) frequently focus on all-cause mortality, but other patient-important outcomes are increasingly used and recommended. Their use, however, is not straightforward: choices and definitions, operationalisation of death, handling of missing data, choice of effect measures, and statistical analyses for these outcomes vary greatly.METHODS: We will conduct a scoping review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. We will search 10 selected general and speciality journals for RCTs conducted in adult ICU patients from 2018 and onwards reporting at least one patient-important outcome other than mortality (including days alive without life support/days alive and out of hospital-type outcomes, health-related quality of life, functional/cognitive/neurological outcomes and other general patient-important outcomes). We will summarise data on outcome measures and definitions, assessment time points, proportions and handling of death, proportions and handling of missing data, and effect measures and statistical methods used for analysis.DISCUSSION: The outlined scoping review will provide an overview of choices, definitions and handling of patient-important outcomes other than mortality in contemporary RCTs conducted in adult ICU patients. This may guide discussions with patients and relatives, the design of future RCTs, and research on optimal outcome choices and handling.

BACKGROUND: Superinfection following viral infection is a known complication, which may lead to longer hospitalisation and worse outcome. Empirical antibiotic therapy may prevent bacterial superinfections, but may also lead to overuse, adverse effects and development of resistant pathogens. Knowledge about the incidence of superinfections in intensive care unit (ICU) patients with severe Coronavirus Disease 2019 (COVID-19) is limited.METHODS: We will conduct a nationwide cohort study comparing the incidence of superinfections in patients with severe COVID-19 admitted to the ICU compared with ICU patients with influenza A/B in Denmark. We will include approximately 1000 patients in each group from the time period of 1 October 2014 to 30 April 2019 and from 10 March 2020 to 1 March 2021 for patients with influenza and COVID-19, respectively. The primary outcome is any superinfection within 90 days of admission to the ICU. We will use logistic regression analysis comparing COVID-19 with influenza A/B after adjustment for relevant predefined confounders. Secondarily, we will use unadjusted and adjusted logistic regression analyses to assess six potential risk factors (sex, age, cancer [including haematological], immunosuppression and use of life support on day 1 in the ICU) for superinfections and compare outcomes in patients with COVID-19 with/without superinfections, and present descriptive data regarding the superinfections.CONCLUSION: This study will provide important knowledge about superinfections in ICU patients with severe COVID-19.

In 2010, following the publication of two large trials of corticosteroids in septic shock, an international survey of corticosteroid use in the management of septic shock reported marked variability in practice. Two large randomised controlled trials of corticosteroids in septic shock (ie, the ADRENAL trial comparing hydrocortisone v placebo 4 and the APROCCHSS trial comparing hydrocortisone plus fludrocortisone v placebo) published in 2018 reported divergent effects of steroids on mortality at day 90, although important secondary outcomes such as duration of shock and mechanical ventilation were improved in both trials.

BACKGROUND/AIM A considerable number of patients with advanced head-and-neck cancer (SCCHN) receive palliative radiotherapy. This study aimed to identify prognostic factors for survival to facilitate personalized treatment for these patients. PATIENTS AND METHODS Ninety-two patients receiving palliative radiotherapy for SCCHN were retrospectively analyzed. Fourteen characteristics were evaluated for survival including age, gender, performance score, pre-radiotherapy hemoglobin, tumor site and stage, histologic grade, p16-status, equivalent dose in 2 Gy-fractions (EQD2), completion of radiotherapy, upfront surgery and systemic therapy. RESULTS On univariate analysis, improved survival was significantly associated with pre-radiotherapy hemoglobin ≥12 g/dl (p=0.003), EQD2 >42.3 Gy (p=0.003) and completion of radiotherapy (p

BACKGROUND/AIM Patients with advanced squamous cell carcinoma of the head-and-neck (SCCHN) may be assigned to palliative irradiation. A survival score was developed for this group to support treatment personalization. PATIENTS AND METHODS Seventy-eight patients who received palliative irradiation for SCCHN and had complete data regarding performance score, pre-radiotherapy hemoglobin levels, and main tumor site were included in this retrospective study. Six-month survival rates of these factors were divided by 10 (factor scores) and added for each patient (total patient scores). RESULTS Total patient scores ranged between 8 and 15 points. Three groups were designed based on the 6-month survival rates, namely 8-9 (n=15), 11-13 (n=36), and 14-15 (n=27) points. Six-month survival rates were 13%, 28%, and 63%, and median survival times were 1, 2, and 11 months (p=0.001). CONCLUSION A new survival score including three prognostic groups was developed. This new tool can help physicians when designing personalized treatments for patients with SCCHN scheduled for palliative irradiation.

The only potentially curative treatment for lung adenocarcinoma patients remains complete resection of early-stage tumors. However, many patients develop recurrence and die of their disease despite curative surgery. Underlying mechanisms leading to establishment of systemic disease after complete resection are mostly unknown. We therefore aimed at identifying molecular signatures of resected lung adenocarcinomas associated with the risk of an early relapse. The study comprised 89 patients with totally resected stage IA–IIIA lung adenocarcinomas. Patients suffering from an early relapse within two years after surgery were compared to patients without a relapse in two years. Patients were clinically and molecular pathologically characterized. Tumor tissues were immunohistochemically analyzed for the expression of Ki67, CD45, CD4, CD8, PD1, PD-L1, PD-L2 and CD34, by Nanostring nCounter PanCancer Immune Profiling Panel as well as a comprehensive methylome profiling using the Infinium MethylationEPIC BeadChip. We detected differential DNA methylation patterns as well as significantly differentially expressed genes associated with an early relapse after complete resection. Especially, CD1A was identified as a potential biomarker, whose reduced expression is associated with an early relapse. These findings might help to develop biomarkers improving risk assessment and patient selection for adjuvant therapy as well as establish novel targeted therapeutic strategies.

Introduction New-onset atrial fibrillation (NOAF) is frequently observed in critically ill patients and may be associated with prolonged hospital stay and increased mortality. Considerable variation exists in the reported frequencies of NOAF due to the lack of a standardised definition and detection method. Importantly, there are limited data on NOAF in the intensive care unit (ICU). Thus, we aim to provide contemporary epidemiological data on NOAF in the ICU.Methods and Analysis We have designed an international inception cohort study including at least 1,000 consecutive adult patients acutely admitted to the ICU without prior history of persistent or permanent AF. We will present data on the incidence, risk factors, used management strategies and outcomes of NOAF. We will register data daily during stay in the ICU for a maximum of 90 days after admission. The incidence of NOAF and management strategies used will be presented descriptively, and we will use Cox regression analyses including competing risk analyses to assess risk factors for NOAF and any association with 90-day mortality.Conclusion The outlined international AFIB-ICU inception cohort study will provide contemporary data on the incidence, risk factors, used management strategies and outcomes of NOAF in adult ICU patients.Ethics and dissemination This observational study poses no risk to the included patients. All participating sites will obtain relevant approvals according to national laws before patient enrollment. Funding sources will have no influence on data handling, analyses or writing of the manuscript. The study report(s) will be submitted to an international peer-reviewed journal.

Background In previous studies of predictors of gastrointestinal (GI) bleeding in the intensive care unit (ICU), most patients received pharmacological stress ulcer prophylaxis (SUP). We aimed to assess associations between potential predictors of clinically important GI bleeding (CIB) and overt GI bleeding in adult ICU patients, while considering the effect and potential interaction with use of SUP. Methods We included 3291 acutely admitted adult ICU patients with risk factors for GI bleeding randomized to SUP (pantoprazole) or placebo in the SUP-ICU trial. We used logistic regression models adjusted for allocation to SUP to estimate associations between 23 potential predictors and CIB (primary outcome) and overt GI bleeding (secondary outcome). Furthermore, we assessed associations between potential predictors and both outcomes in each allocation group and assessed potential interaction with allocation to SUP. Results Increasing SAPS II and SOFA scores, use of circulatory support and renal replacement therapy were associated with increased risk of CIB and overt GI bleeding; chronic lung disease was associated with increased risk of overt GI bleeding. Results for the remaining potential predictors were compatible with both no difference or increased and decreased risks. We found no strong evidence for any interaction between treatment allocation and any potential predictors. Conclusion In adult ICU patients at risk of GI bleeding, severity of illness, use of circulatory support and renal replacement therapy were associated with higher odds of CIB, with no strong evidence of interaction with SUP.

Background Coronavirus disease 2019 (COVID‐19) may be associated with cardiac arrhythmias in hospitalized patients, but data from the ICU setting are limited. We aimed to describe the epidemiology of cardiac arrhythmias in ICU patients with COVID‐19. Methods We conducted a multicenter, retrospective cohort study including all ICU patients with an airway sample positive for severe acute respiratory syndrome corona‐virus 2 from March 1st to June 1st in the Capital Region of Denmark (1.8 million inhabitants). We registered cardiac arrhythmias in ICU, potential risk factors, interventions used in ICU and outcomes. Results From the seven ICUs we included 155 patients with COVID‐19. The incidence of cardiac arrhythmias in the ICU was 57/155 (37%, 95% confidence interval 30‐45), and 39/57 (68%) of these patients had this as new‐onset arrhythmia. Previous history of tachyarrhythmias and higher disease severity at ICU admission were associated with cardiac arrhythmias in the adjusted analysis. Fifty‐four of the 57 (95%) patients had supraventricular origin of the arrhythmia, 39/57 (68%) received at least one intervention against arrhythmia (eg amiodarone, IV fluid or magnesium) and 38/57 (67%) had recurrent episodes of arrhythmia in ICU. Patients with arrhythmias in ICU had higher 60‐day mortality (63%) as compared to those without arrhythmias (39%). Conclusion New‐onset supraventricular arrhythmias were frequent in ICU patients with COVID‐19 and were related to previous history of tachyarrhythmias and severity of the acute disease. The mortality was high in these patients despite the frequent use of interventions against arrhythmias.

ZusammenfassungDie Instillationstherapie stellt im Feld der urothelialen Neoplasien der Harnblase eine einzigartige Therapiemöglichkeit dar, die so in keinem anderen medizinischen Bereich zur Anwendung kommt. Mit der Wahl des zu instillierenden Medikamentes hat sich die Forschung der vergangenen Jahre intensiv beschäftigt, hierbei hat sich besonders der Einsatz von Bacillus Calmette-Guerin (BCG) und Mitomycin C (MMC) bewährt. Weitere Medikamente, die jedoch seltener zum Einsatz kommen, sind Chemotherapeutika wie Gemcitabin, dessen klinische Relevanz in diesem Artikel beleuchtet werden soll.So vielfältig, wie die Therapiemöglichkeiten der Harnblasentumore, ist auch ihre Histopathologie. Das invertierte Papillom stellt im Formenkreis der urologischen Erkrankungen eine seltene Krankheitsentität dar. Eine Assoziation zum nicht-muskelinvasiven Harnblasenkarzinom wird diskutiert.Wir berichten von dem Fall einer Patientin mit invertiertem Papillom der Harnblase, welche nach Versagen einer BCG-Therapie und einer allergischen Reaktion gegen MMC mit einer Gemcitabin-Instillationstherapie behandelt wurde.

A 54-year-old patient with a history of pulmonary tuberculosis and occupational exposure to dust in early adulthood presented with symptoms of coughing with sputum, weight loss, occasional night sweats, and thoracic pain. Non-necrotizing granulomatosis in lung and lymph-node biopsies indicated sarcoidosis. Combined immunosuppressive therapy did not lead to an improvement. An atypical lung resectate with fibroinflammatory changes and obliterative endothelialitis may finally lead to the diagnosis of IgG4-associated lung disease with a bronchovascular pattern of involvement. The question discussed here is whether this is a coexistence of IgG4-associated lung disease with sarcoidosis or the spectrum of one disease.

The spectrum of pulmonary granulomatoses is wide and includes infectious and noninfectious entities, each with very different therapeutic consequences. The first step of histological examination discriminates between necrotizing and non-necrotizing granulomatosis. After this, an infectious cause of the granulomatosis has to be excluded by special histological stains and molecular-pathologic methods, if necessary. Diagnosis also includes clinical, radiological, and microbiological findings. The process of pathological examination should be standardized as described.

Obwohl die histologischen Charakteristika der Lungentuberkulose seit langem bekannt sind, ist die Diagnose einer nicht mikrobiologisch gesicherten Tuberkulose mit den der Pathologie zur Verfugung stehenden Mitteln eine Herausforderung. Eine nekrotisierende epitheliodzellige Granulomatose ist zwar fur eine Tuberkulose typisch, kommt jedoch auch bei einer Reihe anderer infektios, aber auch nichtinfektios bedingter Erkrankungen vor. Mikroskopische und molekularpathologische Verfahren konnen eine Tuberkulose bestatigen und ggf. eine andere Diagnose bahnen. Die Molekularpathologie findet jedoch am formalinfixierten und in Paraffin eingebetteten Material ihre methodischen Grenzen. Dies sollte den einsendenden KlinikerInnen gegenuber offen kommuniziert werden. Nach interdisziplinarer Reevaluation der Befunde muss daher bei negativem Ergebnis der Zusatzuntersuchungen entsprechend eine alternative Losung zur Diagnosesicherung gefunden werden.

Die organisierende Pneumonie (OP) beschreibt ein histologisches Muster des akuten bzw. subakuten Lungenschadens. Klinisch fallen die Patienten mit Husten, Fieber und Dyspnoe auf. Es wird zwischen der idiopathischen bzw. kryptogen organisierenden (COP) und der sekundaren organisierenden Pneumonie (OP) unterschieden. Bei der COP kann weder klinisch/radiologisch noch histologisch eine Ursache bestimmt werden. Sie wird zu den interstitiellen idiopathischen Pneumonien (IIP) gezahlt nach Kriterien der American Thoracic Society (ATS) und der European Respiratory Society (ERS). Bei der sekundaren organisierenden Pneumonie liegt ein bekannter auslosender Mechanismus vor, wie z. B. infektiose Erreger, bestimmte Medikamente oder auch Begleiterscheinungen anderer primar pulmonaler Erkrankungen und Erkrankungen anderer Organsysteme. Beiden Formen gemeinsam ist das histologische Bild der intraalveolaren Mesenchymknospen. Diese sind Myofibroblastenproliferate, welche sich zopfartig entlang der Alveolarraume verzweigen. Sie werden in der Regel von einem bis masigen interstitiellen und alveolaren, chronischen und makrophagenreichen Entzundungszellinfiltrat begleitet. Wichtigste Differenzialdiagnose ist die gewohnliche interstitielle Pneumonie (UIP). Diese zeigt ebenfalls Fibroblastenproliferate, welche allerdings interstitiell liegen. Die korrekte Zuordnung einer IIP als COP mittels klinischer, radiologischer und histologischer Befunderhebung ist essenziell, da die COP im Gegensatz zur UIP sehr gut auf Kortikosteroide anspricht und somit gegenuber der UIP eine exzellente Prognose hat. Der Verlauf sekundarer organisierender Pneumonien hangt von der jeweiligen Grunderkrankung ab. Hier ist es wichtig, dass der Pathologe histologische Begleitcharakteristika einer OP korrekt identifiziert, um Hinweise auf eine mogliche Ursache geben zu konnen.

Background Liberal oxygen supplementation is often used in acute illness but has, in some studies, been associated with harm. Research Question The goal of this study was to assess the benefits and harms of higher vs lower oxygenation strategies in acutely ill adults. Study Design and Methods This study was an updated systematic review with meta-analysis and Trial Sequential Analysis (TSA) of randomized clinical trials. A clear differentiation (separation) was made between a higher (liberal) oxygenation and a lower (conservative) oxygenation strategy and their effects on all-cause mortality, serious adverse events, quality of life, lung injury, sepsis, and cardiovascular events at time points closest to 90 days in acutely ill adults. Results The study included 50 randomized clinical trials of 21,014 participants; 36 trials with a total of 20,166 participants contributed data to the analyses. Meta-analysis and TSAs showed no difference between higher and lower oxygenation strategies in trials at overall low risk of bias except for blinding: mortality relative risk (RR), 0.98 (95% CI, 0.89-1.09; TSA-adjusted CI, 0.86-1.12; low certainty evidence); serious adverse events RR, 0.99 (95% CI, 0.89-1.12; TSA-adjusted CI, 0.83-1.19; low certainty evidence). The corresponding summary estimates including trials with overall low and high risk of bias showed similar results. No difference was found between higher and lower oxygenation strategies in meta-analyses and TSAs regarding quality of life, lung injury, sepsis, and cardiovascular events (very low certainty evidence). Interpretation No evidence was found of beneficial or harmful effects of higher vs lower oxygenation strategies in acutely ill adults (low to very low certainty evidence). Clinical Trial Registration PROSPERO; No.: CRD42017058011; URL: https://www.crd.york.ac.uk/prospero/ .

Cancer will be the leading cause of death in a few decades. In line with minimal invasive lung cancer surgery, surgeons loose most of their tactile tissue information and need an additional tool of intraoperative tissue navigation during surgery. Confocal laser microscopy is a well-established method of tissue investigation. In this ex-vivo pilot study, we evaluated an endoscopic confocal laser microscope (eCLM) that does not need any fluorescent dye as a diagnostic tool in non-malignant and malignant pulmonary tissue and distal stapler resection margins, respectively. In seven cases, an eCLM was used for examining pulmonary tissue ex-vivo. Images of non-malignant and non-small cell lung cancer tissue and distal stapler resection margins were characterized in terms of specific signal-patterns. No fluorescent dye was used. Correlations to findings in conventional histology were systematically recorded and described. Healthy lung tissue showed hyperreflectoric alveolar walls with dark alveolar spaces. Hyperreflective nets indicated the tumor stroma; whereas the hyperreflective areas indicated the tumor cell clusters. Compared to adenocarcinoma tissue, tissue from squamous cell carcinoma showed more distinctive hyperreflective stroma nets. eCLM characteristics seen in non-malignant and malignant tissue were also visible in distal stapler resection margins and so therefore it was feasible to distinguish between healthy lung tissue and lung cancer. This pilot study shows that the assessment of pulmonary tissue with this eCLM for minimally invasive surgical approach without any fluorescent dye is feasible. It enables to differentiate between benign and malignant tissue in pulmonary specimen by easy to evaluate and reproducible parameters.

Prognostication in oesophageal cancer on the basis of preoperative variables is challenging. Many of the accepted predictors of survival are only derived after surgical treatment and may be influenced by neoadjuvant therapy. This study aims to explore the relationship between pre-treatment endoscopic tumour morphology and postoperative survival.Patients with endoscopic descriptions of tumours were identified from the prospectively managed databases including the OCCAMS database. Tumours were classified as exophytic, ulcerating or stenosing. Kaplan Meier survival analysis and multivariable Cox regression analyses were performed to determine hazard ratios (HR) with 95% confidence intervals.262 patients with oesophageal adenocarcinoma undergoing potentially curative resection were pooled from St Thomas' Hospital (161) and the OCCAMS database (101). There were 70 ulcerating, 114 exophytic and 78 stenosing oesophageal adenocarcinomas. Initial tumour staging was similar across all groups (T3/4 tumours 71.4%, 70.2%, 74.4%). Median survival was 55 months, 51 months and 36 months respectively (p 0.001). Rates of lymphovascular invasion (P = 0.0176), pathological nodal status (P = 0.0195) and pathological T stage (P = 0.0007) increased from ulcerating to exophytic to stenosing lesions. Resection margin positivity was 21.4% in ulcerating tumours compared to 54% in stenosing tumours (p 0.001). When compared to stenosing lesions, exophytic and ulcerating lesions demonstrated a significant survival advantage on multivariable analysis (HR 0.56 95% CI 0.31-0.93, HR 0.42 95% CI 0.21-0.82).This study demonstrates that endoscopic morphology may be an important pre-treatment prognostic factor in oesophageal cancer. Ulcerating, exophytic and stenosing tumours may represent different pathological processes and tumour biology.

BACKGROUND Critically ill children are at risk of stress-induced gastrointestinal ulceration. Acid suppressants are frequently used in intensive care units even though there is uncertainty about the benefits and harms. With this systematic review, we aimed to assess patient-important benefits and harms of stress ulcer prophylaxis (SUP) in children in intensive care. METHODS We conducted the review according to the PRISMA statement, the Cochrane Handbook, and GRADE, using conventional meta-analysis and trial sequential analysis (TSA). We included randomised clinical trials comparing SUP with histamine-2-receptor antagonists or proton pump inhibitors vs placebo/no prophylaxis in children admitted for intensive care. Primary outcomes were all-cause mortality and overt gastrointestinal bleeding. Secondary outcomes were serious adverse events, hospital-acquired pneumonia, Clostridium difficile enteritis, myocardial ischemia, acute kidney injury and quality of life. RESULTS We included a total of seven trials (n = 504) with eight trial comparisons. We found no statistically significant difference in all-cause mortality (relative risk (RR) 1.43, 95% confidence interval (CI) 0.86-2.37), overt gastrointestinal bleeding (RR 0.75, 95% CI 0.42-1.35) or hospital-acquired pneumonia (RR 1.18, 95% CI 0.77-1.82) between SUP vs placebo/no prophylaxis. No trials reported on remaining secondary outcomes. TSA was unable to draw firm conclusions for all outcomes and certainty of evidence for all outcomes was "very low." CONCLUSIONS We found no difference in all-cause mortality, overt gastrointestinal bleeding or hospital-acquired pneumonia in children in intensive care receiving acid suppressants compared with placebo/no prophylaxis. However, the quantity and quality of evidence was very low with no firm evidence for benefit or harm.

We present the case of a patient with granulomatous endocarditis of the mitral valve leading to severe valve stenosis caused by granulomatosis with polyangiitis. Endocarditis is a rare complication of granulomatosis with polyangiitis that may be misdiagnosed as infectious endocarditis or, as in our case, thrombotic lesions. (Level of Difficulty: Intermediate.), Graphical abstract

Background: Although supplemental oxygen can be lifesaving, liberal oxygen administration causing hyperoxaemia may be harmful. The targets for oxygenation in patients with acute hypoxaemic respiratory failure acutely admitted to the intensive care unit (ICU) are strongly debated, and consensus on which targets to recommend has not been reached. The Handling Oxygenation Targets in the ICU (HOT-ICU) trial is a multicentre, randomised, parallel-group trial of a lower oxygenation target (arterial partial pressure of oxygen [PaO2] = 8 kPa) versus a higher oxygenation target (PaO2 = 12 kPa) in adult ICU patients with acute hypoxaemic respiratory failure. In this study, we aim to evaluate the effects of these targets on long-term cognitive and pulmonary function in Danish patients, enrolled in the HOT-ICU trial and surviving to 1-year follow-up. We hypothesise that a lower oxygenation target throughout the ICU stay may result in cognitive impairment, whereas a higher oxygenation target may result in impaired pulmonary function. Methods: All patients enrolled in the HOT-ICU trial at Danish sites and surviving to 1 year after randomisation are eligible to participate. The last patient is expected to be included by November 2021. A Repeatable Battery for the Assessment of Neuropsychological Status and a body plethysmography, including diffusion capacity for carbon monoxide, both pre-planned secondary long-term outcomes of the HOT-ICU trial, will be obtained. Conclusion: This study will provide important information on the long-term effects of a lower versus a higher oxygenation target on cognitive and pulmonary function in adult ICU patients with acute hypoxaemic respiratory failure.

BACKGROUND: Mortality is often the primary outcome in randomised clinical trials (RCTs) conducted in critically ill patients. Due to increased awareness on survivors after critical illness and outcomes other than mortality, health-related quality of life (HRQoL) and days alive without life support (DAWOLS) or days alive and out of hospital (DAAOOH) are increasingly being used. DAWOLS and DAAOOH convey more information than mortality, are easier to collect than HRQoL, and are usually assessed at earlier time points, which may be preferable in some situations. However, the associations between DAWOLS-DAAOOH and HRQoL are uncertain.METHODS: We will assess associations between DAWOLS-DAAOOH at day 28 and 90 (independent variables/predictors) and HRQoL assessed using the EuroQol EQ-5D-5L questionnaire (EQ-VAS and EQ-5D-5L index values) at 6 or 12 months (dependent variables) in two RCTs: the COVID STEROID 2 RCT conducted in adult patients with COVID-19 and severe hypoxaemia and the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) RCT conducted in adult intensive care patients with acute hypoxaemic respiratory failure. We will describe associations using best-fitting fractional polynomial transformations separately in each dataset, with the resulting models presented and assessed in both datasets graphically and using measures of fit and prediction adequacy (i.e., internal performance and external validation). We will use multiple imputation if missingness exceeds 5%.DISCUSSION: The outlined study will provide important knowledge on the associations between DAWOLS-DAAOOH and HRQoL in adult critically ill patients, which may help researchers and clinical trialists prioritise and select outcomes in future RCTs conducted in this population.

Purpose: To customize and externally validate the recently proposed Simplified Mortality Score for the ICU (SMS-ICU, a simple score for 90-day mortality that has no need for ancillary testing results) for in-hospital mortality and to compare its performance to SAPS 3. Material and methods: We used data from two distinct large cohorts of adult Brazilian patients with unplanned ICU admissions to perform a first-level customization (43,017 patients admitted to 78 ICUs) of the original SMS-ICU score for in-hospital mortality and, sequentially, externally validate it (313,365 patients admitted to 99 ICUs). Performance of SMS-ICU was assessed through measurements of discrimination and calibration and compared with SAPS 3. Results: In the validation cohort, median SMS-ICU was 13 (IQR 8-16) points and median SAPS 3 was 44 (IQR 36-51). Discrimination of SMS-ICU was good (AUC 0.817; 95% CI 0.814-0.819) but slightly lower than of SAPS 3 (AUC 0.845; 95% CI 0.843-0.848;). The customized SMS-ICU predictions were comparable to SAPS 3 in terms of calibration. Conclusion: In this external validation of the SMS-ICU in a large Brazilian cohort, we observed good discrimination of SMS-ICU and acceptable calibration after first-level customization. SMS-ICU can be used as a measure of illness severity for acutely admitted ICU patients in clinical studies.

Background Thrombocytopenia is frequent in intensive care unit (ICU) patients and may be associated with adverse outcomes. We aimed to assess the incidence, risk factors, and outcomes associated with thrombocytopenia in adult ICU patients. Methods We conducted a scoping review in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We included study reports on adult ICU patients with thrombocytopenia and assessed patient-important outcomes, including mortality and health-related quality-of-life. Results We included a total of 70 studies comprising a total of 215 098 patients; 57 were cohort studies. The incidence of thrombocytopenia varied from 8 to 56 per 100 admissions (very low quality of evidence). We identified several risk factors including age, sepsis, and higher disease severity (low quality of evidence). Thrombocytopenia was associated with bleeding, use of life support, length of stay in the ICU, and increased mortality (low/very low quality of evidence). Data on platelet transfusion before invasive procedures and transfusion thresholds were limited. No studies assessed the benefits and harms of thromboprophylaxis in ICU patients with thrombocytopenia. Conclusions Thrombocytopenia is common and associated with increased morbidity and mortality in adult ICU patients. Several risk factors for thrombocytopenia exists, but the evidence-base on management strategies, including transfusion thresholds and thromboprophylaxis in ICU patients is very limited.

Background Buffered crystalloid solutions are increasingly recommended as first-line resuscitation fluids. However, guidelines do not distinguish between different types of buffered solutions. The aim of the outlined systematic review is to summarize and assess the effects of acetate- vs lactate-buffered crystalloid solutions on patient-important outcomes. Methods We will conduct a systematic review of randomized clinical trials (RCTs) with meta-analysis and trial sequential analysis comparing the use of acetate- vs lactate-buffered crystalloid solutions in hospitalized patients. We will systematically search the Cochrane Library, MEDLINE, EMBASE, and Epistemonikos for relevant literature. We will follow the recommendations set by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The risk of systematic errors (bias) and random errors will be assessed, and the overall quality of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Discussion The outlined systematic review will provide important data on how patient-important outcomes are affected by intravenous administration of acetate- vs lactate-buffered crystalloid solutions in hospitalized patients.

Purpose To describe the incidence of and risk factors for impaired cognitive function in intensive care unit (ICU) survivors. We hypothesized that age, severity of illness, and days in coma, delirium, mechanical ventilation in the ICU would be associated with impaired cognitive function. Methods We included all adults, alive 6 months after acute admission to one of the 24 Danish ICUs participating in the AID-ICU cohort study. Trained professionals assessed cognitive function in patients' homes or in outpatient clinics using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 6 months after ICU admission. Potential risk factors for cognitive impairment were analyzed with linear regression models. Results In total, 237 ICU patients were alive 6 months after ICU admission and did not meet the exclusion criteria. A total of 106 patients completed the cognitive assessment. The median RBANS global cognitive score was 76 (interquartile range, 62-91), and 52% had a global cognitive score 1.5 SD below the normative mean and 36% displayed a global cognitive score 2 SD below the normative mean, similar to that of Alzheimer's disease. Higher age was associated with poorer RBANS global cognitive score (estimate -0.35 [95% confidence interval -0.63 to -0.07] per year). Conclusions In this multicenter study of adult ICU survivors, cognitive impairment was frequent and severe in those assessed at 6 months. Higher age was a risk factor for cognitive impairment, but events related to the ICU stay were not associated with poorer cognitive performance at 6 months.

Motivated by a new randomized trial (the PEPTIC trial) that raised the issue of an increase in mortality with proton pump inhibitors (PPIs) relative to histamine-2 receptor antagonists (H2RAs), we updated our prior systematic review and network meta-analysis (NMA) addressing the impact of pharmacological gastrointestinal bleeding prophylaxis in critically ill patients. We searched for randomized controlled trials that examined the efficacy and safety of gastrointestinal bleeding prophylaxis with PPIs, H2RAs, or sucralfate versus one another or placebo or no prophylaxis in adult critically ill patients. We performed Bayesian random-effects NMA and conducted analyses using all PEPTIC data as well as a restricted analysis using only PEPTIC data from high compliance centers. We used the GRADE approach to quantify absolute effects and assess the certainty of evidence. Seventy-four trials enrolling 39 569 patients proved eligible. Both PPIs (risk ratio (RR) 1.03, 95% credible interval 0.93 to 1.14, moderate certainty) and H2RAs (RR 0.98, 0.89 to 1.08, moderate certainty) probably have little or no impact on mortality compared with no prophylaxis. There may be no important difference between PPIs and H2RAs on mortality (RR 1.05, 0.97 to 1.14, low certainty), the 95% credible interval of the complete analysis has not excluded an important increase in mortality with PPIs. Both PPIs (RR 0.46, 0.29 to 0.66) and H2RAs (RR 0.67, 0.48 to 0.94) probably reduce clinically important gastrointestinal bleeding; the magnitude of reduction is probably greater in PPIs than H2RAs (RR 0.69, 0.45 to 0.93), and the difference may be important in higher, but not lower bleeding risk patients. PPIs (RR 1.08, 0.88 to 1.45, low certainty) and H2RAs (RR 1.07, 0.85 to 1.37, low certainty) may have no important impact on pneumonia compared with no prophylaxis. This updated NMA confirmed that PPIs and H2RAs are most likely to have a similar effect on mortality compared to each other and compared to no prophylaxis; however, the possibility that PPIs may slightly increase mortality cannot be excluded (low certainty evidence). PPIs and H2RAs probably achieve important reductions in clinically important gastrointestinal bleeding; for higher bleeding risk patients, the greater benefit of PPIs over H2RAs may be important. PPIs or H2RAs may not result in important increases in pneumonia but the certainty of evidence is low.

Background In the intensive care unit, fluid overload is frequent and a risk factor for organ dysfunction and increased mortality. Primarily, lung and kidney functions may be impaired by fluid overload resulting in acute respiratory failure and acute kidney injury. No clinical guidelines exist for treatment of fluid overload in intensive care patients. Loop diuretics, most often furosemide, appear to be the most frequently used pharmacological intervention. The aim of this protocol is to describe the methods of a systematic review assessing the evidence of treatment with loop diuretics in adult intensive care patients with fluid overload. Methods We will conduct a systematic review with meta-analysis and report it according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statements, use the recommendations of the Cochrane Handbook and assess the quality of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. We will include randomised clinical trials identified through searches of major international databases and trial registers. Two authors will independently screen and select trials for inclusion, extract data and assess the methodological quality using the Cochrane risk of bias tool. Extracted data will be analysed using Review Manager and Trial Sequential Analysis. The protocol is registered at PROSPERO. Discussion We aim to provide reliable evidence on the use of loop diuretics in adult intensive care patients with fluid overload to guide clinicians, decision makers and trialists on clinical practice.

Objective IV fluids are recommended during the initial management of sepsis, but the quality of evidence is low, and clinical equipoise exists. We aimed to assess patient-important benefits and harms of lower vs higher fluid volumes in adult patients with sepsis. Methods We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized clinical trials of IV fluid volume separation in adult patients with sepsis. We adhered to our published protocol; the Cochrane handbook; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses; and the Grading of Recommendations Assessment, Development and Evaluation statements. The primary outcomes were all-cause mortality, serious adverse events (SAEs), and quality of life. Results We included nine trials (n = 637); all were published after 2015 and had an overall high risk of bias. We found no statistically significant difference between lower vs higher fluid volumes in all-cause mortality (relative risk [RR], 0.87; 95% CI, 0.69-1.10; I2 = 0%; TSA-adjusted CI, 0.34-2.22) or SAEs (RR, 0.91; 95% CI, 0.78-1.05; I2 = 0%; TSA-adjusted CI, 0.68-1.21). No trials reported on quality of life. We did not find differences in the secondary or exploratory outcomes. The quality of evidence was very low across all outcomes. Conclusions In this systematic review, we found very low quantity and quality of evidence supporting the decision on the volumes of IV fluid therapy in adults with sepsis. Trial Registry ClinicalTrials.gov ; No.: NCT03668236 ; URL: www.clinicaltrials.gov

BACKGROUND Use of a lower haemoglobin (Hb) threshold to guide red blood cell (RBC) transfusion is now generally recommended in critically ill patients, but uncertainty remains regarding the optimal Hb threshold for RBC transfusion in patients of different ages. METHODS We conducted a post-hoc analysis of 998 patients with septic shock and anaemia randomised to RBC transfusion at a Hb threshold of 7 g/dl [4.3 mmol/l] vs 9 g/dl [5.6 mmol/l] in the Transfusion Requirements in Septic Shock (TRISS) trial. We assessed if there were heterogeneous effects between the allocated Hb threshold and patient age categorised and on the continuous scale. The primary outcome was 1-year mortality; the secondary outcome was 90-day mortality. Both outcomes were analysed using logistic regression models and in sensitivity analyses with additional adjusting for site of enrolment, presence of haematological malignancy and the Sequential Organ Failure Assessment (SOFA) score. The secondary analyses were Kaplan-Meier curves with corresponding log-rank tests. RESULTS We found no heterogeneity between patient age and the allocated Hb thresholds for RBC transfusion for 1-year mortality or 90-day mortality in the primary analyses. The sensitivity analyses suggested heterogeneity between age groups regarding 90-day mortality, however, this was not consistent for 1-year mortality or when assessing age on the continuous scale. CONCLUSION In this post-hoc study of ICU patients with septic shock, we found no reliable heterogeneous effects of transfusion at a Hb threshold of 7 vs 9 g/dl according to patient age on mortality. However, due to low power, this study should only be considered as hypothesis generating.

Background Randomized clinical trials (RCTs) are occasionally stopped prematurely before reaching their planned sample sizes. It has been suggested that early stopped RCTs are associated with under- and overestimation of the effect estimates. We simulated the effect of hypothetical premature stopping of three large RCTs done in the intensive care unit (ICU) setting. Methods In this post hoc study, we simulated the impact of stopping trials early by calculating mortality effect estimates continuously after the inclusion of each individual patient in three large RCTs, that is the 6S trial on hydroxyethyl starch vs Ringer's acetate in sepsis in ICU, the TRISS trial on lower vs higher haemoglobin threshold for transfusion in septic shock in ICU and the SUP-ICU trial on pantoprazole in patients at risk for gastrointestinal bleeding in the ICU. Results The three trials included a total of 5087 patients; 798 from the 6S trial, 998 from the TRISS trial and 3291 patients from the SUP-ICU trial. The premature mortality effect estimates showed considerable fluctuations until at least 20%-30% of the sample size was included. The premature estimates became stable after inclusion of 205 patients (26% of the final sample size) in the 6S trial, 133 patients(13%) in the TRISS trial and 1926 patients(59%) in the SUP-ICU trial. Conclusions In this post hoc study of three international RCTs within intensive care, we found that the simulated interim mortality effect estimates showed considerable fluctuations until at least 20%-30% of the sample size was included, but remained instable until the final sample sizes had been included. Thus, this study illustrates the necessity for cautious interpretations of prematurely stopped trials.

Objective To develop evidence-based clinical practice recommendations regarding transfusion practices in non-bleeding, critically ill adults. Design A task force involving 13 international experts and three methodologists used the GRADE approach for guideline development. Methods The task force identified four main topics: red blood cell transfusion thresholds, red blood cell transfusion avoidance strategies, platelet transfusion, and plasma transfusion. The panel developed structured guideline questions using population, intervention, comparison, and outcomes (PICO) format. Results The task force generated 16 clinical practice recommendations (3 strong recommendations, 13 conditional recommendations), and identified five PICOs with insufficient evidence to make any recommendation. Conclusions This clinical practice guideline provides evidence-based recommendations and identifies areas where further research is needed regarding transfusion practices and transfusion avoidance in non-bleeding, critically ill adults. Electronic supplementary material The online version of this article (10.1007/s00134-019-05884-8) contains supplementary material, which is available to authorized users.

BACKGROUND: In caring for mechanically ventilated adults with acute respiratory distress syndrome (ARDS), clinicians are faced with an uncertain choice between controlled or spontaneous breathing modes. Observational data indicate considerable practice variation which may be driven by differences in sedation and mobilisation practices. The benefits and harms of either strategy are largely unknown.METHODS: A scoping review will be prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. We will review the clinical literature on controlled vs spontaneous breathing in mechanically ventilated patients with ARDS of any severity. Studies reporting on qualitative and/or quantitative data from any world region will be considered. For inclusion, studies must include data on mechanically ventilated patients with ARDS who are allowed spontaneous (triggered ventilation). Searches will be conducted in four electronic databases without any limitation on publication date and language. We will assess the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, where appropriate.CONCLUSION: We will perform a scoping review of the clinical literature on controlled vs spontaneously breathing in mechanically ventilated patients who fulfil ARDS criteria (including acute lung injury). This is to elucidate if a pragmatic clinical trial comparing controlled and spontaneous mechanical ventilation is warranted and will allow us to formulate relevant research questions.

Die Informationen aus pathologischen Befundberichten zu Prostatastanzbiopsien stellen im Management des Prostatakarzinoms einen essentiellen Bestandteil fur die Risikostratifizierung dar. Durch zusatzliche Parameter ist der Informationsgehalt der Befunde zunehmend komplexer geworden. Mit Hilfe einer reprasentativen Umfrage zu pathologischen Befundberichten von Prostatastanzbiopsien sollte ermittelt werden, wie diese von Urologen interpretiert und fur Therapieentscheidungen berucksichtigt werden. Uber den Berufsverband der Deutschen Urologen e. V. (BDU) wurde ein Fragebogen zu Prostatastanzbiopsiebefunden an seine niedergelassenen Mitglieder verschickt. Bei Abschluss der Studie lagen 109 Antworten, davon 106 auswertbare Fragebogen, vor. Die Anzahl positiver Stanzen und der prozentuale Tumoranteil werden hinsichtlich der Tumorausdehnung fur die Risikostratifizierung als relevanteste Angaben angesehen. Bei mp(multiparametrischen)MRT-Fusionsstanzen wird eine separate Angabe zur Anzahl positiver Stanzen innerhalb des Standardschemas und der mpMRT-positiven Foci bevorzugt. Am haufigsten wird die Stanze mit dem hochsten Gleason-Score berucksichtigt, wobei dem prozentualen Gleason-4-Muster auch eine wichtige Bedeutung zukommt. Etwa die Halfte der Befragten wunscht sich auch die Angabe der neuen „grade groups“ nach ISUP/WHO (International Society of Urological Pathology/World Health Organization). Als weitere gewunschte Parameter werden u. a. der Ki67-Proliferationsindex, der PSMA(„prostate-specific membrane antigen“)-Status sowie Angaben zu intraduktalen oder neuroendokrinen Tumorkomponenten aufgefuhrt. Fur die Angaben histopathologischer Parameter im Befundbericht von Prostatastanzbiopsien existiert kein einheitlicher Standard und bei der Interpretation gibt es eine Variabilitat. Weitere Studien und eine klare Aussage seitens der Leitlinien werden notig sein, um ein einheitliches Diagnose‑/Prognoseschema zu etablieren.

Background We sought to provide a description of surge response strategies and characteristics, clinical management and outcomes of patients with severe COVID-19 in the intensive care unit (ICU) during the first wave of the pandemic in Denmark, Finland, Iceland, Norway and Sweden. Methods Representatives from the national ICU registries for each of the five countries provided clinical data and a description of the strategies to allocate ICU resources and increase the ICU capacity during the pandemic. All adult patients admitted to the ICU for COVID-19 disease during the first wave of COVID-19 were included. The clinical characteristics, ICU management and outcomes of individual countries were described with descriptive statistics. Results Most countries more than doubled their ICU capacity during the pandemic. For patients positive for SARS-CoV-2, the ratio of requiring ICU admission for COVID-19 varied substantially (1.6-6.7%). Apart from age (proportion of patients aged 65 years or over between 29-62%), baseline characteristics, chronic comorbidity burden and acute presentations of COVID-19 disease were similar among the five countries. While utilization of invasive mechanical ventilation was high (59-85%) in all countries, the proportion of patients receiving renal replacement therapy (7-26%) and various experimental therapies for COVID-19 disease varied substantially (e.g. use of hydroxychloroquine 0-85%). Crude ICU mortality ranged from 11% to 33%. Conclusion There was substantial variability in the critical care response in Nordic ICUs to the first wave of COVID-19 pandemic, including usage of experimental medications. While ICU mortality was low in all countries, the observed variability warrants further attention.

Background: In the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial, a lower (8 kPa) vs a higher (12 kPa) PaO2 target did not affect mortality amongst critically ill adult patients. We used Bayesian statistics to evaluate any heterogeneity in the effect of oxygenation targets on mortality between different patient groups within the HOT-ICU trial. Methods: We analysed 90-day all-cause mortality using adjusted Bayesian logistic regression models, and assessed heterogeneous treatment effects according to four selected baseline variables using both hierarchical models of subgroups and models with interactions on the continuous scales. Results are presented as mortality probability (%) and relative risk (RR) with 95% credibility intervals (CrI). Results: All 2888 patients in the intention-to-treat cohort of the HOT-ICU trial were included. The adjusted 90-day mortality rates were 43.0% (CrI: 38.3–47.8%) and 42.3% (CrI: 37.7–47.1%) in the lower and higher oxygenation groups, respectively (RR 1.02 [CrI: 0.93–1.11]), with 36.5% probability of an RR

Background: Intensive care unit (ICU) patients receive numerous interventions, but knowledge about potential interactions between these interventions is limited. Co-enrolment in randomized clinical trials represents a unique opportunity to investigate any such interactions. We aim to assess interactions in four randomized clinical trials with overlap in inclusion periods and patient populations. Methods: This protocol and statistical analysis plan describes a secondary explorative analysis of interactions in four international ICU trials on pantoprazole, oxygenations targets, haloperidol and intravenous fluids, respectively. The primary outcome will be 90-day all-cause mortality. The secondary outcome will be days alive and out of hospital in 90 days after randomization. All patients included in the intention-to-treat populations of the four trials will be included. Four co-primary analyses will be conducted, one with each of the included trials as reference using a logistic regression model adjusted for the reference trial's stratification variables and for the co-interventions with interactions terms. The primary analytical measure of interest will be the analyses’ tests of interaction. A p-value below.05 will be considered statically significant. The stratification variable- and co-intervention-adjusted effect estimates will be reported with 95% confidence intervals without adjustments for multiplicity. Conclusion: This exploratory analysis will investigate the presence of any interactions between pantoprazole, oxygenation targets, haloperidol and amount of intravenous fluids in four international ICU trials using co-enrolment. Assessment of possible interactions represents valuable information to guide the design, statistical powering and conduct of future trials.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Two recent randomized controlled trials (Adjunctive Glucocorticoid Therapy in Patients with Septic Shock [ADRENAL] and Activated Protein C and Corticosteroids for Human Septic Shock [APROCCHSS]) of corticosteroids in patients with septic shock reported different treatment effects on 90-day mortality. Both trials enrolled patients who met the criteria for septic shock using the second international consensus definitions for sepsis and septic shock (Sepsis-2), but the APROCCHSS trial mandated a greater severity of shock as an inclusion criterion. Methods The authors conducted post hoc sensitivity analyses of the ADRENAL trial to determine the effects of hydrocortisone versus placebo in subgroups selected using third international consensus definitions for sepsis and septic shock (Sepsis-3) diagnostic criteria or APROCCHSS inclusion criteria. Results There were 1,950 subjects (973 hydrocortisone and 977 placebo) who met the Sepsis-3 criteria (ADRENAL–Sepsis-3 cohort) and 905 patients (455 hydrocortisone and 450 placebo) who met the APROCCHSS criteria (ADRENAL–APROCCHSS cohort). At 90 days after randomization, in the ADRENAL–Sepsis-3 cohort, 312 of 963 (32.4%) and 337 of 958 (35.2%) patients assigned to hydrocortisone and placebo, respectively, had died (odds ratio, 0.86; 95% CI, 0.70 to 1.06; P = 0.166). The corresponding figures for the ADRENAL–APROCCHSS cohorts were 187 of 453 (41.3%) and 200 of 445 (44.9%), respectively (odds ratio, 0.84; 95% CI, 0.60 to 1.17; P = 0.303). There was no statistically significant difference in the time to death between the groups during the 90 days after randomization (hazard ratio = 0.87; 95% CI, 0.75 to 1.02; P = 0.082 for ADRENAL–Sepsis-3; and hazard ratio = 0.86; 95% CI, 0.71 to 1.06; P = 0.156 for ADRENAL–APROCCHSS cohorts). In both cohorts, patients assigned to hydrocortisone had faster resolution of shock. In the ADRENAL–Sepsis-3 cohort, patients assigned to hydrocortisone had an increase in the number of days alive and free of mechanical ventilation (57.0 ± 37.2 vs. 53.7 ± 38.2 days; 95% CI, 0.40 to 7.04; P = 0.028) and the number of days alive and free of the intensive care unit (54.3 ± 36.0 vs. 51.0 ± 37.1; 95% CI, 0.82 to 7.24; P = 0.014). Conclusions In a post hoc analysis of the ADRENAL trial participants who fulfilled either the Sepsis-3 or the APROCCHSS inclusion criteria, a continuous infusion of hydrocortisone did not result in a lower 90-day mortality than placebo in septic shock.

Background: Haloperidol is the most frequently used drug to treat delirium in the critically ill patients. Yet, no systematic review has focussed on the effects of haloperidol in critically ill patients with delirium. Methods: We conducted a systematic review with meta-analysis and Trial Sequential Analysis of randomized clinical trials (RCTs) assessing the effects of haloperidol vs any intervention on all-cause mortality, serious adverse reactions/events, days alive without delirium, health-related quality of life (HRQoL), cognitive function and delirium severity in critically ill patients with delirium. We also report on QTc prolongation, delirium resolution and extrapyramidal symptoms. Results: We included 8 RCTs with 11 comparisons (n = 951). We adjudicated one trial as having overall low risk of bias. Three trials used rescue haloperidol; excluding these, we did not find an effect of haloperidol vs control on all-cause mortality (RR 1.01; 95% CI 0.33-3.06; I2 = 0%; 112 participants; 3 trials; 4 comparisons; very low certainty) or delirium severity (SMD −0.15; 95% CI −0.61-0.30; I2 = 27%; 134 participants; 3 trials; 4 comparisons; very low certainty). No trials reported adequately on serious adverse reactions/events. Only one trial reported on days alive without delirium, cognitive function and QTc prolongation, and no trials reported on HRQoL. Sensitivity analyses, including trials using rescue haloperidol, did not change the results. Conclusions: The evidence for the use of haloperidol to treat critically ill patients with delirium is sparse, of low quality and inconclusive. We therefore have no certainty regarding any beneficial, harmful or neutral effects of haloperidol in these patients.

Background\ud Sepsis poses a global threat to millions of lives. The Surviving Sepsis Campaign (SSC) guidelines provide evidence-based recommendations on the recognition and management of sepsis and its complications.\ud Methods\ud We formed a panel of 60 experts from 22 countries and 11 members of the public. The panel prioritized questions that are relevant to the recognition and management of sepsis and septic shock in adults. New questions and sections were addressed, relative to the previous guidelines. These questions were grouped under 6 subgroups (screening and early treatment, infection, hemodynamics, ventilation, additional therapies, and long-term outcomes and goals of care). With input from the panel and methodologists, professional medical librarians performed the search strategy tailored to either specific questions or a group of relevant questions. A dedicated systematic review team performed screening and data abstraction when indicated. For each question, the methodologists, with input from panel members, summarized the evidence assessed and graded the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The panel generated recommendations using the evidence-to-decision framework. Recommendations were either strong or weak, or in the form of best practice statements. When evidence was insufficient to support a recommendation, the panel was surveyed to generate “in our practice” statements.\ud Results\ud The SSC panel issued 93 statements: 15 best practice statements, 15 strong recommendations, and 54 weak recommendations and no recommendation was provided for 9 questions. The recommendations address several important clinical areas related to screening tools, acute resuscitation strategies, management of fluids and vasoactive agents, antimicrobials and diagnostic tests and the use of additional therapies, ventilation management, goals of care, and post sepsis care.\ud Conclusion\ud The SSC panel issued evidence-based recommendations to help support key stakeholders caring for adults with sepsis or septic shock and their families.

During the current COVID-19 pandemic, health-care workers and uninfected patients in intensive care units (ICUs) are at risk of being infected with SARS-CoV-2 as a result of transmission from infected patients and health-care workers. In the absence of high-quality evidence on the transmission of SARS-CoV-2, clinical practice of infection control and prevention in ICUs varies widely. Using a Delphi process, international experts in intensive care, infectious diseases, and infection control developed consensus statements on infection control for SARS-CoV-2 in an ICU. Consensus was achieved for 31 (94%) of 33 statements, from which 25 clinical practice statements were issued. These statements include guidance on ICU design and engineering, health-care worker safety, visiting policy, personal protective equipment, patients and procedures, disinfection, and sterilisation. Consensus was not reached on optimal return to work criteria for health-care workers who were infected with SARS-CoV-2 or the acceptable disinfection strategy for heat-sensitive instruments used for airway management of patients with SARS-CoV-2 infection. Well designed studies are needed to assess the effects of these practice statements and address the remaining uncertainties.

BACKGROUND: Coronavirus disease (COVID-19) primarily affects the lungs and lower airways and may present as hypoxaemic respiratory failure requiring admission to an intensive care unit (ICU) for supportive treatment. Here, supplemental oxygen remains essential for COVID-19 patient management, but the optimal dosage is not defined. We hypothesize that targeting an arterial partial pressure of oxygen of 8 kPa throughout ICU admission is superior to targeting 12 kPa.METHODS: The Handling Oxygenation Targets in ICU patients with COVID-19 (HOT-COVID) trial, is an investigator-initiated, pragmatic, multicentre, randomized, parallel-group trial comparing a lower oxygenation target versus a higher oxygenation target in adult ICU patients with COVID-19. The primary outcome is days alive without life-support (use of mechanical ventilation, renal replacement therapy or vasoactive therapy) at day 90. Secondary outcomes are 90-day and 1-year mortality, serious adverse events in the ICU and days alive and out of hospital in the 90-day period, health-related quality-of-life at 1 year, and health economic analyses. One-year follow-up of cognitive and pulmonary function is planned in a subgroup of Danish patients. We will include 780 patients to detect or reject an absolute increase in days alive without life-support of 7 days with an α of 5% and a β of 20%. An interim analysis is planned after 90-day follow-up of 390 patients.CONCLUSIONS: The HOT-COVID trial will provide patient-important data on the effect of two oxygenation targets in ICU patients with COVID-19 and hypoxia. This protocol paper describes the background, design and statistical analysis plan for the trial.

Background Recently, antibodies against the alpha isoform of the glial-fibrillary-acidic-protein (GFAPα) were identified in a small series of patients with encephalomyelitis. Coexisting autoantibodies (NMDA receptor, GAD65 antibodies) have been described in a few of these patients. We describe a patient with rapidly progressive encephalomyeloradiculitis and a combination of anti-ITPR1, anti-GFAP and anti-MOG antibodies. Case presentation and literature review A 44-year old caucasian woman with a flu-like prodrome presented with meningism, progressive cerebellar signs and autonomic symptoms, areflexia, quadriplegia and respiratory insufficiency. MRI showed diffuse bilateral T2w-hyperintense brain lesions in the cortex, white matter, the corpus callosum as well as a longitudinal lesion of the medulla oblongata and the entire spinal cord. Anti-ITPR1, anti-GFAP and anti-MOG antibodies were detected in cerebrospinal fluid along with lymphocytic pleocytosis. Borderline tumor of the ovary was diagnosed. Thus, the disease of the patient was deemed to be paraneoplastic. The patient was treated by surgical removal of tumor, steroids, immunoglobulins, plasma exchange and rituximab. Four months after presentation, the patient was still tetraplegic, reacted with mimic expressions to pain or touch and could phonate solitary vowels. An extensive literature research was performed. Conclusion Our case and the literature review illustrate that multiple glial and neuronal autoantibodies can co-occur, that points to a paraneoplastic etiology, above all ovarian teratoma or thymoma. Clinical manifestation can be a mixture of typically associated syndromes, e.g. ataxia associated with anti-ITPR1 antibodies, encephalomyelitis with anti-GFAPα antibodies and longitudinal extensive myelitis with anti-MOG antibodies.

Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC). DLL3 is expressed on the majority of SCLC samples. Because SCLC is rarely biopsied in the course of disease, data regarding DLL3 expression in relapses is not available. The aim of this study was to investigate the expression of DLL3 in chemorelapsed (but untreated with Rova-T) SCLC samples and compare the results with chemonaive counterparts. Two evaluation methods to assess DLL3 expression were explored. Additionally, we assessed if DLL3 expression of chemorelapsed and/or chemonaive samples has prognostic impact and if it correlates with other clinicopathological data. The study included 30 paired SCLC samples, which were stained with an anti DLL3 antibody. DLL3 expression was assessed using tumor proportion score (TPS) and H-score and was categorized as DLL3 low (TPS < 50%, H-score ≤ 150) and DLL3 high (TPS ≥ 50%, H-score > 150). Expression data were correlated with clinicopathological characteristics. Kaplan–Meier curves were used to illustrate overall survival (OS) depending on DLL3 expression in chemonaive and chemorelapsed samples, respectively, and depending on dynamics of expression during course of therapy. DLL3 was expressed in 86.6% chemonaive and 80% chemorelapsed SCLC samples without significant differences between the two groups. However, the extent of expression varied in a substantial proportion of pairs (36.6% with TPS, 43.3% with H-score), defined as a shift from low to high or high to low expression. TPS and H-score provided comparable results. There were no profound correlations with clinicopathological data. Survival analysis revealed a trend toward a more favorable OS in DLL low-expressing chemonaive SCLC (p = 0.57) and, in turn, in DLL3 high-expressing chemorelapsed SCLC (p = 0.42) as well as in SCLC demonstrating a shift from low to high expression (p = 0.56) without being statistically significant. This is the first study to investigate DLL3 expression in a large cohort of rare paired chemonaive-chemorelapsed SCLC specimens. Comparative analysis revealed that DLL3 expression was not stable during the course of therapy, suggesting therapy-based alterations. Unlike in chemonaive samples, a high DLL3 expression in chemorelapsed samples indicated a trend for a more favorable prognosis. Our results highlight the importance to investigate DLL3 in latest chemorelapsed SCLC tumor tissue.