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BACKGROUND: Intensive care unit (ICU) patients with Coronavirus disease 2019 (COVID-19) have an increased risk of thromboembolic complications. We describe the occurrence of thromboembolic and bleeding events in all ICU patients with COVID-19 in Denmark during the first and second waves of the pandemic.METHODS: This was a sub-study of the Danish Intensive Care Covid database, in which all patients with SARS-CoV-2 admitted to Danish ICUs from 10th March 2020 to 30th June 2021 were included. We registered coagulation variables at admission, and all thromboembolic and bleeding events, and the use of heparins during ICU stay. Variables associated with thrombosis and bleeding and any association with 90-day mortality were estimated using Cox regression analyses.RESULTS: We included 1369 patients in this sub-study; 158 (12%, 95% confidence interval 10-13) had a thromboembolic event in ICU and 309 (23%, 20-25) had a bleeding event, among whom 81 patients (6%, 4.8-7.3) had major bleeding. We found that mechanical ventilation and increased D-dimer were associated with thrombosis and mechanical ventilation, low platelet count and presence of haematological malignancy were associated with bleeding. Most patients (76%) received increased doses of thromboprophylaxis during their ICU stay. Thromboembolic events were not associated with mortality in adjusted analysis (hazard ratio 1.35 [0.91-2.01, p = .14], whereas bleeding events were 1.55 [1.18-2.05, p = .002]).CONCLUSIONS: Both thromboembolic and bleeding events frequently occurred in ICU patients with COVID-19. Based on these data, it is not apparent that increased doses of thromboprophylaxis were beneficial.

Thrombocytopenia is a common condition in several populations of hospitalized patients, including those with hematological and solid tumor cancer,1, 2 those with chronic liver disease,3 and critically ill neonates4 and adults,5 and it has been associated with increased rates of bleeding, transfusion requirements, and mortality.6-9 Prophylactic platelet transfusions are often recommended in patients with severe thrombocytopenia, but the supporting evidence is primarily derived from trials in hematological patients10-12 and clinical practice varies considerably.13-15 Prior to prophylactic platelet transfusion, the risk of bleeding and the beneficial effects of transfusion must be viewed in light of the potentially harmful effects, which, although rare, include serious and potentially life-threatening reactions, such as anaphylaxis, transfusion-transmitted infections, and transfusion-related acute lung injury.16 Harm from platelet transfusions has been observed in randomized clinical trials (RCTs) among preterm infants17 and patients with intracerebral hemorrhage.18 Therefore, we aimed to assess the benefits and harms of prophylactic platelet transfusions versus no prophylaxis on patient-important outcomes in hospitalized patients with thrombocytopenia. We hypothesized that the evidence base for non-hematological patients would be sparse and uncertain.

Background Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an emergency procedure that is potentially lifesaving in major noncompressible torso hemorrhage. It may also improve outcome in nontraumatic cardiac arrest. However, the procedure can be technically challenging and requires the immediate presence of a qualified operator. Thus, evidence-based training and assessment of operator skills are essential for successful implementation and patient safety. A prerequisite for this is a valid and reliable assessment tool specific for the procedure. The aim of this study was to develop a tool for assessing procedural competence in REBOA based on best-available knowledge from international experts in the field. Methods We invited international REBOA experts from multiple specialties to participate in an anonymous three-round iterative Delphi study to reach consensus on the design and content of an assessment tool. In round 1, participants suggested items to be included. In rounds 2 and 3, the relevance of each suggested item was evaluated by all participants to reach consensus. Interround data processing was done systematically by a steering group. Results Forty panelists representing both clinical and educational expertise in REBOA from 16 countries (in Europe, Asia, and North and South America) and seven different specialties participated in the study. After 3 Delphi rounds and 532 initial item suggestions, the panelists reached consensus on a 10-item assessment tool with behaviorally anchored rating scales. It includes assessment of teamwork, procedure time, selection and preparation of equipment, puncture technique, guidewire handling, sheath handling, placement of REBOA catheter, occlusion, and evaluation. Conclusion We present the REBOA-RATE assessment tool developed systematically by international experts in the field to optimize content validity. Following further studies of its validity and reliability, this tool represents an important next step in evidence-based training programs in REBOA, for example, using mastery learning. Level of evidence Therapeutic, level V.

Background Despite an increase in our understandings of pathogenesis of thrombotic thrombocytopenic purpura (TTP), the approaches for initial diagnosis and management of TTP vary significantly. Objective The evidence-based guidelines of the International Society on Thrombosis and Haemostasis (ISTH) are intended to support patients, clinicians, and other health care professionals in their decisions about the initial diagnosis and management of acute TTP. Methods In June 2018, ISTH formed a multidisciplinary panel that included hematologists, an intensive care physician, nephrologist, clinical pathologist, biostatistician, and patient representatives, as well as a methodology team from McMaster University. The panel composition was designed to minimize the potential conflicts of interests. The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach and the Population, Intervention, Comparison, Outcome framework to develop and grade their recommendations. Public comments were sought and incorporated in the final document. Results The panel agreed on three recommendations covering the initial diagnosis with emphasis on the importance of ADAMTS13 testing (eg, activity, anti-ADAMTS13 IgG or inhibitor) and assessment of the pretest probability of TTP by clinical assessment and/or the risk assessment models like the PLASMIC or French score. The panel noted how availability and turnaround time of ADAMTS13 test results might affect early diagnosis and management, in particular the use of caplacizumab. Conclusions There is a lack of high-quality evidence to support strong recommendations for the initial diagnosis and management of a suspected TTP. The panel emphasized the importance of obtaining ADAMTS13 testing in a proper clinical context. Future research should focus on how to monitor and act on ADAMTS13 levels during remission.

Background Despite advances in treatment options for thrombotic thrombocytopenic purpura (TTP), there are still limited high quality data to inform clinicians regarding its appropriate treatment. Methods In June 2018, the ISTH formed a multidisciplinary guideline panel to issue recommendations about treatment of TTP. The panel discussed 12 treatment questions related to immune-mediated TTP (iTTP) and hereditary or congenital TTP (cTTP). The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach, including evidence-to-decision frameworks, to appraise evidence and formulate recommendations. Results The panel agreed on 11 recommendations based on evidence ranging from very low to moderate certainty. For first acute episode and relapses of iTTP, the panel made a strong recommendation for adding corticosteroids to therapeutic plasma exchange (TPE) and a conditional recommendation for adding rituximab and caplacizumab. For asymptomatic iTTP with low plasma ADAMTS13 activity, the panel made a conditional recommendation for the use of rituximab outside of pregnancy, but prophylactic TPE during pregnancy. For asymptomatic cTTP, the panel made a strong recommendation for prophylactic plasma infusion during pregnancy, and a conditional recommendation for plasma infusion or a wait and watch approach outside of pregnancy. Conclusions The panel's recommendations are based on all the available evidence for the effects of an individual component of various treatment approaches, including suppressing inflammation, blocking platelet clumping, replacing the missing and/or inhibited ADAMTS13, and suppressing the formation of ADAMTS13 autoantibody. There was insufficient evidence for further comparing different treatment approaches (eg, TPE, corticosteroids, rituximab, and caplacizumab, etc.), for which high quality studies are needed.

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.

BackgroundIt is necessary to train a large number of healthcare workers (HCW) within a limited time to ensure adequate human resources during an epidemic. There remains an urgent need for best practices on development and implementation of training programmes.ObjectiveTo explore published literature in relation to training and education for viral epidemics as well as the effect of these interventions to inform training of HCW.Data sourcesSystematic searches in five databases performed between 1 January 2000 and 24 April 2020 for studies reporting on educational interventions in response to major viral epidemics.Study eligibility criteriaAll studies on educational interventions developed, implemented and evaluated in response to major global viral outbreaks from 2000 to 2020.ParticipantsHealthcare workers.InterventionsEducational or training interventions.Study appraisal and synthesis methodsDescriptive information were extracted and synthesised according to content, competency category, educational methodology, educational effects and level of educational outcome. Quality appraisal was performed using a criterion-based checklist.ResultsA total of 15 676 records were identified and 46 studies were included. Most studies were motivated by the Ebola virus outbreak with doctors and nurses as primary learners. Traditional didactic methods were commonly used to teach theoretical knowledge. Simulation-based training was used mainly for training of technical skills, such as donning and doffing of personal protective equipment. Evaluation of the interventions consisted mostly of surveys on learner satisfaction and confidence or tests of knowledge and skills. Only three studies investigated transfer to the clinical setting or effect on patient outcomes.Conclusions and implications of findingsThe included studies describe important educational experiences from past epidemics with a variety of educational content, design and modes of delivery. High-level educational evidence is limited. Evidence-based and standardised training programmes that are easily adapted locally are recommended in preparation for future outbreaks.

Thrombotic thrombocytopenic purpura (TTP) is fatal in 90% of patients if left untreated and must be diagnosed early to optimize patient outcomes. However, the very low incidence of TTP is an obstacle to the development of evidence-based clinical practice recommendations, and the very wide variability in survival rates across centers may be partly ascribable to differences in management strategies due to insufficient guidance. We therefore developed an expert statement to provide trustworthy guidance about the management of critically ill patients with TTP. As strong evidence was difficult to find in the literature, consensus building among experts could not be reported for most of the items. This expert statement is timely given the recent advances in the treatment of TTP, such as the use of rituximab and of the recently licensed drug caplacizumab, whose benefits will be maximized if the other components of the management strategy follow a standardized pattern. Finally, unanswered questions are identified as topics of future research on TTP.

Background The effects of anemia and red blood cell (RBC) transfusion on markers of clot formation and platelet function in patients with septic shock are unknown. We assessed these effects in a randomized transfusion trial of patients with septic shock. Study design and methods We performed a prospective substudy of the Transfusion Requirements in Septic Shock (TRISS) trial, randomly assigning patients in the intensive care unit with septic shock and hemoglobin concentration of 9.0 g/dL or less to transfusion with one unit of RBCs at a hemoglobin level of 9.0 g/dL or a level of 7.0 g/dL. We assessed thromboelastography (TEG), multiple electrode aggregometry (MEA), platelet count, and international normalized ratio (INR) immediately before and after the first blood transfusion and again 3 hours after. The effects of hemoglobin level were analyzed using multiple linear regression and the association between markers of hemostasis and subsequent bleeding by Cox regression models. Results We included 58 patients in this substudy. We observed no differences in whole blood clot formation, platelet count or function, or INR between patients with hemoglobin levels of 7.0 and 9.0 g/dL, and we found no effect of RBC transfusion on these markers. Platelet function, assessed by MEA, but not whole blood clot formation, was associated with subsequent bleeding. Conclusions In patients with septic shock, the level of anemia and the transfusion of RBCs did not appear to influence clot formation or platelet function. Low platelet function, as evaluated by MEA, was associated with increased risk of subsequent bleeding.

Purpose Point of care ultrasound (POCUS) is widely used, but the sensitivity and specificity of the findings are highly user-dependent. There are many different approaches to ultrasound training. The aim of this study was to explore the effects of hands-on practice when learning POCUS.Methods Junior doctors with no or limited ultrasound experience were included in the study and divided into three groups. They all completed a Focused Assessment with Sonography for Trauma (FAST) course with different amounts of hands-on practice: 40 minutes (n=67), 60 minutes (n=12), and 90 minutes of hands-on time (n=27). By the end of the course, they all completed a previously validated test.Results More hands-on time improved the mean test scores and decreased the test time. The scores of the 40-, 60-, and 90-minute groups were 11.6 (SD 2.1), 12.8 (SD 2.5), and 13.7 (SD 2.5), respectively (pConclusion The necessary amount of hands-on training is unknown. This study demonstrates that performance increases with prolonged hands-on time but the inter-individual variation among trainees is very large, thereby making it impossible to define the “optimal” time. This supports the use of the concept of mastery learning where each individual trainee can continue training until proficiency is reached.

Background Due to an expected surge of COVID-19 patients in need of mechanical ventilation, the intensive care capacity was doubled at Rigshospitalet, Copenhagen, in March 2020. This resulted in an urgent need for doctors with competence in working with critically ill COVID-19 patients. A training course and a theoretical test for non-intensivist doctors were developed. The aims of this study were to gather validity evidence for the theoretical test and explore the effects of the course. Methods The one-day course was comprised of theoretical sessions and hands-on training in ventilator use, haemodynamic monitoring, vascular access and use of personal protective equipment. Validity evidence was gathered for the test by comparing answers from novices and experts in intensive care. Doctors who participated in the course completed the test before (pre-test), after (post-test) and again within eight weeks following the course (retention-test). Results Fifty-four non-intensivist doctors from 15 different specialties with a wide range in clinical experience level completed the course. The test consisted of 23 questions and demonstrated a credible pass-fail standard at 16 points. Mean pre-test score was 11.9 (SD 3.0), mean post-test score 20.6 (1.8) and mean retention-test score 17.4 (2.2). All doctors passed the post-test. Conclusion Non-intensivist doctors, irrespective of experience level, can acquire relevant knowledge for working in the ICU through a focused one-day evidence-based course. This knowledge was largely retained as shown by a multiple-choice test supported by validity evidence. The test is available in appendix and online.

Objective To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients. Methods We conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related. Results From April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated. Conclusion CNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes suggested autoimmune-mediated mechanisms.

BACKGROUND In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID-19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low-dose hydrocortisone on patient-centred outcomes in adults with COVID-19 and severe hypoxia. METHODS In this multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10��L/min) to either hydrocortisone (200��mg/d) vs a matching placebo for 7��days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. RESULTS The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: -1.1��days, 95% CI -9.5 to 7.3, P��=��.79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. CONCLUSIONS In this trial of adults with COVID-19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. TRIAL REGISTRATION ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020-001395-15.

ObjectiveTo identify theoretical and technical aspects regarding treatment, prevention of spread and protection of staff to inform the development of a comprehensive training curriculum on COVID-19 management.DesignCross-sectional study.SettingNine hospitals caring for patients with COVID-19 in Wuhan, China.Participants134 Chinese healthcare professionals (74 doctors and 60 nurses) who were deployed to Wuhan, China during the COVID-19 epidemic were included. A two-round Delphi process was initiated between March and May 2020. In the first round, the participants identified knowledge, technical and behavioural (ie, non-technical) skills that are needed to treat patients, prevent spread of the virus and protect healthcare workers. In round 2, the participants rated each item according to its importance to be included in a training curriculum on COVID-19. Consensus for inclusion in the final list was set at 80%.Primary outcome measuresKnowledge, technical and behavioural (ie, non-technical) skills that could form the basis of a training curriculum for COVID-19 management.ResultsIn the first round 1398 items were suggested by the doctors and reduced to 67 items after content analysis (treatment of patients: n=47; infection prevention and control: n=20). The nurses suggested 1193 items that were reduced to 70 items (treatment of patients: n=49; infection prevention and control: n=21). In round 2, the response rates were 82% in doctors and 93% in nurses. Fifty-eight items of knowledge, technical and behavioural skills were agreed on by the doctors to include in the final list. For the nurses, 58 items were agreed on.ConclusionsThis needs assessment process resulted in a comprehensive list of knowledge, technical and behavioural skills for COVID-19 management. Educators can use these to guide decisions regarding content of training curricula not only for COVID-19 management but also in preparation for future viral pandemic outbreaks.

Purpose Resuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged as a salvage technique changing the paradigm in the management of noncompressible torso hemorrhage. However, training for the REBOA procedure is rarely performed. The endovascular training for REBOA (ET-REBOA) course was conducted to develop the endovascular skills of participants. Methods Sixteen residents and 12 specialists participated in this educational course. All participants were provided with precourse learning materials. The ET-REBOA course consisted of 2 sections; an ultrasound-guided sheath insertion on the puncture model, and a balloon manipulation on the vascular circuit model. A 13-item procedure checklist and the time required to perform the procedure were examined. Pre/post self-reported confidence score and course satisfaction questionnaire were obtained. Results Twenty-eight participants performed the 56 REBOA procedures. On the first attempt, the median total time for REBOA from ultrasound-guided vascular access to balloon inflation was 1,139 ± 250 seconds in the resident group and 828 ± 280 seconds in the specialist group. The median shortened time for completion was 273 seconds and 290 seconds respectively. A significant decrease in procedure task time was observed between first and second attempts in the resident group (P = 0.016), specialist group (P = 0.004), and in total among all participants (P < 0.001). Conclusion The ET-REBOA course significantly decreased the time taken to perform the REBOA procedure with high satisfaction of the participants. The course could be an effective curriculum for the development of endovascular skills for performing REBOA.

Background Despite advances in treatment options for thrombotic thrombocytopenic purpura (TTP), there are still limited high quality data to inform clinicians regarding its management. Methods In June 2018, the ISTH formed a multidisciplinary guideline panel to issue recommendations about treatment of TTP. The panel discussed 12 treatment questions related to both immune-mediated TTP (iTTP) and hereditary/congenital TTP (cTTP). The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including evidence-to-decision frameworks, to appraise evidence and formulate recommendations. Results The panel agreed on eleven recommendations based on evidence ranging from very low to moderate certainty. For first episode and relapses of acute iTTP, the panel made a strong recommendation for the addition of corticosteroids to therapeutic plasma exchange (TPE), and a conditional recommendation for addition of rituximab and caplacizumab. For asymptomatic iTTP with low ADAMTS13, the panel made a conditional recommendation for rituximab outside of pregnancy, and for prophylactic TPE during pregnancy. For asymptomatic cTTP, the panel made a strong recommendation for prophylactic plasma infusion during pregnancy, but a conditional recommendation for plasma infusion or a wait and watch approach outside of pregnancy. Conclusions The panel's recommendations are based on all the available evidence for the treatment effects of various approaches including suppressing inflammation, blocking platelet clumping, replacing the missing and/or inhibited ADAMTS13, and suppressing ADAMTS13 antibody production. There was insufficient evidence for further comparison of different treatment approaches, for which future high-quality studies in iTTP (e.g., rituximab, corticosteroids, recombinant ADAMTS13, and caplacizumab) and in cTTP (eg, recombinant ADAMTS13) are needed.

INTRODUCTION Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists. METHODS The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals. DISCUSSION The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.

BACKGROUND In patients with septic shock mortality is high, and survivors experience long-term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive versus (vs) standard-care intravenous (IV) fluid therapy. The hypothesis is that IV fluid restriction improves patient-important long-term outcomes. AIM To assess the predefined patient-important long-term outcomes in patients randomised into the CLASSIC trial. METHODS In this pre-planned follow-up study of the CLASSIC trial, we will assess all-cause mortality, Health-Related Quality of Life (HRQoL) and cognitive function one year after randomisation in the two intervention groups. The 1-year mortality will be collected from electronic patient records or central national registries in most participating countries. We will contact survivors and assess EuroQol 5-Dimension, -5-Level (EQ-5D-5L) and EuroQol-Visual Analogue Scale and Montreal Cognitive Assessment 5-minute protocol score. We will analyse mortality by logistic regression and use general linear models to assess HRQoL and cognitive function. DISCUSSION With this pre-planned follow-up study of the CLASSIC trial, we will provide patient-important data on long-term survival, HRQoL and cognitive function of restrictive vs standard-care IV fluid therapy in patients with septic shock.

Background The routine use of empiric combination therapy with aminoglycosides during critical illness is associated with uncertain benefit and increased risk of acute kidney injury. This study aimed to assess the benefits of aminoglycosides in immunocompromised patients with suspected bacterial pneumonia and sepsis. Methods Secondary analysis of a prospective multicenter study. Adult immunocompromised patients with suspected bacterial pneumonia and sepsis or septic shock were included. Primary outcome was hospital mortality. Secondary outcomes were needed for renal replacement therapy (RRT). Mortality was also assessed in neutropenic patients and in those with confirmed bacterial pneumonia. Results were further analyzed in a cohort matched on risk of receiving aminoglycosides combination. Results Five hundred thirty-five patients were included in this analysis, of whom 187 (35%) received aminoglycosides in addition to another antibiotic effective against gram-negative bacteria. Overall hospital mortality was 59.6% (58.3% vs. 60.3% in patients receiving and not receiving combination therapy; P = 0.71). Lack of association between mortality and aminoglycosides was confirmed after adjustment for confounders and center effect (adjusted OR 1.14 [0.69-1.89]) and in a propensity matched cohort (adjusted OR = 0.89 [0.49-1.61]). No association was found between aminoglycosides and need for RRT (adjusted OR = 0.83 [0.49-1.39], P = 0.477), nor between aminoglycoside use and outcome in neutropenic patients or in patients with confirmed bacterial pneumonia (adjusted OR 0.66 [0.23-1.85] and 1.25 [0.61-2.57], respectively). Conclusion Aminoglycoside combination therapy was not associated with hospital mortality or need for renal replacement therapy in immunocompromised patients with pulmonary sepsis.

BackgroundThrombocytopenia is a common condition in hospitalised critically ill children and most platelet transfusions are given as prophylaxis to non-bleeding children prior to invasive procedures such as central venous catheterisation and lumbar puncture. Platelet transfusion may reduce bleeding complications but have also been associated with potential adverse effects and variation in clinical practice exist. To direct future research, we aim to assess the current evidence regarding prophylactic platelet transfusion prior to procedures in hospitalised thrombocytopenic children. MethodsWe will conduct a scoping review of all study designs in accordance with the Preferred Reporting Items for Systematic and Meta‐Analyses (PRISMA) statement. We will include studies on hospitalised children undergoing invasive procedures where the prevalence of thrombocytopenia and the predefined outcome measures, including bleeding, transfusion related adverse events and use of blood products and life support are reported. We will provide descriptive analyses of the included studies/trials and the quality of evidence will be assessed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. ConclusionThe outlined scoping review will provide an overview on the benefits and harms of prophylactic platelet transfusion prior to invasive procedures in thrombocytopenic hospitalised children.

Background Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a potentially life-saving but high-risk emergency procedure in patients with haemorrhagic shock. Lack of physicians with competence in the procedure is a barrier to implementation of REBOA. It is currently unclear how training and assessment of competence should be done. Objectives To report and evaluate research in training and assessment of competence in REBOA and femoral arterial access with the aim to investigate the effect of simulation-based training in the procedure and to provide suggestions for the future design of training programs and assessment tools. Methods Following PRISMA guidelines, PubMed, Embase, and Cochrane Library databases were searched for studies on training or assessment of competence in REBOA and femoral arterial access. Bias assessment was done using the Medical Education Research Study Quality Instrument. Evidence level was assessed using GRADE. Results Sixteen studies were included, six of them published as abstracts. Full-text studies included 189 trainees ranging in experience level from military medics to surgical specialists. Outcome measures were heterogenous; the most used were rater checklists, knowledge testing, and procedure time. All studies confirmed an effect of training of REBOA on procedural competence in a simulation setting but had a high degree of bias. No study developed or used an assessment tool supported by validity evidence and no study investigated mid and long-term outcomes. Conclusion Simulation-based training of REBOA improves skills, however, the evidence level is very low and data cannot answer important questions on effect size, skill transfer and retention, and optimal course design. To advance research and training programmes, an assessment tool supported by validity evidence with broad applicability is needed.

PURPOSE The aim of this study was to develop and gather validity evidence for a standardised test of competence in Focused Assessment with Sonography for Trauma (FAST) and to define the appropriate cut-off point in simulation-based learning of the FAST protocol. METHODS A 20-item simulation-based test for assessing competence in FAST was created. The test was administered to thirteen novices and twelve radiologists experienced in abdominal ultrasound diagnostics. The Contrasting Groups' method was used to establish a credible passing score. RESULTS The internal consistency was high (Cronbach's α = 0.90) and the test had good discriminatory ability (P

Background Patients with malignant haematological disease and especially those who require intensive care have an increased risk of bleeding and thrombosis, but none of these data were obtained in ICU patients only. We assessed the incidence of bleeding and thrombotic complications, use of blood products and risk factors for bleeding in an adult population of ICU patients with haematological malignancies. Methods We screened all patients with acute leukaemia and myelodysplastic syndrome admitted to a university hospital ICU during 2008–2012. Bleeding in ICU was scored according to the WHO grading system, and risk factors were evaluated using unadjusted and adjusted analyses. Results In total, 116 of 129 ICU patients were included; their median length of stay was 7 (IQR 2–16) days. Of these, 66 patients (57%) had at least one bleeding episode in ICU; they bled for 3 (2–6) days and most often from lower and upper airways and upper GI tract. Thirty-nine (59%) of the 66 patients had severe or debilitating (WHO grade 3 or 4) bleeding. The median platelet count on the day of grade 3 or 4 bleeding was 23 × 109 per litre (IQR 13–39). Nine patients (8%) died in ICU following a bleeding episode; five of these had intra-cerebral haemorrhage. Platelet count on admission was associated with subsequent bleeding (adjusted odds ratio 1.18 (95% CI 1.03–1.35) for every 10 × 109 per litre drop in platelet count, p = 0.016). Eleven of the 116 patients (9%) developed a clinically significant thrombosis in ICU, which was the cause of death in four patients. The median platelet count was 20 × 109 per litre (15–48) at the time of thrombosis. The patients received a median of 6 units of red blood cells, 1 unit of fresh frozen plasma and 8 units of platelet concentrates in ICU. Conclusions Severe and debilitating bleeding complications were frequent in our ICU patients with haematological malignancies, but thrombosis also occurred in spite of low platelet counts. Platelet count on ICU admission was associated with subsequent bleeding. Electronic supplementary material The online version of this article (10.1186/s13613-017-0341-y) contains supplementary material, which is available to authorized users.

Purpose We assessed the value of standard biochemical coagulation parameters in predicting bleeding, thrombosis and mortality in adult Intensive Care Unit (ICU) patients with haematological malignancies. Methods We screened all patients with acute leukaemia and myelodysplastic syndrome admitted to a university hospital ICU during 2008-2012. Data were obtained from the clinical chemistry laboratory database and patient files. We graded bleeding according to the World Health Organisation (WHO)-system within 24-h, within 5-days and during the whole ICU stay. We analysed the predictive values of laboratory parameters using multiple logistic regression and receiver operator characteristics (ROC) curves. As we previously have established that platelet count at admission was associated with bleeding, we focused on International Normalised Ratio (INR), activated pro-thrombin time (APTT), anti-thrombin, D-dimer and fibrinogen, and markers of infection (C-reactive protein, pro-calcitonin), kidney function (creatinine) and tissue damage (lactate dehydrogenase (LDH)). Results We included 116 patients; 66 (57%) had at least one bleeding episode and 11 (9%) patients had at least one thrombotic event. The differences in coagulation values when bleeding compared to baseline values were minor. INR was the only variable we found associated with subsequent bleeding within 24 h from admission to ICU (odds ratio 2.91, 95% CI: 1.01-8.43, P = 0.048). ROC analyses did not show predictive value of any of the other variables with regards to bleeding and none of the variables were associated with thrombosis in adjusted analyses. Increased levels of LDH at admission were associated with increased 7-day and 30-day mortality. Conclusions Increased INR at admission was associated with a higher rate of bleeding in ICU patients with haematological malignancies. No other biochemical coagulation or other parameter had any association with bleeding, thrombosis or mortality except increased LDH, which at ICU admission was associated with increased 30-day mortality.

The original version of this article unfortunately contained a mistake. The penultimate row of Table 4 shows INR > 1.5 which is incorrect. The correct figure is INR

INTRODUCTION: Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the Conservative versus Liberal Approach to fluid therapy of Septic Shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock.METHODS: CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analyst-blinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events, serious adverse reactions, days alive at day 90 without life support, days alive and out of hospital at day 90, and mortality, health-related quality of life, and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat population.DISCUSSION: The CLASSIC trial results will provide important evidence to guide clinicians' choice regarding IV fluid therapy in adults with septic shock. This article is protected by copyright. All rights reserved.

Background: Anaesthesiologists are expected to master an increasing number of technical procedures. Simulation-based procedural training can supplement and, in some areas, replace the classical apprenticeship approach during patient care. However, simulation-based training is very resource-intensive and must be prioritised and optimised. Developing a curriculum for simulation-based procedural training should follow a systematic approach, eg the Six-Step Approach developed by Kern. The aim of this study was to conduct a national general needs assessment to identify and prioritise technical procedures for simulation-based training in anaesthesiology. Methods: A three-round Delphi process was completed with anaesthesiology key opinion leaders. In the first round, the participants suggested technical procedures relevant to simulation-based training. In the second round, a needs assessment formula was used to explore the procedures and produce a preliminary prioritised list. In the third round, participants evaluated the preliminary list by eliminating and re-prioritising the procedures. Results: All teaching departments in Denmark were represented with high response rates in all three rounds: 79%, 77%, and 75%, respectively. The Delphi process produced a prioritised list of 30 procedure groups suitable for simulation-based training from the initial 138 suggestions. Top-5 on the final list was cardiopulmonary resuscitation, direct- and video laryngoscopy, defibrillation, emergency cricothyrotomy, and fibreoptic intubation. The needs assessment formula predicted the final prioritisation to a great extent. Conclusion: The Delphi process produced a prioritised list of 30 procedure groups that could serve as a guide in future curriculum development for the simulation-based training of technical procedures in anaesthesiology.

ICU patients with haematological malignancy have an increased risk of bleeding. Recently, global haemostatic methods such as thromboelastography (TEG) have gained impact in evaluating coagulation. The aim of this study was to observe whether TEG could predict bleeding in haematological ICU patients with severe sepsis. Post-hoc single-centre analysis of patients with haematological malignancy included in the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial. Clinical characteristics, TEG measurements and details regarding bleeding complications were retrieved from the 6S database. The association between TEG and bleeding were analysed by Cox regression and receiver operating characteristic curves. A total of 202 patients with severe sepsis were admitted to the ICU of Rigshospitalet, Copenhagen and included in the 6S trial. Forty-one had haematological malignancy and were analysed in the current study. During ICU stay, 20 patients (49%) had bleeding complications and 13 (32%) patients bled within the first 5 ICU days. We observed no associations between TEG and subsequent bleeding in Cox regression models. TEG variables at baseline had low predictive value for bleeding. Baseline TEG variables did not add value in identifying patients with high risk of bleeding in ICU patients with haematological malignancy and severe sepsis.

Background Thrombocytopenia is a common condition in critically ill patients in the intensive care unit (ICU). It is associated with prolonged stay in the ICU, increased transfusion requirements, risk of bleeding and mortality. The evidence regarding the use of prophylactic platelet transfusion and thrombosis prophylaxis in patients with thrombocytopenia in the ICU is unknown. To direct future research, we aim to assess the current evidence regarding prophylactic platelet transfusion and thrombosis prophylaxis on patient-important benefits and harms in the ICU population. Methods We will conduct a topical systematic review of all study designs (ie no study design will per se be excluded from the proposed review) in accordance with the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) statements. We will include studies on adult patients in the ICU where the incidence of thrombocytopenia and the predefined outcome measures, including mortality, quality-of-life, thrombotic events and haemorrhagic events are reported. We will provide descriptive analyses of the included studies/trials, ie no meta-analyses will be conducted, and the quality of evidence will be assessed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Conclusion The outlined topical systematic review will provide important data on the benefits and harms of prophylactic platelet transfusion and thrombosis prophylaxis in ICU patients with thrombocytopenia and provide estimates on the rate of thrombocytopenia in this vulnerable population.

The effects of anemia and red blood cell (RBC) transfusion on markers of clot formation and platelet function in patients with septic shock are unknown. We assessed these effects in a randomized transfusion trial of patients with septic shock.We performed a prospective substudy of the Transfusion Requirements in Septic Shock (TRISS) trial, randomly assigning patients in the intensive care unit with septic shock and hemoglobin concentration of 9.0 g/dL or less to transfusion with one unit of RBCs at a hemoglobin level of 9.0 g/dL or a level of 7.0 g/dL. We assessed thromboelastography (TEG), multiple electrode aggregometry (MEA), platelet count, and international normalized ratio (INR) immediately before and after the first blood transfusion and again 3 hours after. The effects of hemoglobin level were analyzed using multiple linear regression and the association between markers of hemostasis and subsequent bleeding by Cox regression models.We included 58 patients in this substudy. We observed no differences in whole blood clot formation, platelet count or function, or INR between patients with hemoglobin levels of 7.0 and 9.0 g/dL, and we found no effect of RBC transfusion on these markers. Platelet function, assessed by MEA, but not whole blood clot formation, was associated with subsequent bleeding.In patients with septic shock, the level of anemia and the transfusion of RBCs did not appear to influence clot formation or platelet function. Low platelet function, as evaluated by MEA, was associated with increased risk of subsequent bleeding.

BACKGROUND: Blood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established.METHODS: In this multicenter, parallel-group trial, we randomly assigned patients in the intensive care unit (ICU) who had septic shock and a hemoglobin concentration of 9 g per deciliter or less to receive 1 unit of leukoreduced red cells when the hemoglobin level was 7 g per deciliter or less (lower threshold) or when the level was 9 g per deciliter or less (higher threshold) during the ICU stay. The primary outcome measure was death by 90 days after randomization.RESULTS: We analyzed data from 998 of 1005 patients (99.3%) who underwent randomization. The two intervention groups had similar baseline characteristics. In the ICU, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0 to 3) and the higher-threshold group received a median of 4 units (interquartile range, 2 to 7). At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P=0.44). The results were similar in analyses adjusted for risk factors at baseline and in analyses of the per-protocol populations. The numbers of patients who had ischemic events, who had severe adverse reactions, and who required life support were similar in the two intervention groups.CONCLUSIONS: Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions. (Funded by the Danish Strategic Research Council and others; TRISS ClinicalTrials.gov number, NCT01485315.).

Flexible fibreoptic intubation (FOI) is a key element in difficult airway management. Training of FOI skills is an important part of the anaesthesiology curriculum. Simulation-based training has been shown to be effective when learning FOI, but the optimal structure of the training is debated. The aspect of dividing the training into segments (part-task training) or assembling into one piece (whole-task training) has not been studied.The aims of this study were to compare the effect of training the motor skills of FOI as part-task training or as whole-task training and to relate the performance levels achieved by the novices to the standard of performance of experienced FOI practitioners.A randomised controlled study.Centre for Clinical Education, University of Copenhagen and the Capital Region of Denmark, between January and April 2013.Twenty-three anaesthesia residents in their first year of training in anaesthesiology with no experience in FOI, and 10 anaesthesia consultants experienced in FOI.The novices to FOI were allocated randomly to receive either part-task or whole-task training of FOI on virtual reality simulators. Procedures were subsequently trained on a manikin and assessed by an experienced anaesthesiologist. The experienced group was assessed in the same manner with no prior simulation-based training.The primary outcome measure was the score of performance on testing FOI skills on a manikin.A positive learning effect was observed in both the part-task training group and the whole-task training group. There was no statistically significant difference in final performance scores of the two novice groups (P = 0.61). Furthermore, both groups of novices were able to improve their skill level significantly by the end of manikin training to levels comparable to the experienced anaesthesiologists.Part-task training did not prove more effective than whole-task training when training novices in FOI skills. FOI is very suitable for simulation-based training and segmentation of the procedure during training is not necessary.

Background Anthrax had become extremely rare in Europe, but in 2010 an outbreak of anthrax among heroin users in Scotland increased awareness of contaminated heroin as a source of anthrax. We present the first two Danish cases of injectional anthrax and discuss the clinical presentations, which included both typical and more unusual manifestations. Case presentations The first patient, a 55-year old man with HIV and hepatitis C virus co-infection, presented with severe pain in the right thigh and lower abdomen after injecting heroin into the right groin. Computed tomography and ultrasonographic examination of the abdomen and right thigh showed oedematous thickened peritoneum, distended oedematous mesentery and subcutaneous oedema of the right thigh. At admission the patient was afebrile but within 24 hours he progressed to severe septic shock and abdominal compartment syndrome. Cultures of blood and intraperitoneal fluid grew Bacillus anthracis. The patient was treated with meropenem, clindamycin, ciprofloxacin and metronidazole. Despite maximum supportive care including mechanical ventilation, vasopressor treatment and continuous veno-venous hemodiafiltration the patient died on day four. The second patient, a 39-year old man with chronic hepatitis C virus infection, presented with fever and a swollen right arm after injecting heroin into his right arm. The arm was swollen from the axilla to the wrist with tense and discoloured skin. He was initially septic with low blood pressure but responded to crystalloids. During the first week, swelling progressed and the patient developed massive generalised oedema with a weight gain of 40 kg. When blood cultures grew Bacillus anthracis antibiotic treatment was changed to meropenem, moxifloxacin and metronidazole, and on day 7 hydroxycloroquin was added. The patient responded to treatment and was discharged after 29 days. Conclusions These two heroin-associated anthrax cases from Denmark corroborate that heroin contaminated with anthrax spores may be a continuous source of injectional anthrax across Europe. Clinicians and clinical microbiologists need to stay vigilant and suspect anthrax in patients with a history of heroin use who present with soft tissue or generalised infection. Marked swelling of affected soft tissue or unusual intra-abdominal oedema should strengthen clinical suspicion.