Restriction of Intravenous Fluid in ICU Patients with Septic Shock.

BACKGROUND: Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU). METHODS: In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization. RESULTS: We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], -4.7 to 4.9; P = 0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, -1.7 percentage points; 99% CI, -7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups. CONCLUSIONS: Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, NCT03668236.).

Platelet transfusions in adult thrombocytopenic ICU patients: Protocol for a sub-study of the PLOT-ICU cohort.

INTRODUCTION: Platelet transfusions are frequently used in intensive care unit (ICU) patients, but contemporary epidemiological data are sparse. We aim to present contemporary international data on the use of platelet transfusions in adult ICU patients with thrombocytopenia. METHODS: This is a protocol and statistical analysis plan for a post hoc sub-study of 504 thrombocytopenic patients from the 'Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU)'. The primary outcome will be the number of patients receiving platelet transfusion in the ICU reported according to the type of product received (apheresis-derived versus pooled whole-blood-derived transfusions). Secondary platelet transfusion outcomes will include platelet transfusion volumes; timing of platelet transfusion; approach to platelet transfusion dosing (fixed dosing versus weight-based dosing) and platelet count increments for prophylactic transfusions. Secondary clinical outcomes will include the number of patients receiving red blood cell- and plasma transfusions during ICU stay; the number of patients who bled in the ICU, the number of patients who had a new thrombosis in the ICU, and the number of patients who died. The duration of follow-up was 90 days. Baseline characteristics and secondary clinical outcomes will be stratified according to platelet transfusion status in the ICU and severity of thrombocytopenia. Data will be presented descriptively. CONCLUSIONS: The outlined study will provide detailed epidemiological data on the use of platelet transfusions in adult ICU patients with thrombocytopenia using data from the large international PLOT-ICU cohort study. The findings will inform the design of future randomised trials evaluating platelet transfusions in ICU patients.

Platelet transfusions in adult ICU patients with thrombocytopenia: A sub-study of the PLOT-ICU inception cohort study.

BACKGROUND: Platelet transfusions are frequently used in the intensive care unit (ICU), but current practices including used product types, volumes, doses and effects are unknown. STUDY DESIGN AND METHODS: Sub-study of the inception cohort study 'Thrombocytopenia and Platelet Transfusions in the ICU (PLOT-ICU)', including acutely admitted, adult ICU patients with thrombocytopenia (platelet count <150 × 109/L). The primary outcome was the number of patients receiving platelet transfusion in ICU by product type. Secondary outcomes included platelet transfusion details, platelet increments, bleeding, other transfusions and mortality. RESULTS: Amongst 504 patients with thrombocytopenia from 43 hospitals in 10 countries in Europe and the United States, 20.8% received 565 platelet transfusions; 61.0% received pooled products, 21.9% received apheresis products and 17.1% received both with a median of 2 (interquartile range 1-4) days from admission to first transfusion. The median volume per transfusion was 253 mL (180-308 mL) and pooled products accounted for 59.1% of transfusions, however, this varied across countries. Most centres (73.8%) used fixed dosing (medians ranging from 2.0 to 3.5 × 1011 platelets/transfusion) whilst some (mainly in France) used weight-based dosing (ranging from 0.5 to 0.7 × 1011 platelets per 10 kg body weight). The median platelet count increment for a single prophylactic platelet transfusion was 2 (-1 to 8) × 109/L. Outcomes of patients with thrombocytopenia who did and did not receive platelet transfusions varied. CONCLUSIONS: Among acutely admitted, adult ICU patients with thrombocytopenia, 20.8% received platelet transfusions in ICU of whom most received pooled products, but considerable variation was observed in product type, volumes and doses across countries. Prophylactic platelet transfusions were associated with limited increases in platelet counts.

Thromboembolic and bleeding events in ICU patients with COVID-19: A nationwide, observational study.

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.

Red Blood Cell Transfusion in the Intensive Care Unit.

Importance: Red blood cell (RBC) transfusion is common among patients admitted to the intensive care unit (ICU). Despite multiple randomized clinical trials of hemoglobin (Hb) thresholds for transfusion, little is known about how these thresholds are incorporated into current practice. Objective: To evaluate and describe ICU RBC transfusion practices worldwide. Design, Setting, and Participants: International, prospective, cohort study that involved 3643 adult patients from 233 ICUs in 30 countries on 6 continents from March 2019 to October 2022 with data collection in prespecified weeks. Exposure: ICU stay. Main Outcomes and Measures: The primary outcome was the occurrence of RBC transfusion during ICU stay. Additional outcomes included the indication(s) for RBC transfusion (consisting of clinical reasons and physiological triggers), the stated Hb threshold and actual measured Hb values before and after an RBC transfusion, and the number of units transfused. Results: Among 3908 potentially eligible patients, 3643 were included across 233 ICUs (median of 11 patients per ICU [IQR, 5-20]) in 30 countries on 6 continents. Among the participants, the mean (SD) age was 61 (16) years, 62% were male (2267/3643), and the median Sequential Organ Failure Assessment score was 3.2 (IQR, 1.5-6.0). A total of 894 patients (25%) received 1 or more RBC transfusions during their ICU stay, with a median total of 2 units per patient (IQR, 1-4). The proportion of patients who received a transfusion ranged from 0% to 100% across centers, from 0% to 80% across countries, and from 19% to 45% across continents. Among the patients who received a transfusion, a total of 1727 RBC transfusions were administered, wherein the most common clinical indications were low Hb value (n = 1412 [81.8%]; mean [SD] lowest Hb before transfusion, 7.4 [1.2] g/dL), active bleeding (n = 479; 27.7%), and hemodynamic instability (n = 406 [23.5%]). Among the events with a stated physiological trigger, the most frequently stated triggers were hypotension (n = 728 [42.2%]), tachycardia (n = 474 [27.4%]), and increased lactate levels (n = 308 [17.8%]). The median lowest Hb level on days with an RBC transfusion ranged from 5.2 g/dL to 13.1 g/dL across centers, from 5.3 g/dL to 9.1 g/dL across countries, and from 7.2 g/dL to 8.7 g/dL across continents. Approximately 84% of ICUs administered transfusions to patients at a median Hb level greater than 7 g/dL. Conclusions and Relevance: RBC transfusion was common in patients admitted to ICUs worldwide between 2019 and 2022, with high variability across centers in transfusion practices.

Platelet transfusions and thrombocytopenia in intensive care units: Protocol for an international inception cohort study (PLOT-ICU).

INTRODUCTION: Thrombocytopenia is frequent in intensive care unit (ICU) patients and has been associated with worse outcome. Platelet transfusions are often used in the management of ICU patients with severe thrombocytopenia. However, the reported frequencies of thrombocytopenia and platelet transfusion practices in the ICU vary considerably. Therefore, we aim to provide contemporary epidemiological data on thrombocytopenia and platelet transfusion practices in the ICU. METHODS: We will conduct an international inception cohort, including at least 1000 acutely admitted adult ICU patients. Routinely available data will be collected at baseline (ICU admission), and daily during ICU stay up to a maximum of 90 days. The primary outcome will be the number of patients with thrombocytopenia (a recorded platelet count < 150 × 109 /L) at baseline and/or during ICU stay. Secondary outcomes include mortality, days alive and out of hospital, days alive without life-support, the number of patients with at least one bleeding episode, at least one thromboembolic event and at least one platelet transfusion in the ICU, the number of platelet transfusions and the indications for transfusion. The primary and secondary outcomes will be presented descriptively. In addition, we will assess risk factors for developing thrombocytopenia during ICU stay and the association between thrombocytopenia at baseline and 90-day mortality using logistic regression analyses. CONCLUSION: The outlined international PLOT-ICU cohort study will provide contemporary epidemiological data on the burden and clinical significance of thrombocytopenia in adult ICU patients and describe the current platelet transfusion practice.

Pre-procedural platelet transfusion thresholds in hospitalised children - Protocol for a scoping review.

BACKGROUND: Thrombocytopenia 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. METHODS: We 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. CONCLUSION: The outlined scoping review will provide an overview on the benefits and harms of prophylactic platelet transfusion prior to invasive procedures in thrombocytopenic hospitalised children.

Thrombocytopenia in intensive care unit patients: A scoping review.

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.

Prophylactic platelet transfusions in hospitalised patients with thrombocytopenia-Protocol for a systematic review with meta-analysis.

BACKGROUND: Prophylactic platelet transfusions are frequently used to prevent bleeding in hospitalised patients with thrombocytopenia. Recommendations regarding the use of prophylactic platelet transfusions in non-haematological patients are based on extrapolations, observational studies, and expert opinions, and transfusion with platelets has been associated with adverse effects. We aim to assess the overall benefits and harms of prophylactic platelet transfusions in hospitalised patients with thrombocytopenia. METHODS/DESIGN: We will conduct a systematic review with meta-analyses and trial sequential analyses in compliance with the recommendations by the Cochrane Collaboration and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We will prepare the manuscript in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. We will include randomised clinical trials assessing prophylactic platelet transfusion versus no prophylaxis or placebo in hospitalised patients with thrombocytopenia. The primary outcome is mortality at longest follow-up. Secondary outcomes include episodes of clinically important bleeding, nosocomial infections, transfusion-related adverse events, thromboembolic events, length of hospital stay, quality of life, and days alive without the use of life support. We will conduct prespecified subgroup analyses and sensitivity analyses and assess the risk of random errors by trial sequential analyses. DISCUSSION: The proposed systematic review will provide an overview of the certainty of evidence for the benefits and harms of prophylactic platelet transfusion in hospitalised patients with thrombocytopenia.

Training non-intensivist doctors to work with COVID-19 patients in intensive care units.

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 1-day course was comprised of theoretical sessions and hands-on training in ventilator use, hemodynamic 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 (pretest), after (posttest), and again within 8 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 pretest score was 11.9 (SD 3.0), mean posttest score 20.6 (1.8), and mean retention test score 17.4 (2.2). All doctors passed the posttest. CONCLUSION: Non-intensivist doctors, irrespective of experience level, can acquire relevant knowledge for working in the ICU through a focused 1-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.

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial.

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.

Long-term patient-important outcomes after septic shock: A protocol for 1-year follow-up of the CLASSIC trial.

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 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 1 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.

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial-Protocol and statistical analysis plan.

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.

Bleeding and thrombosis in intensive care patients with thrombocytopenia-Protocol for a topical systematic review.

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.

Consensus on technical procedures for simulation-based training in anaesthesiology: A Delphi-based general needs assessment.

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.

Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial-Protocol and statistical analysis plan.

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 thus 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 (SAEs), serious adverse reactions (SARs), days alive at day 90 without life support, days alive and out of the hospital at day 90 and mortality, health-related quality of life (HRQoL), 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 (ITT) population. DISCUSSION: The CLASSIC trial results will provide important evidence to guide clinicians' choice regarding the IV fluid therapy in adults with septic shock.

Effects of anemia and blood transfusion on clot formation and platelet function in patients with septic shock: a substudy of the randomized TRISS trial.

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.

Lower versus higher hemoglobin threshold for transfusion in septic shock.

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.).

Simulation-based training in flexible fibreoptic intubation: A randomised study.

BACKGROUND: 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. OBJECTIVE: 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. DESIGN: A randomised controlled study. SETTING: Centre for Clinical Education, University of Copenhagen and the Capital Region of Denmark, between January and April 2013. PARTICIPANTS: Twenty-three anaesthesia residents in their first year of training in anaesthesiology with no experience in FOI, and 10 anaesthesia consultants experienced in FOI. INTERVENTIONS: 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. MAIN OUTCOME MEASURES: The primary outcome measure was the score of performance on testing FOI skills on a manikin. RESULTS: 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. CONCLUSION: 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.