Hypernatremia in hospitalised adult patients: A protocol for a scoping review.

BACKGROUND: Hypernatremia is a common electrolyte disturbance in hospitalised patients associated with adverse outcomes. The aetiology is diverse but often related to fluid therapy and sodium-containing medicaments. We aim to outline the evidence base on hypernatremia in adult hospitalised patients. METHODS: We will conduct a scoping review and adhere to the preferred reporting items for systematic and meta-analysis extension for scoping reviews (PRISMA-ScR). We will systematically search the Cochrane Library, Medline, Pubmed, and Embase from inception with no limitations to language, and include all study designs. We will use the population, exposure, comparator, and outcome-based approach to define eligibility criteria. The population: adult hospitalised patients; exposure: hypernatremia; comparator: no hypernatremia or all types of treatments of hypernatremia; and outcomes: all reported outcomes. Two authors will independently screen and select studies followed by full-text assessment and data extraction in duplicate. All outcome measures will be reported, and descriptive analyses will be performed. The certainty of evidence will be assessed according to an adapted grading of recommendations assessment, development, and evaluation (GRADE) approach. DISCUSSION: This scoping review will provide an overview of the current evidence regarding the incidence of hypernatremia, treatment modalities, and outcomes reported for hospitalised adult patients with hypernatremia.

GRADE pearls and pitfalls-Part 1: Systematic reviews and meta-analyses.

BACKGROUND: The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach is used to assess the certainty of evidence in systematic reviews and meta-analyses. METHODS: We describe how the GRADE approach is used in systematic reviews and meta-analyses, including key points and examples. This overview is aimed at clinicians and researchers who are, or plan to be, involved in the development or assessment of systematic reviews with meta-analyses using GRADE. RESULTS: We outline how the certainty of evidence is assessed, how the evidence is summarized using GRADE evidence profiles or summary of findings tables, how the results are communicated, and we discuss challenges, advantages, and disadvantages with using GRADE. CONCLUSIONS: This overview aims to provide an overview of how GRADE is used in systematic reviews and meta-analyses, and may be used by systematic review developers, methodologists, and evidence end-users.

GRADE pearls and pitfalls-Part 2: Clinical practice guidelines.

BACKGROUND: The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach is the de facto standard framework for summarising evidence in systematic reviews and developing recommendations in clinical practice guidelines. METHODS: We describe how the GRADE approach is used in clinical practice guidelines, including key points and examples. The intended audience of this overview of GRADE is clinicians and researchers who are, or plan to be, involved in the development or assessment of clinical practice guidelines. RESULTS: We cover guideline endorsement and adaptation; guideline panels and sponsors; conflicts of interest; guideline questions and outcome prioritisation; systematic review creation, updating and re-use; rating the overall certainty of evidence; development of recommendations and implications; and peer review, publication, implementation and updating of guidelines. CONCLUSIONS: This overview aims to help developers, assessors and users of clinical practice guidelines understand how trustworthy, high-quality guidelines are developed using the GRADE approach.

Glucose evaluation and management in the ICU (GEM-ICU): Protocol for a bi-centre cohort study.

INTRODUCTION: Hyperglycaemia is common in intensive care unit (ICU) patients. Glycaemic monitoring and effective glycaemic control with insulin are crucial in the ICU to improve patient outcomes. However, glycaemic control and insulin use vary between ICU patients and hypo- and hyperglycaemia occurs. Therefore, we aim to provide contemporary data on glycaemic control and management, and associated outcomes, in adult ICU patients. We hypothesise that the occurrence of hypoglycaemia in acutely admitted ICU patients is lower than that of hyperglycaemia. METHODS: We will conduct a bi-centre cohort study of 300 acutely admitted adult ICU patients. Routine data will be collected retrospectively at baseline (ICU admission) and daily during ICU stay up to a maximum of 30 days. The primary outcome will be the number of patients with hypoglycaemia during their ICU stay. Secondary outcomes will be occurrence of severe hypoglycaemia, occurrence of hyperglycaemia, time below blood glucose target range, time above target range, all-cause mortality at Day 30, number of days alive without life support at Day 30 and number of days alive and out of hospital at Day 30. Process outcomes include the number of in-ICU days, glucose measurements (number of measurements and method) and use of insulin (including route of administration and dosage). All statistical analyses will be descriptive. CONCLUSIONS: This cohort study will provide a contemporary overview of glucose evaluation and management practices in adult ICU patients and, thus, highlight potential areas for improvement through future clinical trials in this area.

Awake proning in patients with COVID-19-related hypoxemic acute respiratory failure: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

BACKGROUND: Awake proning in spontaneously breathing patients with hypoxemic acute respiratory failure was applied during the coronavirus disease 2019 (COVID-19) pandemic to improve oxygenation while avoiding tracheal intubation. An updated systematic review and meta-analysis on the topic was published. METHODS: The Clinical practice committee (CPC) of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI) assessed the clinical practice guideline "Awake proning in patients with COVID-19-related hypoxemic acute respiratory failure: A rapid practice guideline" for possible endorsement. The Appraisal of Guidelines for REsearch and Evaluation (AGREE) II tool was used. RESULTS: Four out of six SSAI CPC members completed the appraisal. The individual domain totals were: Scope and Purpose 90%; Stakeholder Involvement 89%; Rigour of Development 74%; Clarity of Presentation 85%; Applicability 75%; Editorial Independence 98%; Overall Assessment 79%. CONCLUSION: The SSAI CPC endorses the clinical practice guideline "Awake proning in patients with COVID-19-related hypoxemic acute respiratory failure: A rapid practice guideline". This guideline serves as a useful decision aid for clinicians caring for critically ill patients with COVID-19-related acute hypoxemic respiratory failure and can be used to provide guidance on use of prone positioning in this group of patients.

ESAIC focused guideline for the use of cardiac biomarkers in perioperative risk evaluation: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

BACKGROUND: The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the clinical practice guideline "ESAIC focused guideline for the use of cardiac biomarkers in perioperative risk evaluation." The guideline can provide guidance to Nordic anaesthesiologists on the perioperative use of cardiac biomarkers in patients undergoing non-cardiac surgery.

Health-related quality of life trajectories in critical illness: Protocol for a Monte Carlo simulation study.

BACKGROUND: Health-related quality of life (HRQoL) is a patient-centred outcome increasingly used as a secondary outcome in critical care research. It may cover several important dimensions of clinical status in intensive care unit (ICU) patients that arguably elude other more easily quantified outcomes such as mortality. Poor associations with harder outcomes, conflicting data on HRQoL in critically ill compared to the background population, and paradoxical effects on HRQoL and mortality complicate the current operationalisation in critical care trials. This protocol outlines a simulation study that will gauge if the areas under the HRQoL trajectories could be a viable alternative. METHODS: We will gauge the behaviour of the proposed HRQoL operationalisation through Monte Carlo simulations, under clinical scenarios that reflect a broad critical care population eligible for inclusion in a large pragmatic trial. We will simulate 15,360 clinical scenarios based on a full factorial design with the following seven simulation parameters: number of patients per arm, relative mortality reduction in the interventional arm, acceleration of HRQoL improvement in the interventional arm, the relative improvement in final HRQoL in the interventional arm, dampening effect of mortality on HRQoL values at discharge from the ICU, proportion of so-called mortality benefiters in the interventional arm and mortality trajectory shape. For each clinical scenario, we will simulate 100,000 two-arm trials with 1:1 randomisation. HRQoL will be sampled fortnightly after ICU discharge. Outcomes will include HRQoL in survivors and all patients at the end of follow-up; mean areas under the HRQoL trajectories in both arms; and mean difference between areas under the HRQoL trajectories and single-sampled HRQoLs at the end of follow-up. DISCUSSION: In the outlined simulation study, we aim to assess whether the area under the HRQoL trajectory curve could be a candidate for reconciling the seemingly paradoxical effects on improved mortality and reduced HRQoL while remaining sensitive to early or accelerated improvement in patient outcomes. The resultant insights will inform subsequent methodological work on prudent collection and statistical analysis of such data from real critically ill patients.

Perioperative hypotension and use of vasoactive agents in non-cardiac surgery: A scoping review.

BACKGROUND: Perioperative hypotension is common and associated with adverse patient outcomes. Vasoactive agents are often used to manage hypotension, but the ideal drug, dose and duration of treatment has not been established. With this scoping review, we aim to provide an overview of the current body of evidence regarding the vasoactive agents used to treat perioperative hypotension in non-cardiac surgery. METHODS: We included all studies describing the use of vasoactive agents for the treatment of perioperative hypotension in non-cardiac surgery. We excluded literature reviews, case studies, and studies on animals and healthy subjects. We posed the following research questions: (1) in which surgical populations have vasoactive agents been studied? (2) which agents have been studied? (3) what doses have been assessed? (4) what is the duration of treatment? and (5) which desirable and undesirable outcomes have been assessed? RESULTS: We included 124 studies representing 10 surgical specialties. Eighteen different agents were evaluated, predominantly phenylephrine, ephedrine, and noradrenaline. The agents were administered through six different routes, and numerous comparisons between agents, dosages and routes were included. Then, 88 distinct outcome measures were assessed, of which 54 were judged to be non-patient-centred. CONCLUSIONS: We found that studies concerning vasoactive agents for the treatment of perioperative hypotension varied considerably in all aspects. Populations were heterogeneous, interventions and exposures included multiple agents compared against themselves, each other, fluids or placebo, and studies reported primarily non-patient-centred outcomes.

Real-world causal evidence for planned predictive enrichment in critical care trials: A scoping review.

BACKGROUND: Randomised clinical trials in critical care are prone to inconclusiveness due, in part, to undue optimism about effect sizes and suboptimal accounting for heterogeneous treatment effects. Although causal evidence from rich real-world critical care can help overcome these challenges by informing predictive enrichment, no overview exists. METHODS: We conducted a scoping review, systematically searching 10 general and speciality journals for reports published on or after 1 January 2018, of randomised clinical trials enrolling adult critically ill patients. We collected trial metadata on 22 variables including recruitment period, intervention type and early stopping (including reasons) as well as data on the use of causal evidence from secondary data for planned predictive enrichment. RESULTS: We screened 9020 records and included 316 unique RCTs with a total of 268,563 randomised participants. One hundred seventy-three (55%) trials tested drug interventions, 101 (32%) management strategies and 42 (13%) devices. The median duration of enrolment was 2.2 (IQR: 1.3-3.4) years, and 83% of trials randomised less than 1000 participants. Thirty-six trials (11%) were restricted to COVID-19 patients. Of the 55 (17%) trials that stopped early, 23 (42%) used predefined rules; futility, slow enrolment and safety concerns were the commonest stopping reasons. None of the included RCTs had used causal evidence from secondary data for planned predictive enrichment. CONCLUSION: Work is needed to harness the rich multiverse of critical care data and establish its utility in critical care RCTs. Such work will likely need to leverage methodology from interventional and analytical epidemiology as well as data science.

Albumin use in patients with septic shock-Post-hoc analyses of an international randomised fluid trial.

BACKGROUND: Albumin administration is suggested in patients with sepsis and septic shock who have received large volumes of crystalloids. Given lack of firm evidence, clinical practice variation may exist. To address this, we investigated if patient characteristics or trial site were associated with albumin use in septic shock. METHODS: We conducted a post-hoc study of the CLASSIC international, randomised clinical trial of fluid volumes in septic shock. Associations between selected baseline variables and trial site with albumin use during ICU stay were assessed in Cox models considering death, ICU discharge, and loss-to-follow-up as competing events. Baseline variables were first assessed individually, adjusted for treatment allocation (restrictive vs. standard IV fluid), and then adjusted for allocation and the other baseline variables. Site was assessed in a model adjusted for allocation and baseline variables. RESULTS: We analysed 1541 of 1554 patients randomised in CLASSIC (99.2%). During ICU stay, 36.3% of patients in the restrictive-fluid group and 52.6% in the standard-fluid group received albumin. Gastrointestinal focus of infection and higher doses of norepinephrine were most strongly associated with albumin use (subgroup with highest quartile of norepinephrine doses, hazard ratio (HR) 2.58, 95% CI 1.89 to 3.53). HRs for associations between site and albumin use ranged from 0.11 (95% CI 0.05 to 0.26) to 1.70 (95% CI 1.06 to 2.74); test for overall effect of site: p < .001. CONCLUSIONS: In adults with septic shock, gastrointestinal focus of infection and higher doses of norepinephrine at baseline were associated with albumin use, which also varied substantially between sites.

Associations between enteral nutrition and outcomes in the SUP-ICU trial: Results of exploratory post hoc analyses.

BACKGROUND: Enteral nutrition may affect risks of gastrointestinal bleeding, pneumonia and mortality in critically ill patients and may also modify the effects of pharmacological stress ulcer prophylaxis. We undertook post hoc analyses of the stress ulcer prophylaxis in the intensive care unit trial to assess for any associations and interactions between enteral nutrition and pantoprazole. METHODS: Extended Cox models with time-varying co-variates and competing events were used to assess potential associations, adjusted for baseline severity of illness. Potential interactions between daily enteral nutrition and allocation to pantoprazole on outcomes were similarly assessed. RESULTS: Enteral nutrition was associated with lower risk of clinically important gastrointestinal bleeding (cause-specific hazard ratio [HR]: 0.29, 95% confidence interval: [CI] 0.19-0.44, p < .001), higher risk of pneumonia (HR: 1.44, 95% CI: 1.14-1.82, p = .003), and lower risk of all-cause mortality (HR: 0.22, 95% CI: 0.18-0.27, p < .001). Enteral nutrition with allocation to pantoprazole was associated with a lower risk of mortality (HR: 0.27, 95% CI: 0.21-0.35, p < .001), similar to enteral nutrition with allocation to placebo (HR: 0.17, 95% CI: 0.13-0.23, p < .001). Allocation to pantoprazole with no enteral nutrition had little effect on mortality (HR: 0.83, 95% CI: 0.63-1.09, p = .179), whilst allocation to pantoprazole and receipt of enteral nutrition was mostly compatible with increased all-cause mortality (HR: 1.27, 95% CI: 0.99-1.64, p = .061). The test of interaction between enteral nutrition and pantoprazole treatment allocation for all-cause mortality was statistically significant (p = .024). CONCLUSIONS: Enteral nutrition was associated with an increased risk of pneumonia and a reduced risk of gastrointestinal bleeding. The interaction between pantoprazole and enteral nutrition suggesting an increased risk of mortality requires further study.

Empirical carbapenems or piperacillin/tazobactam for infections in intensive care: An international retrospective cohort study.

BACKGROUND: Critically ill patients in intensive care units (ICU) are frequently administered broad-spectrum antibiotics (e.g., carbapenems or piperacillin/tazobactam) for suspected or confirmed infections. This retrospective cohort study aimed to describe the use of carbapenems and piperacillin/tazobactam in two international, prospectively collected datasets. METHODS: We conducted a post hoc analysis of data from the "Adjunctive Glucocorticoid Therapy in Patients with Septic Shock" (ADRENAL) trial (n = 3713) and the "Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure" (DIANA) study (n = 1488). The primary outcome was the proportion of patients receiving initial antibiotic treatment with carbapenems and piperacillin/tazobactam. Secondary outcomes included mortality, days alive and out of ICU and ICU length of stay at 28 days. RESULTS: In the ADRENAL trial, carbapenems were used in 648 out of 3713 (17%), whereas piperacillin/tazobactam was used in 1804 out of 3713 (49%) participants. In the DIANA study, carbapenems were used in 380 out of 1480 (26%), while piperacillin/tazobactam was used in 433 out of 1488 (29%) participants. Mortality at 28 days was 23% for patients receiving carbapenems and 24% for those receiving piperacillin/tazobactam in ADRENAL and 23% and 19%, respectively, in DIANA. We noted variations in secondary outcomes; in DIANA, patients receiving carbapenems had a median of 13 days alive and out of ICU compared with 18 days among those receiving piperacillin/tazobactam. In ADRENAL, the median hospital length of stay was 27 days for patients receiving carbapenems and 21 days for those receiving piperacillin/tazobactam. CONCLUSIONS: In this post hoc analysis of ICU patients with infections, we found widespread initial use of carbapenems and piperacillin/tazobactam in international ICUs, with the latter being more frequently used. Randomized clinical trials are needed to assess if the observed variations in outcomes may be drug-related effects or due to confounders.

Dexamethasone doses in patients with COVID-19 and hypoxia: A systematic review and meta-analysis.

BACKGROUND: The optimal dose of dexamethasone for severe/critical COVID-19 is uncertain. We compared higher versus standard doses of dexamethasone in adults with COVID-19 and hypoxia. METHODS: We searched PubMed and trial registers until 23 June 2023 for randomised clinical trials comparing higher (>6 mg) versus standard doses (6 mg) of dexamethasone in adults with COVID-19 and hypoxia. The primary outcome was mortality at 1 month. Secondary outcomes were mortality closest to 90 days; days alive without life support; and the occurrence of serious adverse events/reactions (SAEs/SARs) closest to 1 month. We assessed the risk of bias using the Cochrane RoB2 tool, risk of random errors using trial sequential analysis, and certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included eight trials (2478 participants), of which four (1293 participants) had low risk of bias. Higher doses of dexamethasone probably resulted in little to no difference in mortality at 1 month (relative risk [RR] 0.97, 95% CI: 0.79-1.19), mortality closest to Day 90 (RR 1.01, 95% CI: 0.86-1.20), and SAEs/SARs (RR 1.00, 95% CI: 0.97-1.02). Higher doses of dexamethasone probably increased the number of days alive without invasive mechanical ventilation and circulatory support but had no effect on days alive without renal replacement therapy. CONCLUSIONS: Based on low to moderate certainty evidence, higher versus standard doses of dexamethasone probably result in little to no difference in mortality, SAEs/SARs, and days alive without renal replacement therapy, but probably increase the number of days alive without invasive mechanical ventilation and circulatory support.

Restrictive versus standard IV fluid therapy in adult ICU patients with septic shock-Bayesian analyses of the CLASSIC trial.

BACKGROUND: The CLASSIC trial assessed the effects of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock. This pre-planned study provides a probabilistic interpretation and evaluates heterogeneity in treatment effects (HTE). METHODS: We analysed mortality, serious adverse events (SAEs), serious adverse reactions (SARs) and days alive without life-support within 90 days using Bayesian models with weakly informative priors. HTE on mortality was assessed according to five baseline variables: disease severity, vasopressor dose, lactate levels, creatinine values and IV fluid volumes given before randomisation. RESULTS: The absolute difference in mortality was 0.2%-points (95% credible interval: -5.0 to 5.4; 47% posterior probability of benefit [risk difference <0.0%-points]) with restrictive IV fluid. The posterior probabilities of benefits with restrictive IV fluid were 72% for SAEs, 52% for SARs and 61% for days alive without life-support. The posterior probabilities of no clinically important differences (absolute risk difference ≤2%-points) between the groups were 56% for mortality, 49% for SAEs, 90% for SARs and 38% for days alive without life-support. There was 97% probability of HTE for previous IV fluid volumes analysed continuously, that is, potentially relatively lower mortality of restrictive IV fluids with higher previous IV fluids. No substantial evidence of HTE was found in the other analyses. CONCLUSION: We could not rule out clinically important effects of restrictive IV fluid therapy on mortality, SAEs or days alive without life-support, but substantial effects on SARs were unlikely. IV fluids given before randomisation might interact with IV fluid strategy.

Effects of IV fluid restriction according to site-specific intensity of standard fluid treatment-protocol.

BACKGROUND: Variation in usual practice in fluid trials assessing lower versus higher volumes may affect overall comparisons. To address this, we will evaluate the effects of heterogeneity in treatment intensity in the Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care trial. This will reflect the effects of differences in site-specific intensities of standard fluid treatment due to local practice preferences while considering participant characteristics. METHODS: We will assess the effects of heterogeneity in treatment intensity across one primary (all-cause mortality) and three secondary outcomes (serious adverse events or reactions, days alive without life support and days alive out of hospital) after 90 days. We will classify sites based on the site-specific intensity of standard fluid treatment, defined as the mean differences in observed versus predicted intravenous fluid volumes in the first 24 h in the standard-fluid group while accounting for differences in participant characteristics. Predictions will be made using a machine learning model including 22 baseline predictors using the extreme gradient boosting algorithm. Subsequently, sites will be grouped into fluid treatment intensity subgroups containing at least 100 participants each. Subgroups differences will be assessed using hierarchical Bayesian regression models with weakly informative priors. We will present the full posterior distributions of relative (risk ratios and ratios of means) and absolute differences (risk differences and mean differences) in each subgroup. DISCUSSION: This study will provide data on the effects of heterogeneity in treatment intensity while accounting for patient characteristics in critically ill adult patients with septic shock. REGISTRATIONS: The European Clinical Trials Database (EudraCT): 2018-000404-42, ClinicalTrials. gov: NCT03668236.

Empirical meropenem versus piperacillin/tazobactam for adult patients with sepsis (EMPRESS) trial: Protocol.

BACKGROUND: Piperacillin/tazobactam may be associated with less favourable outcomes than carbapenems in patients with severe bacterial infections, but the certainty of evidence is low. METHODS: The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an investigator-initiated, international, parallel-group, randomised, open-label, adaptive clinical trial with an integrated feasibility phase. We will randomise adult, critically ill patients with sepsis to empirical treatment with meropenem or piperacillin/tazobactam for up to 30 days. The primary outcome is 30-day all-cause mortality. The secondary outcomes are serious adverse reactions within 30 days; isolation precautions due to resistant bacteria within 30 days; days alive without life support and days alive and out of hospital within 30 and 90 days; 90- and 180-day all-cause mortality and 180-day health-related quality of life. EMPRESS will use Bayesian statistical models with weak to somewhat sceptical neutral priors. Adaptive analyses will be conducted after follow-up of the primary outcome for the first 400 participants concludes and after every 300 subsequent participants, with adaptive stopping for superiority/inferiority and practical equivalence (absolute risk difference <2.5%-points) and response-adaptive randomisation. The expected sample sizes in scenarios with no, small or large differences are 5189, 5859 and 2570 participants, with maximum 14,000 participants and ≥99% probability of conclusiveness across all scenarios. CONCLUSIONS: EMPRESS will compare the effects of empirical meropenem against piperacillin/tazobactam in adult, critically ill patients with sepsis. Due to the pragmatic, adaptive design with high probability of conclusiveness, the trial results are expected to directly inform clinical practice.

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.

Higher versus lower oxygenation targets in adult ICU patients: A rapid practice guideline.

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

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.

Effects of sceptical priors on the performance of adaptive clinical trials with binary outcomes.

It is unclear how sceptical priors impact adaptive trials. We assessed the influence of priors expressing a spectrum of scepticism on the performance of several Bayesian, multi-stage, adaptive clinical trial designs using binary outcomes under different clinical scenarios. Simulations were conducted using fixed stopping rules and stopping rules calibrated to keep type 1 error rates at approximately 5%. We assessed total sample sizes, event rates, event counts, probabilities of conclusiveness and selecting the best arm, root mean squared errors (RMSEs) of the estimated treatment effect in the selected arms, and ideal design percentages (IDPs; which combines arm selection probabilities, power, and consequences of selecting inferior arms), with RMSEs and IDPs estimated in conclusive trials only and after selecting the control arm in inconclusive trials. Using fixed stopping rules, increasingly sceptical priors led to larger sample sizes, more events, higher IDPs in simulations ending in superiority, and lower RMSEs, lower probabilities of conclusiveness/selecting the best arm, and lower IDPs when selecting controls in inconclusive simulations. With calibrated stopping rules, the effects of increased scepticism on sample sizes and event counts were attenuated, and increased scepticism increased the probabilities of conclusiveness/selecting the best arm and IDPs when selecting controls in inconclusive simulations without substantially increasing sample sizes. Results from trial designs with gentle adaptation and non-informative priors resembled those from designs with more aggressive adaptation using weakly-to-moderately sceptical priors. In conclusion, the use of somewhat sceptical priors in adaptive trial designs with binary outcomes seems reasonable when considering multiple performance metrics simultaneously.