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RATIONALE: Critically ill adults can develop stress-related mucosal damage from gastrointestinal hypoperfusion and reperfusion injury, predisposing them to clinically important stress-related upper gastrointestinal bleeding (UGIB). OBJECTIVES: The objective of this guideline was to develop evidence-based recommendations for the prevention of UGIB in adults in the ICU. DESIGN: A multiprofessional panel of 18 international experts from dietetics, critical care medicine, nursing, and pharmacy, and two methodologists developed evidence-based recommendations in alignment with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Conflict-of-interest policies were strictly followed during all phases of guideline development including task force selection and voting. METHODS: The panel members identified and formulated 13 Population, Intervention, Comparison, and Outcome questions. We conducted a systematic review for each question to identify the best available evidence, statistically analyzed the evidence, and then assessed the certainty of the evidence using the GRADE approach. We used the evidence-to-decision framework to formulate the recommendations. Good practice statements were included to provide additional guidance. RESULTS: The panel generated nine conditional recommendations and made four good practice statements. Factors that likely increase the risk for clinically important stress-related UGIB in critically ill adults include coagulopathy, shock, and chronic liver disease. There is no firm evidence for mechanical ventilation alone being a risk factor. Enteral nutrition probably reduces UGIB risk. All critically ill adults with factors that likely increase the risk for stress-related UGIB should receive either proton pump inhibitors or histamine-2 receptor antagonists, at low dosage regimens, to prevent UGIB. Prophylaxis should be discontinued when critical illness is no longer evident or the risk factor(s) is no longer present despite ongoing critical illness. Discontinuation of stress ulcer prophylaxis before transfer out of the ICU is necessary to prevent inappropriate prescribing. CONCLUSIONS: The guideline panel achieved consensus regarding the recommendations for the prevention of stress-related UGIB. These recommendations are intended for consideration along with the patient's existing clinical status.
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Cuidados Críticos , Enfermedad Crítica , Hemorragia Gastrointestinal , Humanos , Hemorragia Gastrointestinal/prevención & control , Adulto , Cuidados Críticos/métodos , Cuidados Críticos/normas , Inhibidores de la Bomba de Protones/uso terapéutico , Estrés Psicológico/complicaciones , Estrés Psicológico/prevención & control , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Medicina Basada en la EvidenciaRESUMEN
BACKGROUND: This Intensive Care Medicine Rapid Practice Guideline (ICM-RPG) provides an evidence-based recommendation to address the question: in adult patients in intensive care units (ICUs), should we use small-volume or conventional blood collection tubes? METHODS: We included 23 panelists in 8 countries and assessed and managed financial and intellectual conflicts of interest. Methodological support was provided by the Guidelines in Intensive Care, Development, and Evaluation (GUIDE) group. We conducted a systematic review, including evidence from observational and randomized studies. Using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, we evaluated the certainty of evidence and developed recommendations using the Evidence-to-Decision framework. RESULTS: We identified 8 studies (1 cluster and 2 patient-level randomized trials; 5 observational studies) comparing small-volume to conventional tubes. We had high certainty evidence that small-volume tubes reduce daily and cumulative blood sampling volume; and moderate certainty evidence that they reduce the risk of transfusion and mean number of red blood cell units transfused, but these estimates were limited by imprecision. We had high certainty that small-volume tubes have a similar rate of specimens with insufficient quantity. The panel considered that the desirable effects of small-volume tubes outweigh the undesirable effects, are less wasteful of resources, and are feasible, as demonstrated by successful implementation across multiple countries, although there are upfront implementation costs to validate small-volume tubes on laboratory instrumentation. CONCLUSION: This ICM-RPG panel made a strong recommendation for the use of small-volume sample collection tubes in adult ICUs based on overall moderate certainty evidence.
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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.
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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.
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Antibacterianos , Meropenem , Combinación Piperacilina y Tazobactam , Sepsis , Humanos , Meropenem/uso terapéutico , Meropenem/administración & dosificación , Sepsis/tratamiento farmacológico , Sepsis/mortalidad , Combinación Piperacilina y Tazobactam/uso terapéutico , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Adulto , Enfermedad Crítica , MasculinoRESUMEN
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.
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Fluidoterapia , Choque Séptico , Humanos , Fluidoterapia/métodos , Choque Séptico/terapia , Cuidados Críticos/métodos , Teorema de Bayes , Aprendizaje AutomáticoRESUMEN
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.
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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.
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Antibacterianos , Carbapenémicos , Combinación Piperacilina y Tazobactam , Humanos , Combinación Piperacilina y Tazobactam/uso terapéutico , Carbapenémicos/uso terapéutico , Estudios Retrospectivos , Femenino , Masculino , Antibacterianos/uso terapéutico , Persona de Mediana Edad , Anciano , Estudios de Cohortes , Cuidados Críticos , Unidades de Cuidados Intensivos , Tiempo de Internación/estadística & datos numéricos , Enfermedad CríticaRESUMEN
BACKGROUND: The management of blood pressure targets during intensive care after out-of-hospital cardiac arrest (OHCA) remains a topic of debate. The blood Pressure and Oxygenation Targets After OHCA (BOX) trial explored the efficacy of two different blood pressure targets in 789 patients during intensive care after OHCA. In the primary frequentist analysis, no statistically significant differences were found for neurological outcome after 90 days. METHODS: This protocol outlines secondary Bayesian analyses of 365-day all-cause mortality and two secondary outcomes: neurological outcome after 365 days, and plasma neuron-specific enolase, a biomarker of brain injury, after 48 h. We will employ adjusted Bayesian logistic and linear regressions, presenting results as relative and absolute differences with 95% confidence intervals. We will use weakly informative priors for the primary analyses, and skeptical and evidence-based priors (where available) in sensitivity analyses. Exact probabilities for any benefit/harm will be presented for all outcomes, along with probabilities of clinically important benefit/harm (risk differences larger than 2%-points absolute) and no clinically important differences for the binary outcomes. We will assess whether heterogeneity of treatment effects on mortality is present according to lactate at admission, time to return of spontaneous circulation, primary shockable rhythm, age, hypertension, and presence of ST-elevation myocardial infarction. DISCUSSION: This secondary analysis of the BOX trial aim to complement the primary frequentist analysis by quantifying the probabilities of beneficial or harmful effects of different blood pressure targets. This approach seeks to provide clearer insights for researchers and clinicians into the effectiveness of these blood pressure management strategies in acute medical conditions, particularly focusing on mortality, neurological outcomes, and neuron-specific enolase.
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Reanimación Cardiopulmonar , Hipertensión , Paro Cardíaco Extrahospitalario , Humanos , Paro Cardíaco Extrahospitalario/terapia , Presión Sanguínea , Teorema de Bayes , Coma/terapia , Hipertensión/complicaciones , Fosfopiruvato Hidratasa , Reanimación Cardiopulmonar/métodosRESUMEN
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.
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Guías de Práctica Clínica como Asunto , Humanos , Medicina Basada en la EvidenciaRESUMEN
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.
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Metaanálisis como Asunto , Humanos , Literatura de Revisión como Asunto , Medicina Basada en la Evidencia/métodos , Revisiones Sistemáticas como AsuntoRESUMEN
PURPOSE: We assessed long-term outcomes in acutely admitted adult patients with delirium treated in intensive care unit (ICU) with haloperidol versus placebo. METHODS: We conducted pre-planned analyses of 1-year outcomes in the Agents Intervening against Delirium in the ICU (AID-ICU) trial, including mortality and health-related quality of life (HRQoL) assessed by Euroqol (EQ) 5-dimension 5-level questionnaire (EQ-5D-5L) index values and EQ visual analogue scale (EQ VAS) (deceased patients were assigned the numeric value zero). Outcomes were analysed using logistic and linear regressions with bootstrapping and G-computation, all with adjustment for the stratification variables (site and delirium motor subtype) and multiple imputations for missing HRQoL values. RESULTS: At 1-year follow-up, we obtained vital status for 96.2% and HRQoL data for 83.3% of the 1000 randomised patients. One-year mortality was 224/501 (44.7%) in the haloperidol group versus 251/486 (51.6%) in the placebo group, with an adjusted absolute risk difference of - 6.4%-points (95% confidence interval [CI] - 12.8%-points to - 0.2%-points; P = 0.045). These results were largely consistent across the secondary analyses. For HRQoL, the adjusted mean differences were 0.04 (95% CI - 0.03 to 0.11; P = 0.091) for EQ-5D-5L-5L index values, and 3.3 (95% CI - 9.3 to 17.5; P = 0.142) for EQ VAS. CONCLUSIONS: In acutely admitted adult ICU patients with delirium, haloperidol treatment reduced mortality at 1-year follow-up, but did not statistically significantly improve HRQoL.
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Delirio , Haloperidol , Adulto , Humanos , Delirio/tratamiento farmacológico , Haloperidol/uso terapéutico , Hospitalización , Unidades de Cuidados Intensivos , Calidad de VidaRESUMEN
Background: In the COVID-STEROID 2 trial there was suggestion of heterogeneity of treatment effects (HTE) between patients enrolled from Europe vs. India on the primary outcome. Whether there was HTE for the remaining patient-centred outcomes is unclear. Methods: In this post hoc analysis of the COVID-STEROID 2 trial, which compared 12 mg vs. 6 mg dexamethasone in adults with COVID-19 and severe hypoxemia, we evaluated HTE by geographical region (Europe vs. India) for secondary outcomes with analyses adjusted for stratification variables. Results are presented as risk differences (RDs) or mean differences (MDs) with 99% confidence intervals (CIs) and P-values from interaction tests. Findings: There were differences in mortality at day 28 (RD for Europe -8.3% (99% CI: -17.7 to 1.0) vs. India 0.1% (99% CI: -10.0 to 10.0)), mortality at day 90 (RD for Europe -7.4% (99% CI: -17.1 to 2.0) vs. India -1.4% (99% CI: -12.8 to 9.8)), mortality at day 180 (RD for Europe -6.7% (99% CI: -16.4 to 2.9) vs. India -1.0% (99% CI: -12.3 to 10.3)), and number of days alive without life support at day 90 (MD for Europe 6.1 days (99% CI: -1.3 to 13.4) vs. India 1.7 days (99% CI: -8.4 to 11.8)). For serious adverse reactions, the direction was reversed (RD for Europe -1.0% (99% CI: -7.1 to 5.2) vs. India -5.3% (99% CI: -16.2 to 5.0). Interpretation: Our analysis suggests higher dose dexamethasone may have less beneficial effects for patients in India as compared with those in Europe; however, the evidence is weak, and this could represent a chance finding. Funding: None for this analysis. The COVID STEROID 2 trial was funded by The Novo Nordisk Foundation and supported by Rigshospitalet's Research Council.
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Different combined outcome-data lags (follow-up durations plus data-collection lags) may affect the performance of adaptive clinical trial designs. We assessed the influence of different outcome-data lags (0-105 days) on the performance of various multi-stage, adaptive trial designs (2/4 arms, with/without a common control, fixed/response-adaptive randomisation) with undesirable binary outcomes according to different inclusion rates (3.33/6.67/10 patients/day) under scenarios with no, small, and large differences. Simulations were conducted under a Bayesian framework, with constant stopping thresholds for superiority/inferiority calibrated to keep type-1 error rates at approximately 5%. We assessed multiple performance metrics, including mean sample sizes, event counts/probabilities, probabilities of conclusiveness, root mean squared errors (RMSEs) of the estimated effect in the selected arms, and RMSEs between the analyses at the time of stopping and the final analyses including data from all randomised patients. Performance metrics generally deteriorated when the proportions of randomised patients with available data were smaller due to longer outcome-data lags or faster inclusion, that is, mean sample sizes, event counts/probabilities, and RMSEs were larger, while the probabilities of conclusiveness were lower. Performance metric impairments with outcome-data lags ≤45 days were relatively smaller compared to those occurring with ≥60 days of lag. For most metrics, the effects of different outcome-data lags and lower proportions of randomised patients with available data were larger than those of different design choices, for example, the use of fixed versus response-adaptive randomisation. Increased outcome-data lag substantially affected the performance of adaptive trial designs. Trialists should consider the effects of outcome-data lags when planning adaptive trials.
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Proyectos de Investigación , Humanos , Teorema de Bayes , Estudios de Seguimiento , Tamaño de la Muestra , Recolección de DatosRESUMEN
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.
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COVID-19 , Adulto , Humanos , Tratamiento Farmacológico de COVID-19 , Pacientes , Dexametasona/efectos adversos , HipoxiaRESUMEN
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.
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Choque Séptico , Adulto , Humanos , Teorema de Bayes , Fluidoterapia , Unidades de Cuidados Intensivos , Choque Séptico/terapia , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
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.
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Sepsis , Choque Séptico , Adulto , Humanos , Choque Séptico/tratamiento farmacológico , Choque Séptico/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/etiología , Norepinefrina/uso terapéutico , Albúminas/uso terapéutico , Fluidoterapia/efectos adversosRESUMEN
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.
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COVID-19 , Cuidados Críticos , Adulto , HumanosRESUMEN
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.
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COVID-19 , Humanos , SARS-CoV-2 , Enfermedad Crítica/terapia , Calidad de Vida , Método de MontecarloRESUMEN
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."