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.

Issuing of isotonic crystalloid solutions to Danish public hospitals in 2021-A retrospective nationwide observational study.

BACKGROUND: Intravenous (IV) fluid therapy is a ubiquitous intervention in daily clinical practice. However, nationwide detailed hospital- and departmental-level information on IV fluid use is limited. Hence, we aimed to describe the current issuing of isotonic crystalloid solutions across Danish public hospitals. METHODS: We conducted a nationwide, retrospective observational study describing the issuing of isotonic crystalloid solutions for IV administration, including 0.9% saline, acetate- and lactate-buffered crystalloid solutions. We assessed fluid issuing at national-, regional-, hospital- and departmental-level from 1 January 2021 to 31 December 2021. We obtained sales figures from the Danish Regional Hospital Pharmacies. Regional characteristics were acquired from the Danish Health Data Authorities online resources. Results are presented graphically and descriptively, including frequencies (%). RESULTS: The total amount of isotonic crystalloid solutions issued across Danish public hospitals in 2021 was 1,487,144 L (67.4% saline, 25.9% acetate- and 6.7% lactate-buffered solutions) equivalent to 2.1 L per hospitalised patient within the study period. Both the issuing of saline versus. buffered crystalloid solutions and the issuing of acetate- versus lactate-buffered solutions varied across geographical regions. Medical departments used saline more frequently (85.3%) than emergency departments (71.5%), surgical departments (70.6%) and anaesthesiological departments including intensive care units (43.0%). CONCLUSIONS: In this nationwide observational study, we found that the issuing of different isotonic crystalloid solutions varied based on geographical location. Furthermore, the issuing of different crystalloid solutions differed across departmental settings with medical departments using the highest proportion of saline and anaesthesiological departments using the highest proportion of buffered crystalloid solutions. EDITORIAL COMMENT: IV fluid administration practices can be assessed across specialties by examining hospital purchasing. This study analysed the use of IV isotonic crystalloid solutions across all major departments of Danish public hospitals for 1 year. Isotonic sodium chloride was the most commonly used fluid in emergency medicine (71%), internal medicine (85%) and surgical departments (71%). Only anaesthesia and intensive care medicine departments used more buffered crystalloid solutions (57%) than isotonic natrium chloride.

Causal inference for planning randomised critical care trials: Protocol for a scoping review.

BACKGROUND: Randomised clinical trials in critical care are prone to inconclusiveness owing, in part, to undue optimism about effect sizes and suboptimal accounting for heterogeneous treatment effects. Planned predictive enrichment based on secondary critical care data (often very rich with respect to both data types and temporal granularity) and causal inference methods may help overcome these challenges, but no overview exists about their use to this end. METHODS: We will conduct a scoping review to assess the extent and nature of the use of causal inference from secondary data for planned predictive enrichment of randomised clinical trials in critical care. We will systematically search 10 general and specialty journals for reports published on or after 1 January 2018, of randomised clinical trials enrolling adult critically ill patients. We will collect trial metadata (e.g., recruitment period and phase) and, when available, information pertaining to the focus of the review (predictive enrichment based on causal inference estimates from secondary data): causal inference methods, estimation techniques and software used; types of patient populations; data provenance, types and models; and the availability of the data (public or not). The results will be reported in a descriptive manner. DISCUSSION: The outlined scoping review aims to assess the use of causal inference methods and secondary data for planned predictive enrichment in randomised critical care trials. This will help guide methodological improvements to increase the utility, and facilitate the use, of causal inference estimates when planning such trials in the future.

Acetate- versus lactate-buffered crystalloid solutions: A systematic review with meta-analysis and trial sequential analysis.

OBJECTIVE: There is a widespread use of buffered crystalloid solutions in clinical practice. However, guidelines do not distinguish between specific types of buffered solutions and clinical equipoise exists. We aimed to assess the desirable and undesirable effects of acetate- versus lactate-buffered solutions in hospitalised patients. METHODS: We conducted a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials assessing the use of acetate- versus lactate-buffered solutions for intravenous administration in hospitalised adults and children. The primary outcome was all-cause short-term mortality. We adhered to our published protocol, the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, the Cochrane Handbook and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. RESULTS: We included five RCTs enrolling 390 patients. We found no statistically significant difference in short-term mortality (random effects, risk ratio [RR] 0.29; 95% confidence interval [CI] 0.06-1.51, p = .14, I2  = 0%) or hospital length of stay (LOS) (random effects, mean difference [MD]-1.31, 95% CI -3.66 to 1.05, p = .28, I2  = 0%) between acetate- versus lactate-buffered solutions. The quality of evidence was very low. Data regarding intensive care unit LOS were reported by three trials and duration of vasopressor treatment by one trial; none of these data allowed for pooling in meta-analyses. No trials reported data on long-term mortality, health-related quality of life, adverse events, duration of mechanical ventilation or renal replacement therapy. CONCLUSION: In this systematic review, we found very low quantity and quality of evidence on the use of acetate- versus lactate-buffered solutions in hospitalised patients.

Use of crystalloids and colloids in Europe per year from 2010 to 2019: Protocol for an international descriptive study.

INTRODUCTION: Intravenous (IV) fluids are widely used in everyday clinical practice. In the last two decades, several trials and clinical practice guidelines have been published on the use of different types and dosages of IV fluid. This may have led to a change in clinical practice. Thus, we aim to describe the use of IV crystalloids and colloids in Europe over a 10-year period. METHODS AND ANALYSIS: We will collect national or regional data on the use of IV crystalloids and colloids in European hospitals through companies and/or federal medical agencies that provide pharmaceutical data concerning the type and amount of fluids used from January 1st, 2010 to December 31st, 2019. We will use run charts to describe time trends in the use of fluids. CONCLUSION: This study will provide insight into the use of IV fluids in Europe between 2010 and 2019. It will enable the observation of changes over time and among the different European countries and regions. This will provide information on the extent to which landmark trials and clinical practice guidelines on fluids have affected clinical practice in Europe regarding the use of IV fluids.

Acetate- vs lactate-buffered crystalloid solutions: Protocol for a systematic review with meta-analysis and trial sequential analysis.

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

Maternal obesity and its effect on labour duration in nulliparous women: a retrospective observational cohort study.

BACKGROUND: Obesity is increasing among primipara women. We aimed to describe the association between body mass index (BMI) during early-pregnancy and duration of labour in nulliparous women. METHODS: Retrospective observational cohort study of 1885 nulliparous women with a single cephalic presentation from 37 0/7 to 42 6/7 weeks of completed gestation and spontaneous or induced labour at Nordsjællands Hospital, University of Copenhagen, Denmark, in 2011 and 2012. Total duration of labour and the first and second stages of labour were compared between early-pregnancy normal-weight (BMI <25 kg/m2), overweight (BMI 25-29.9 kg/m2), and obese (BMI ≥30 kg/m2) women. Proportional hazards and multiple logistic regression models were applied. RESULTS: Early pregnancy BMI classified 1246 (66.1%) women as normal weight, 350 (18.6%) as overweight and 203 (10.8%) as obese. No difference in the duration of total or first stage of active labour was found for overweight (adjusted HR = 1.01, 95% CI 0.88-1.16) or obese (adjusted HR = 1.07, 95% CI 0.90-1.28) compared to normal weight women. Median active labour duration was 5.83 h for normal weight, 6.08 h for overweight and 5.90 h for obese women. The risk of caesarean delivery increased significantly for overweight and obese compared to normal weight women (odds ratios (OR) 1.62; 95%CI 1.18-2.22 and 1.76; 95%CI 1.20-2.58, respectively). Caesarean deliveries were performed earlier in labour in obese than normal-weight women (HR = 1.80, 95%CI 1.28-2.54). CONCLUSION: BMI had no significant effect on total duration of active labour. Risk of caesarean delivery increased with increasing BMI. Caesarean deliveries are undertaken earlier in obese women compared to normal weight women following the onset of active labour, shortening the total duration of active labour.