Critical Care Trials Research Articles

Outcome Measures in Critical Care Nutrition Interventional Trials: A Systematic Review.

Historically, randomized controlled trials (RCTs) in critical care have used mortality as the primary outcome, yet most show no effect on this outcome. Therefore, there has been a shift in the literature to focus on alternative outcomes. This review aimed to describe primary outcomes selected in RCTs of nutrition interventions in critical illness. Systematic search of the literature identified RCTs of nutrition interventions in critically ill adults published between January 2007 and December 2018. Primary outcomes were documented and categorized as mortality, morbidity, health service/cost-effectiveness, or nutrition outcome. The direction of effect of the intervention on the primary outcome (positive, neutral, or negative) was extracted. Of 1163 citations identified and assessed for eligibility, 125 articles were included. However, 52 articles (42%) did not provide a sample-size calculation, leaving 73 articles (58%) for data extraction. The primary outcomes reported were morbidity (n = 24, 32.9%); health service/cost-effectiveness (n = 21, 28.8%); nutrition outcomes (n = 16, 21.9%); mortality (n = 11, 15.1%); and other (n = 1, 1.4%). No RCTs with mortality as the primary outcome reported a difference between intervention and control. Trials that included other primary outcomes frequently reported a difference (n = 27 of 62; 43.5%). Morbidity was the most frequently reported outcome category in RCTs that evaluated a nutrition intervention in critically ill adults, with mortality least frequent. Power calculations were only reported in 58% of included studies. Trials were more likely to show a significant result when an outcome other than mortality was the primary outcome.

THE HIGH RISK OF TRANSFERS FROM EXTERNAL HOSPITALS TO TERTIARY CARDIAC INTENSIVE CARE UNITS: DATA FROM THE CRITICAL CARE CARDIOLOGY TRIALS NETWORK (CCCTN) REGISTRY

Pts treated in tertiary cardiac intensive care units (CICUs) often arrive via transfer from other hospitals, yet this “transfer population” is poorly described and has been largely excluded from trials in critical care. The CCCTN is an investigator-initiated multicenter network of CICUs in the

Contemporary strategies to improve clinical trial design for critical care research: insights from the First Critical Care Clinical Trialists Workshop.

BackgroundConducting research in critically-ill patient populations is challenging, and most randomized trials of critically-ill patients have not achieved pre-specified statistical thresholds to conclude that the intervention being investigated was beneficial.MethodsIn 2019, a diverse group of patient representatives, regulators from the USA and European Union, federal grant managers, industry representatives, clinical trialists, epidemiologists, and clinicians convened the First Critical Care Clinical Trialists (3CT) Workshop to discuss challenges and opportunities in conducting and assessing critical care trials. Herein, we present the advantages and disadvantages of available methodologies for clinical trial design, conduct, and analysis, and a series of recommendations to potentially improve future trials in critical care.ConclusionThe 3CT Workshop participants identified opportunities to improve critical care trials using strategies to optimize sample size calculations, account for patient and disease heterogeneity, increase the efficiency of trial conduct, maximize the use of trial data, and to refine and standardize the collection of patient-centered and patient-informed outcome measures beyond mortality.Electronic supplementary materialThe online version of this article (10.1007/s00134-020-05934-6) contains supplementary material, which is available to authorized users.

Review of Outcomes Used in Nutrition Trials in Pediatric Critical Care.

Generating robust evidence within pediatric intensive care (PIC) can be challenging because of low patient numbers and patient heterogeneity. Systematic reviews may overcome small study biases but are limited by lack of standardization in outcome measures and their definition. Trials of nutrition interventions in PIC are increasing; thus, we wanted to examine the outcome measures being used in these trials. Our objective was to systematically describe outcome measures used when a nutrition intervention has been evaluated in a PIC randomized controlled trial. A systematic literature review of all studies involving a PIC trial of a nutrition intervention was undertaken from January 1, 1996, until February 20, 2018. Twenty-nine trials met the criteria and were reviewed. They included a total of 3226 patients across all trials. Thirty-seven primary outcomes and 83 secondary outcomes were found. These were categorized into PIC-related outcomes (infection, intensive care dependency, organ dysfunction, and mortality) and nutrition outcomes (energy targets, nutrition parameters, and feeding tolerance). We found large variation in the outcome measures used. Outcome domains of energy targets, feeding tolerance, and infection were not adequately defined. Considerable variation in the outcome measures chosen and their definitions exist within PIC nutrition trials. Optimal nutrition outcomes for PIC must be agreed upon and defined, specifically domains of nutrition efficiency, nutrition tolerance, and non-nutrition PIC outcomes. The next step is to conduct an international Delphi study to gain expert consensus and develop a core outcome set to be reported in future pediatric nutrition trials.

Data initiatives supporting critical care research and quality improvement in Canada: an environmental scan and narrative review.

Collection and analysis of health data are crucial to achieving high-quality clinical care, research, and quality improvement. This review explores existing hospital, regional, provincial and national data platforms in Canada to identify gaps and barriers, and recommend improvements for data science. The Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group undertook an environmental survey using list-identified names and keywords in PubMed and the grey literature, from the Canadian context. Findings were grouped into sections, corresponding to geography, purpose, and patient sub-group initiatives, using a narrative qualitative approach. Emerging themes, impressions, and recommendations towards improving data initiatives were generated. In Canada, the Canadian Institute for Health Information Discharge Abstract Database contains high-level clinical data on every adult and child discharged from acute care facilities; however, it does not contain data from Quebec, critical care-specific severity of illness risk-adjustment scores, physiologic data, or data pertaining to medication use. Provincially mandated critical care platforms in four provinces contain more granular data, and can be used to risk adjust and link to within-province data sets; however, no inter-provincial collaborative mechanism exists. There is very limited infrastructure to collect and link biological samples from critically ill patients nationally. Comprehensive international clinical data sets may inform future Canadian initiatives. Clinical and biological data collection among critically ill patients in Canada is not sufficiently coordinated, and lags behind other jurisdictions. An integrated and inclusive critical care data platform is a key clinical and scientific priority in Canada.

Research Collaboration in Pediatric Critical Care Randomized Controlled Trials: A Social Network Analysis of Coauthorship.

Clinical research is a collaborative enterprise; researchers benefit from the expertise, experience, and resources of their collaborators. We sought to describe the extent and patterns of collaboration among pediatric critical care trialists, and to identify the most influential individuals, centers, and countries. Social network analysis of coauthorship. Publications of pediatric critical care randomized controlled trials (1986-2018). We manually extracted the names of all authors and their affiliations. We used productivity (number of randomized controlled trials), influence (number of citations), and four measures of prominence in the social network (degree, betweenness, closeness, and eigenvector centrality) to identify the most influential individuals. From 415 randomized controlled trials in pediatric critical care, we identified 2,176 trialists from 377 centers in 43 countries. The coauthorship network is highly disconnected and dominated by a single large cluster of trialists publishing 142 (34%) of the randomized controlled trials. However, 119 (29%) of the randomized controlled trials were published by 28 smaller clusters-a median (interquartile range) of 3 (2-4) randomized controlled trials each. The remaining 154 (37%) randomized controlled trials were coauthored by researchers publishing a single randomized controlled trial each. This overall structure has remained constant with the publication of new randomized controlled trials over 33 years. The most influential trialists and centers varied according to the metric we used; only one trialist and three centers ranked in the top 10 for all measures of influence. Thirty-five of the 40 trialists (88%) ranking in the top 10 of any of the measures were from the United States, the United Kingdom, and Canada. Pediatric critical care has made considerable progress in the number of trialists and randomized controlled trials, but the research enterprise remains highly clustered and fragmented, particularly geographically. Efforts to further increase the quantity and quality of research in the field should include steps to increase the level and range of collaboration.

Adjunctive continuous ketamine infusion to conventional sedation in mechanically ventilated patients: It is time for a randomized trial

Managing sedative and analgesic medications is an essential part of critical care medicine. There is a shift toward favoring the use of nonbenzodiazepine agents because of their side effects. There is an increasing interest in using ketamine as an analgo-sedative in the intensive care unit because of its unique pharmacologic properties. A comprehensive literature search was performed to capture all the studies involving ketamine use in critical care. We searched PubMed, EMBASE, and Cochrane databases. We also extracted the references from major review articles and recent guidelines. In this review, we present the most up-to-date studies done on this topic. We also present the proposal for a future multicenter randomized trial through the Saudi Critical Care Trials Group.

Timing and dose of pharmacological thromboprophylaxis in adult trauma patients

Pharmacological venous thromboembolism prophylaxis in the trauma population is considered a real challenge. Issues like the ideal time to start therapy, type and dose of the medication, and how to monitor these patients are controversial. We searched PUBMED, EMBASE, and COCHRANE Databases. We also extracted the references from major review articles and recent guidelines. The timing to start thromboembolic prophylaxis in patients with traumatic brain injuries, Spinal Cord Injuries (SCI), and solid organ injuries is not very well defined in the literature. This is because of the associated bleeding risk. At the same time, the type of chemical prophylaxis and dose are not well defined as well. In this review, we present the most up to date studies done on this topic. We discuss the areas of controversy and the challenges behind starting chemical prophylaxis. We also discuss areas of future research potentials to do multicenter studies through the Saudi Critical Care Trials Group.

How the COVID-19 Pandemic Affected the Care of the Surgical Patients in the Intensive Care Unit

The World Health Organization has announced COVID-19 as a pandemic in late 2019. It spread around the world, and the first case in Saudi Arabia was discovered in February of 2020. All types of patients have been affected including the surgical patients. In this review, we describe how the care of the surgical patients affected by the pandemic. The types of the surgical patients during the pandemic are described. These patients could be non-COVID patients or COVID patients requiring surgery. We describe as well how we take care of these patients if they require a surgical intervention. This review is part of the collaborative initiatives of the Saudi critical care trials group.

Remote Consent Clinical Research

Recruitment in clinical research trials can be challenging in trials that are time-sensitive and/or are rare disease and critical care trials. One of the hurdles for recruitment in these types of clinical trials is due to the consent process, and the need to have consent of the patient within a certain timeframe, or the patient unable to consent for themselves. This paper will discuss the usage of the utilization of remote consent options for these trials.

Research without prior consent in paediatric emergency and critical care medicine

Abstract Children and young peoples' healthcare should be evidence-based yet many treatments are unlicensed or prescribed off-label. Research is needed, but prospective informed consent for many emergency and critical care trials is neither feasible nor ethical – treatments are time critical, and delays for research discussions may cause harm. Research without prior consent (RWPC) is a practical approach which facilitates such research. Trial interventions are administered immediately to eligible patients, and consent for ongoing study involvement is sought after the emergency situation has passed. This has been permitted in the United Kingdom since an amendment to legislation in 2008, and subsequently employed by several trials. Studies demonstrate that most parents are supportive of this approach provided their child's safety is not compromised, and research discussions are appropriately timed. Practitioners with no experience of RWPC often initially report anxiety about taking this approach, but study experience and training helps change perspectives. Sadly, some children enrolled into such studies will die. Approaching bereaved families for consent requires a bespoke approach, conducted with care and sensitivity. Future research should explore the acceptability of higher risk trials, the viewpoints of children with first-hand experience of this method, and international perspectives.

Synthesis of qualitative research studies regarding the factors surrounding UK critical care trial infrastructure

Conducting clinical trials in critical care is integral to improving patient care. Unique practical and ethical considerations exist in this patient population that make patient recruitment challenging, including narrow recruitment...

P.169: Canada-DONATE: Preliminary results from a mutlicentre prospective observational study.

On behalf of the Canadian Critical Care Trials Group and. the Canadian Donation and Transplant Research Program. Background: Canadian donor management practices have not been reported. Our aim was to inform clinicians and other stakeholders about the range of current practices. Methods: We consecutively enrolled all consented adult deceased organ donors [donation after neurological determination of death (DND) and donation after circulatory determination of death (DCD)] in 32 participating hospitals across Canada, utilizing a waiver of research consent,. Research staff prospectively recorded detailed data from various hospital sources included death determination procedures, cardiopulmonary monitoring technologies, general prophylactic interventions, organ donation specific therapies and clinical complications, defined a priori, from one day prior to donation consent up to the time of organ recovery. Organ Donation Organizations provided reasons of organ decline, date, time and location of transplant procedure, and recipient age and sex. We formally compared practices across multiple provinces. Results: From August 2015 to August 2018, we screened 641 potential donors and enrolled 622, classified at baseline as having a neurological death (NDD donors; 403) or imminent circulatory death (DCD donors; 219). Mean age was 51.5 ± 16.6 and 40.0% were female. The most prevalent diagnoses leading to organ donation were anoxic brain injury (34.4%), brain hemorrhage (30.1%), brain trauma (23.6%), and stroke (6.6%). The mean time from donation consent to organ retrieval was similarly 1.6 days (±0.7SD) among NDD and DCD donors who ultimately donated organs. NDD donors, were more hemodynamically unstable: most received vasopressin and norepinephrine infusions, and a large majority received high-dose corticosteroids and intravenous thyroxine. Among DCD donors, 61.6% received corticosteroids, and 8.9% received thyroxine. Most donors (NDD and DCD) did not receive lung-protective tidal volumes or end expiratory pressures. Nutrition was generally continued for DCD donors, and discontinued for NDD donors. Case selection, death determinations, hormone, nutrition and heparin therapies all varied significantly across provinces. Conclusions: Study findings highlight areas for knowledge translation. Interprovincial discrepancies will pose unique challenges to national randomized trials.

Population enrichment for critical care trials: phenotypes and differential outcomes.

Sepsis and acute respiratory distress syndrome (ARDS) are two heterogenous acute illnesses where numerous RCTs have indeterminate results. We present a narrative review on the recent developments in enriching patient populations for future sepsis and ARDS trials. Many researchers are actively pursuing enrichment strategies to reduce heterogeneity to increase the sensitivity of future trials. Enrichment refers to the use of measurable patient characteristics, known before randomisation, to refine trial populations. Biomarkers could increase the diagnostic certainty of sepsis, whereas chest radiology training to enhance reliability of interpretation and stabilisation period of mechanical ventilation have been considered to increase the diagnostic certainty of ARDS. Clinical and biomarker data analyses identifies four to six sepsis clinical phenotypes and two ARDS clinical phenotypes. Similarly, leukocyte gene expression data identifies two to four sepsis molecular phenotypes. Use of a test-dose identifies ARDS subpopulations who are likely to benefit from higher PEEP. Early-phase trials report how a biomarker that is altered by the intervention, such as lymphocyte count for recombinant interleukin-7 therapy and higher check point inhibitor expression for anti-check point treatments in sepsis, could identify a higher treatment effect population for future trials. Enrichment reduces heterogeneity and will enhance the sensitivity of future trials. However, enrichment, even when it identifies more homogenous populations, may not be efficient to deploy in trials or clinical practice.

Difficulties in knowing which critical care trial data warrant change in practice.

Difficulties in knowing which critical care trial data warrant change in practice.

Measuring and Analyzing Length of Stay in Critical Care Trials.

In randomized clinical trials among critically ill patients, it is uncertain how choices regarding the measurement and analysis of nonmortal outcomes measured in terms of duration, such as intensive care unit (ICU) length of stay (LOS), affect studies' conclusions. Assess the definitions and analytic methods used for ICU LOS analyses in published randomized clinical trials. This is a systematic review and statistical simulation study. Among the 80 of 150 trials providing sufficient information regarding the chosen definition of ICU LOS, 3 different start times (ICU admission, trial enrollment/randomization, receipt of intervention) and 2 end times (discharge readiness, actual discharge) were used. In roughly three quarters of these studies, ICU LOS was compared using approaches that did not explicitly account for death, either by ignoring it entirely or stratifying the analyses by survival status. The remaining studies used time-to-event (discharge) models censoring at death or applied a fixed LOS value to patients who died. In statistical simulations, we showed that each analytic approach tested a different question regarding ICU LOS, and that approaches that do not explicitly account for death often produce misleading or ambiguous conclusions when treatments produce small effects on mortality, even if those are not detected as significant in the trial. There is considerable variability in how ICU LOS is measured and analyzed which impairs the ability to compare results across trials and can produce spurious conclusions. Analyses of duration-based outcomes such as LOS should jointly assess the impact of the intervention on mortality to yield correct interpretations.

Brain-related outcome measures in trials recruiting critically-ill children.

Randomized controlled trials leading to innovations that improve outcomes in acute life-threatening illnesses in children are scarce. A key issue is how we refocus research on outcomes that matter and are more relevant to those making emergency decisions, and those involved with managing and living with the late-outcome. We have used information from recent trials in critically ill children - in particular those illnesses without any primary neurologic involvement - to develop an approach to brain-related outcomes that will maximize child and family benefit from research. Fifteen recent pediatric critical care trials illustrate four types of brain-related outcomes assessment: death or organ-system-failures - as illustrated by studies in systemic illness; neurological and neuropsychological outcomes - as illustrated by the glycemic control studies; cognitive outcomes - as illustrated by a sedative trial; and composite outcomes - as illustrated by the therapeutic hypothermia studies. The 15 research trials point to five areas that will need to be addressed and incorporated into future trial design, including use of: neurologic monitoring during intensive care unit admission; postdischarge outcomes assessments; strategies to improve retention in long-term follow-up; child and family-centered outcomes; and core outcomes datasets.

Assessing the relationship between near-infrared spectroscopy-derived regional cerebral oxygenation and neurological dysfunction in critically ill adults: a prospective observational multicentre protocol, on behalf of the Canadian Critical Care Trials Group

IntroductionSurvivors of critical illness frequently exhibit acute and chronic neurological complications. The underlying aetiology of this dysfunction remains unknown but may be associated with cerebral ischaemia. This study will use...

Using Bayesian adaptive designs to improve phase III trials: a respiratory care example

BackgroundBayesian adaptive designs can improve the efficiency of trials, and lead to trials that can produce high quality evidence more quickly, with fewer patients and lower costs than traditional methods. The aim of this work was to determine how Bayesian adaptive designs can be constructed for phase III clinical trials in critical care, and to assess the influence that Bayesian designs would have on trial efficiency and study results.MethodsWe re-designed the High Frequency OSCillation in Acute Respiratory distress syndrome (OSCAR) trial using Bayesian adaptive design methods, to allow for the possibility of early stopping for success or futility. We constructed several alternative designs and studied their operating characteristics via simulation. We then performed virtual re-executions by applying the Bayesian adaptive designs using the OSCAR data to demonstrate the practical applicability of the designs.ResultsWe constructed five alternative Bayesian adaptive designs and identified a preferred design based on the simulated operating characteristics, which had similar power to the original design but recruited fewer patients on average. The virtual re-executions showed the Bayesian sequential approach and original OSCAR trial yielded similar trial conclusions. However, using a Bayesian sequential design could have led to a reduced sample size and earlier completion of the trial.ConclusionsUsing the OSCAR trial as an example, this case study found that Bayesian adaptive designs can be constructed for phase III critical care trials. If the OSCAR trial had been run using one of the proposed Bayesian adaptive designs, it would have terminated at a smaller sample size with fewer deaths in the trial, whilst reaching the same conclusions. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials.Trial registrationOSCAR Trial registration ISRCTN, ISRCTN10416500. Retrospectively registered 13 June 2007.

Effects of simulated sample sizes on mortality estimates-Protocol for a study in 3 randomised ICU trials.

An increasing number of trials are stopped earlier than originally planned. It has been suggested that trials stopped pre-maturely overestimate the treatment effect. With the outlined observational study, we aim to simulate the results of stopping trials before they reach their planned sample size to assess the effects on mortality estimates. Based on 3 international, randomised clinical trials (RCTs) in critical care: Scandinavian Starch for Severe Sepsis and Septic Shock (6S) trial, the Transfusion Requirements in Septic Shock (TRISS) trial and the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial, we will estimate relative risks with 95% confidence intervals for the primary outcome 90-day mortality after the inclusion of each individual patient in each RCT. This will be presented graphically with the primary outcome as a function of the number of included patients. The outlined study will provide important knowledge about the effects of stopping critical care trials early. This may have important implications for patients, relatives, clinicians, researchers, guideline committee members and policy makers. We will use data from consenting patients enrolled in RCTs approved by the relevant ethical committees; this study requires no further permissions. We will report the results in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement and submit the final approved manuscript to a peer-reviewed journal.