Clinical Trials In Critical Care Research Articles

Gender Disparity in Leading Authorship of Critical Care Clinical Trials: A Systematic Review and Meta-Analysis.

In critical care medicine, research trials serve as crucial avenues for disseminating knowledge, influencing clinical practices, and fostering innovation. Notably, a significant gender imbalance exists within this field, potentially mirrored in the authorship of critical care research. This study aimed to investigate an exploration to ascertain the presence and extent of female representation in first and senior authorship roles within critical care literature. To this end, a systematic search was conducted across PubMed, Google Scholar, and Web of Science databases for original articles published up to February 2024, coupled with a methodological quality assessment via the Newcastle-Ottawa Scale (NOS) and statistical analyses through Review Manager software (RevMan, version 5.4.1, The Cochrane Collaboration, 2020). The study's findings, distilled from seven studies included in the final analysis, reveal a pronounced gender disparity. Specifically, in critical care literature examining mixed populations, female first authors were significantly less common than their male counterparts, with an odds ratio (OR) of 4.25 (95% confidence interval (CI): 3.18-5.68; p < 0.00001). Conversely, pediatric critical care studies did not show a significant difference in gender distribution among first authors (OR: 1.37; 95% CI: 0.31-6.10; p = 0.68). The investigation also highlighted a stark underrepresentation of female senior authors in critical care research across both mixed (OR: 11.67; 95% CI: 7.76-17.56; p < 0.00001) and pediatric populations (OR: 5.41; 95% CI: 1.88-15.56; p = 0.002). These findings underscore the persistent underrepresentation of women in critical care literature authorship and their slow progression into leadership roles, as evidenced by the disproportionately low number of female senior authors.

Public perception of participation in low-risk clinical trials in critical care using waived consent: a Canadian national survey.

The acceptability of waiver of consent for participation in clinical research in intensive care unit (ICU) settings is uncertain. We sought to survey the Canadian public to assess levels of support, comfort, and acceptability for waived consent for low-risk clinical trials. We performed a prospective cross-sectional survey of the Canadian public aged 18yr or older. The survey was conducted by Ipsos between 19 and 23 November 2020. The survey content was derived from a literature review and in consultation with a patient and family partnership committee. The survey focused on attitudes and beliefs on waived consent for participation in low-risk clinical trials in ICU settings. The survey contained 35 items focused on sociodemographics, general health status, participation in medical research, and levels of support and comfort with research and with waived consent. The survey used a case study of a low-risk clinical trial intervention in ICU patients. Analysis was descriptive. We included 2,000 participants, 38% of whom reported experience with ICU and 16% with medical research. Participation in medical research was more common among those with postsecondary education, those with chronic disease, and those who were employed in health care. Most (80%) would support a model of waived consent for low-risk clinical trials, citing medical benefits (36%) and low perceived risk (34%). Most (77%) were comfortable with personally participating in a low-risk clinical trial. Most (80%) believed waived consent approaches were acceptable. Half (52%) believed the waived consent process should provide information about the research and include the option of opting out. When asked whether participants should always give full informed consent, regardless of the practicality or level of risk, 74% and 72% agreed, respectively. There is public support for models of waived consent for participation in low-risk pragmatic clinical trials in ICU settings in Canada; however, this is not universal. This information can inform and guide education, ethics, policy, and legal discussion on consent models.

Barriers and Facilitators of Surrogates Providing Consent for Critically Ill Patients in Clinical Trials: A Qualitative Study

BackgroundEnrollment into critical care clinical trials is often hampered by the need to rely on surrogate decision-makers. To identify potential interventions facilitating enrollment into critical care clinical trials, a better understanding of surrogate decision-making for critical care clinical trial enrollment is needed. Research QuestionWhat are the barriers and facilitators of critical care trial enrollment? What are surrogate decision makers’ perspectives on proposed interventions to facilitate trial enrollment? Study Design and MethodsThe authors conducted semi-structured interviews with 20 surrogate decision-makers of critically ill patients receiving mechanical ventilation. The interviews were recorded and transcribed verbatim, and analyzed for themes using an inductive approach. ResultsTwenty surrogate decision-makers of critically ill patients participated in the semi-structured interviews. Thematic analysis confirmed previous research showing that trust in the system, assessing the risks and benefits of trial participation, the desire to help others, and building medical knowledge as important motivating factors for trial enrollment. Two previously undescribed concerns among surrogate decision makers of critically ill patients were identified, including the potential to interfere with clinical treatment decisions and negative sentiment about placebos. Surrogates viewed public recognition and charitable donations for participation as favorable potential interventions to encourage trial enrollment. However, participants viewed direct financial incentives and prioritizing research participants during medical rounds negatively. InterpretationThis study confirms and extends previous findings that health system trust, study risks and benefits, altruism, knowledge generation, interference with clinical care and placebos are key concerns and barriers for surrogate decision-makers to enroll patients in critical care trials. Future studies are needed to evaluate if charitable giving on the patient's behalf and public recognition are effective strategies to promote enrollment into critical care trials.

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

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. 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. 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. 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.

A negative trial for vasoactive intestinal peptide in COVID-19-associated acute hypoxaemic respiratory failure

A negative trial for vasoactive intestinal peptide in COVID-19-associated acute hypoxaemic respiratory failure

Trend in Clinical Trial Participation During COVID-19: A Secondary Analysis of the I-SPY COVID Clinical Trial.

Secondary analysis of data from the I-SPY COVID randomized controlled trial (RCT). Thirty-one hospitals throughout the United States. Patients who were approached, either directly or via a legally authorized representative, for consent and enrollment into the I-SPY COVID RCT. None. Among 1,338 patients approached for the I-SPY COVID trial from July 30, 2020, to February 17, 2022, the number of patients who enrolled (n = 1,063) versus declined participation (n = 275) was used to calculate monthly enrollment rates. Overall, demographic and baseline clinical characteristics were similar between those who enrolled versus declined. Enrollment rates fluctuated over the course of the COVID-19 pandemic, but there were no significant trends over time (Mann-Kendall test, p = 0.21). Enrollment rates were also comparable between vaccinated and unvaccinated patients. In multivariable logistic regression analysis, age, sex, region of residence, COVID-19 severity of illness, and vaccination status were not significantly associated with the decision to decline consent. In this secondary analysis of the I-SPY COVID clinical trial, there was no significant association between the enrollment rate and time period or vaccination status among all eligible patients approached for clinical trial participation. Additional studies are needed to better understand whether the COVID-19 pandemic has altered clinical trial participation and to develop strategies for encouraging participation in future COVID-19 and critical care clinical trials.

Heterogeneity of surrogate outcome measures used in critical care studies: A systematic review.

The choice of outcome measure is a critical decision in the design of any clinical trial, but many Phase III clinical trials in critical care fail to detect a difference between the interventions being compared. This may be because the surrogate outcomes used to show beneficial effects in early phase trials (which informed the design of the subsequent Phase III trials) are not valid guides to the differences between the interventions for the main outcomes of the Phase III trials. We undertook a systematic review (1) to generate a list of outcome measures used in critical care trials, (2) to determine the variability in the outcome reporting in the respiratory subgroup and (3) to create a smaller list of potential early phase endpoints in the respiratory subgroup. Data related to outcomes were extracted from studies published in the six top-ranked critical care journals between 2010 and 2020. Outcomes were classified into subcategories and categories. A subset of early phase endpoints relevant to the respiratory subgroup was selected for further investigation. The variability of the outcomes and the variability in reporting was investigated. A total of 6905 references were retrieved and a total of 294 separate outcomes were identified from 58 studies. The outcomes were then classified into 11 categories and 66 subcategories. A subset of 22 outcomes relevant for the respiratory group were identified as potential early phase outcomes. The summary statistics, time points and definitions show the outcomes are analysed and reported in different ways. The outcome measures were defined, analysed and reported in a variety of ways. This creates difficulties for synthesising data in systematic reviews and planning definitive trials. This review once again highlights an urgent need for standardisation and validation of surrogate outcomes reported in critical care trials. Future work should aim to validate and develop a core outcome set for surrogate outcomes in critical care trials.

Prospective Study of Immune Phenotype and Associated Outcomes in Patients with Leukemia and Acute Respiratory Distress Syndrome

Background: Patients with active malignancy are frequently admitted to intensive care units (ICUs) and experience organ failure including acute respiratory distress syndrome (ARDS). In ARDS clinical trial populations, two immune phenotypes have been identified which seem to differ based on plasma protein expression, predicted mortality, and response to several randomized therapies. It is unknown if similar patters exist among ICU patients with hematologic malignancies as these patients are often excluded from clinical trials in critical care. We therefore sought to classify patients with leukemia who develop ARDS secondary to septic insult according to validated immune phenotyping algorithms and describe their characteristics and outcomes. Methods: We conducted a prospective cohort study of sepsis subjects admitted to the ICU. Eligible patients had suspected infection and organ injury upon ICU admission; exclusion criteria included non-infectious causes of organ failure, a desire for comfort measures only, or lack of informed consent. Plasma collected on day 0 of ICU admission was profiled for proteins including IL8 and sTNFR1 by electrochemiluminescence. We limited our investigation to subjects with a diagnosis of active leukemia (acute or chronic) who developed ARDS (by Berlin criteria) within 6 days of ICU admission. Using a published parsimonious algorithm incorporating plasma IL8, sTNFR1, and bicarbonate, we assigned either a hyper- or hypo-inflammatory ARDS immune phenotype. We then constructed a multivariable Cox proportional hazards model controlling for APACHE III, history of BMT, sex, acute vs. chronic leukemia, and site of infection to assess the independent effect of phenotype assignment on mortality. Univariate comparisons between patients assigned to either phenotype were made as appropriate with T or Chi-Square tests. Results: 86 subjects diagnosed with leukemia and ARDS between 2008 and 2017 were identified. In-hospital mortality was 76%. 64 (74.4%) were assigned a hyper-inflammatory phenotype using the 3-marker algorithm. Male sex, higher APACHE III, and non-pulmonary infectious source appeared to be associated with hyper-inflammatory assignment in univariate comparison, while tumor-specific characteristics such as leukemia type and cytogenetic features were not (table 1). Median survival in the hyper-inflammatory group was 6 days vs. 20 in the hypo-inflammatory group (log-rank p = 0.04, figure 1). However in our Cox proportional hazards model ARDS immune phenotype was not significantly associated with mortality (HR 1.63, 95% CI 0.87 - 3.08, p = 0.12). A sub-analysis of patients diagnosed with AML did not reveal any association between European LeukemiaNet cytogenetic risk category and mortality, controlling for the same baseline covariates and immune phenotype. Interpretation: We identified previously described ARDS immune phenotypes among leukemic ARDS patients, though we did not observe an independent association between immune phenotype and mortality when controlling for relevant baseline covariates. At 76%, overall mortality was consistent with prior estimates in oncologic ICU patients and higher than the general population (~40%). A higher proportion of leukemia subjects were assigned to the hyper-inflammatory phenotype (74.4%) than described in non-oncologic trial populations (30-35% in 5 prior ARDS trials). Limitations include small sample size and knowledge that both malignancy and immunosuppression may affect cytokine expression such that phenotypic assignment is unreliable. Future efforts might focus on re-deriving ARDS phenotypes from a larger cohort of patients with hematologic malignancies in order to better understand how tumor interacts with the immunopathology of their critical illness. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

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. 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. 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.

Randomised clinical trials in critical care: past, present and future.

Randomised clinical trials (RCTs) are the gold standard for providing unbiased evidence of intervention effects. Here, we provide an overview of the history of RCTs and discuss the major challenges and limitations of current critical care RCTs, including overly optimistic effect sizes; unnuanced conclusions based on dichotomization of results; limited focus on patient-centred outcomes other than mortality; lack of flexibility and ability to adapt, increasing the risk of inconclusive results and limiting knowledge gains before trial completion; and inefficiency due to lack of re-use of trial infrastructure. We discuss recent developments in critical care RCTs and novel methods that may provide solutions to some of these challenges, including a research programme approach (consecutive, complementary studies of multiple types rather than individual, independent studies), and novel design and analysis methods. These include standardization of trial protocols; alternative outcome choices and use of core outcome sets; increased acceptance of uncertainty, probabilistic interpretations and use of Bayesian statistics; novel approaches to assessing heterogeneity of treatment effects; adaptation and platform trials; and increased integration between clinical trials and clinical practice. We outline the advantages and discuss the potential methodological and practical disadvantages with these approaches. With this review, we aim to inform clinicians and researchers about conventional and novel RCTs, including the rationale for choosing one or the other methodological approach based on a thorough discussion of pros and cons. Importantly, the most central feature remains the randomisation, which provides unparalleled restriction of confounding compared to non-randomised designs by reducing confounding to chance.

A Bayesian analysis of mortality outcomes in multicentre clinical trials in critical care

BackgroundMulticentre RCTs are widely used by critical care researchers to answer important clinical questions. However, few trials evaluating mortality outcomes report statistically significant results. We hypothesised that the low proportion of trials reporting statistically significant differences for mortality outcomes is plausibly explained by lower-than-expected effect sizes combined with a low proportion of participants who could realistically benefit from studied interventions. MethodsWe reviewed multicentre trials in critical care published over a 10-yr period in the New England Journal of Medicine, the Journal of the American Medical Association, and the Lancet. To test our hypothesis, we analysed the results using a Bayesian model to investigate the relationship between the proportion of effective interventions and the proportion of statistically significant results for prior distributions of effect size and trial participant susceptibility. ResultsFive of 54 trials (9.3%) reported a significant difference in mortality between the control and the intervention groups. The median expected and observed differences in absolute mortality were 8.0% and 2.0%, respectively. Our modelling shows that, across trials, a lower-than-expected effect size combined with a low proportion of potentially susceptible participants is consistent with the observed proportion of trials reporting significant differences even when most interventions are effective. ConclusionsWhen designing clinical trials, researchers most likely overestimate true population effect sizes for critical care interventions. Bayesian modelling demonstrates that that it is not necessarily the case that most studied interventions lack efficacy. In fact, it is plausible that many studied interventions have clinically important effects that are missed.

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...

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.

Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial

Precision medicine approaches that target patients on the basis of disease subtype have transformed treatment approaches to cancer, asthma, and other heterogeneous syndromes. Two distinct subphenotypes of acute respiratory distress syndrome (ARDS) have been identified in three US-based clinical trials, and these subphenotypes respond differently to positive end-expiratory pressure and fluid management. We aimed to investigate whether these subphenotypes exist in non-US patient populations and respond differently to pharmacotherapies. HARP-2 was a multicentre, randomised controlled trial of simvastatin (80 mg) versus placebo done in general intensive care units (ICUs) at 40 hospitals in the UK and Ireland within 48 h of onset of ARDS. The primary outcome was ventilator-free days, and secondary outcomes included non-pulmonary organ failure-free days and mortality. In a secondary analysis of HARP-2, we applied latent class analysis to baseline data without consideration of outcomes to identify subphenotypes, and we compared clinical outcomes across subphenotypes and treatment groups. 540 patients were recruited to HARP-2. One patient withdrew consent for the use of their data, so data from 539 patients were analysed. In our secondary analysis, a two-class (two subphenotype) model was an improvement over a one-class model (p<0·0001), with 353 (65%) patients in the hypoinflammatory subphenotype group and 186 (35%) in the hyperinflammatory subphenotype group. Additional classes did not improve model fit. Clinical and biological characteristics of the two subphenotypes were similar to previous studies. Patients with the hyperinflammatory subphenotype had fewer ventilator-free days (median 2 days [IQR 0-17] vs 18 [IQR 0-23]; p<0·0001), fewer non-pulmonary organ failure-free days (15 [0-25] vs 27 [21-28]; p<0·0001), and higher 28-day mortality (73 [39%] vs 59 [17%]; p<0·0001) than did those with the hypoinflammatory subphenotype. Although HARP-2 found no difference in 28-day survival between placebo and simvastatin, significantly different survival was identified across patients stratified by treatment and subphenotype (p<0·0001). Specifically, within the hyperinflammatory subphenotype, patients treated with simvastatin had significantly higher 28-day survival than did those given placebo (p=0·008). A similar pattern was observed for 90-day survival. Two subphenotypes of ARDS were identified in the HARP-2 cohort, with distinct clinical and biological features and disparate clinical outcomes. The hyperinflammatory subphenotype had improved survival with simvastatin compared with placebo. These findings support further pursuit of predictive enrichment strategies in critical care clinical trials. UK Efficacy and Mechanism Evaluation Programme and National Institutes of Health.

Asian intensive care research and education

Collaboration in both research and education are crucial in advancing Intensive Care in Asia. Progress in collaborative research is already being made through the Asian Critical Care Clinical Trials group and national groups and in collaborative education through the BASIC Collaboration.

Exploring obstacles to critical care trials in the UK: A qualitative investigation

Clinical trials in critical care are often resource-intense, with many unique challenges. Barriers to effective recruitment and implementation of study intervention have not been explored in a UK context. To identify facilitating factors and barriers to enrolling patients into critical care clinical trials within the UK from clinician's perspectives. A qualitative interview study was undertaken on behalf of the National Institute of Health Research critical care specialty group, in which research active clinicians across different Clinical Research Networks were interviewed. A loosely structured interview schedule was used, based on themes generated from the literature associated with accessing critical care trials. Research teams (critical care doctors, research nurses, and trial coordinators) from hospitals from each Clinical Research Network were contacted to try to achieve representation across the UK. Interviews were carried out across nine UK Clinical Research Networks with a range of doctors and research nurses. All hospitals were teaching hospitals with varying research nurse numbers and allocated consultant research sessions. There were a range of six to nine ongoing clinical trials in critical care for each centre representative interviewed. Data were analysed using framework analysis, and six final themes were identified related to factors associated with: centre, unit, resources, study, clinician, and patient/family. The most commonly cited barrier to conducting clinical trials was related to resources, namely insufficient human and financial resources, leading to staff and study recruitment difficulties. Clinical uncertainty and equipoise regarding comparative merits of trials were challenging in terms of engaging critical care teams. A number of patient and family factors added complexities in terms of recruitment; however, refusal rates were generally reported as low. Flexibility in funding and employment by research teams enables continuity of studies and staff. Innovative measures to incentivise research nurses and clinical teams can help recruit more patients into trials. Research teams are highly committed to providing cover to recruit critical care trials, and a significant effort to anticipate barriers is undertaken; these endeavours are summarised to provide guidance for other teams wishing to address any potential difficulties.

Determinants of Citation Impact in Large Clinical Trials in Critical Care: The Role of Investigator-Led Clinical Trials Groups.

Randomized clinical trials provide the best evidence of treatment effectiveness; factors determining their impact are unknown. We sought to determine the influence of funding (industry vs nonindustry), research (comparative effectiveness vs technology evaluation), and organizational models (investigator-led trials group vs others) on the impact of large trials in critical care medicine. We searched MEDLINE for randomized clinical trials published between 1990 and 2012 in five critical care, five general interest, and one pediatrics journal. Impact was evaluated as annual citation rates measured using the ISI Web of Knowledge database. Eligible trials enrolled at least 100 critically ill adults, children, or neonates, evaluated an intervention that was applied during the ICU stay, and reported mortality and/or length of ICU or hospital stay. Two reviewers identified eligible studies, and two separate reviewers extracted data. We identified 391 randomized clinical trials, recruiting 208,154 subjects. Funding source--industry versus peer review versus mixed--did not impact citation rates. Comparative effectiveness studies made up 52.5% of the reports and were cited more frequently than studies evaluating novel technologies (median, 15.6 vs 10.3 citations/yr; p = 0.002). Trials conducted by investigator-led trials groups (n = 45) were cited a median of 45.7 (interquartile range [IQR], 17.3-86.2) times per year, significantly more often (p < 0.0001) than multicenter trials conducted by ad hoc groups (n = 89; median, 19 [IQR, 8.7-30.4]) or industry (n = 85; median, 12.3 [IQR, 5.4-24.1]), and more than single-center trials (n = 116; median, 6.8 [IQR, 3.5-12.8]) or small ad hoc trials involving two to five centers (n = 59; median, 11.0 [IQR, 4.5-22.4]). Although only 11.5% of all trials included, randomized clinical trials from investigator-led research consortia accounted for nine of the 16 studies cited more than 100 times per year and 23.4% of all citations; their costs were substantially less than the typical costs of industry-run trials.. Clinical trials conducted by investigator-led research groups are significantly more frequently cited than industry-led trials in critical care medicine. In addition, costs appear to be substantially lower with investigator-led trials. Support for and expansion of this model of research can ensure that critical care research is clinically relevant and practice changing.

The tens of thousands of lives saved by randomized clinical trials in critical care.

The tens of thousands of lives saved by randomized clinical trials in critical care.

Registration and design alterations of clinical trials in critical care: a cross-sectional observational study.

In 2005 the International Committee of Medical Journal Editors issued a requirement that all randomized controlled trials (RCTs) be registered primarily to prevent selective reporting (publication bias). However, registries allow for alterations in study protocol. Changes occurring before (or after) study completion could invalidate the original study intent, leading to publication of misleading conclusions. In RCTs involving critically ill patients, these concerns may be particularly acute because mortality is high and conditions investigated are usually syndromes rather than specific diseases. This study was conducted to estimate the registration rate of RCTs in critical care; and, among registered RCTs, to determine timing of registration and whether sample size or primary outcome were altered. We searched the MEDLINE database for RCTs that began after or continued through July 2005. We determined whether each trial had been registered and, for registered trials, compared registry data to data in the published manuscript. Approximately two-thirds (66%) of trials were registered. Of these, 66% of registrations occurred after enrolment had commenced. Overall, 6% (5/90) of trials appropriately registered a sample size which was unchanged from the interval between registration and publication, and only 12% (11/90) reported primary outcomes that were both appropriately registered and unchanged. Non-registration, or registration after trial initiation, are common in RCTs of critically ill patients. Among registered trials important protocol changes are often made between trial commencement and publication. This study identifies and quantifies the extent of this serious-but correctable-problem for RCTs in critically ill patients.

Research networks and clinical trials in critical care in Brazil: current status and future perspectives.

Research networks and clinical trials in critical care in Brazil: current status and future perspectives.