Critical Care Trials Research Articles

Pediatric intensive care stress ulcer prevention (PIC-UP): a protocol for a pilot randomized trial

BackgroundDespite sparse pediatric data on effectiveness, the majority of critically ill children receive medications to prevent gastrointestinal (GI) bleeding. Stress ulcer prophylaxis may have unintended consequences—increasing the risk of nosocomial infections—which may be more serious and common than the bleeding which these drugs are prescribed to prevent. Randomized controlled trials (RCTs) in pediatric critical care are exceptionally challenging to complete, thus a rigorous pilot RCT is crucial. The objective of this pilot RCT is to assess the feasibility of a large multicentre RCT of stress ulcer prophylaxis with pantoprazole to prevent upper GI bleeding vs. placebo.MethodsA multi-centre blinded pilot RCT of 120 children in six Canadian PICUs. Children expected to require mechanical ventilation for more than 48 h will be randomized to receive intravenous pantoprazole 1 mg/kg or identical placebo once daily until they no longer need mechanical ventilation. We have four feasibility outcomes and will consider the trial successful if we achieve:Effective screening: If >80% of eligible patients are approached for consent.Timely enrollment: if >80% of participants receive their first dose of the assigned study drug within 1 day of becoming eligible.Participant accrual: If the average monthly enrolment is two or more participants per centre per month.Protocol adherence: if >90% of doses are administered according to the protocol.DiscussionThere are many uncertainties about the risks and benefits of stress ulcer prophylaxis. In an era of widespread use—where clinicians prescribe prophylaxis to the more severely ill—a large, rigorous RCT is required. A trial to determine if a strategy of withholding stress ulcer prophylaxis is not inferior to a strategy of routine stress ulcer prophylaxis will be challenging. A carefully designed and implemented pilot trial is essential.Trial registrationClinicalTrials.gov:NCT02929563 (Registered October 3, 2016).

High-Quality Randomized Controlled Trials in Pediatric Critical Care: A Survey of Barriers and Facilitators.

High-quality, adequately powered, randomized controlled trials are needed to inform the care of critically ill children. Unfortunately, such evidence is not always available. Our objective was to identify barriers and facilitators of conducting high-quality randomized controlled trials in pediatric critical care, from the perspective of trialists in this field. Self-administered online survey. Respondents rated the importance of barriers and effectiveness of facilitators on seven-point scales. Authors of 294 pediatric critical care randomized controlled trials (published 1986 to June 2015). One hundred sixteen researchers from 25 countries participated. None. Respondents reported a median (Q1, Q3) of 21 years (15, 26 yr) of experience and 41 (36%) had authored more than one randomized controlled trial. More survey respondents, compared with nonrespondents, had published more than one trial (35% vs 26%; p = 0.002) and their trials were more often cited (median citations/yr, 2.4 vs 1.5; p < 0.001). Of the barriers listed, the five most important were primarily related to lack of funding. The five facilitators perceived as most effective were protected time for research, ability to recruit participants 24 hours per day/7 days per week, conducting randomized controlled trials in collaboration with a research network, funding from government agencies specifically for randomized controlled trials in critically ill children, and academic department support for conducting randomized controlled trials. Respondent experience and country income level were associated with differences in importance ratings for eight of 41 barriers. There were fewer such differences for facilitators. Lack of funding and time are major barriers to conducting pediatric critical care randomized controlled trials worldwide. Although barriers varied among country income levels, the facilitators of such trials were more consistent. In addition to increased funding, respondents identified other strategies such as research networks that are within the purview of the pediatric critical care research community, to facilitate the conduct of rigorous randomized controlled trials.

Patient Eligibility for Randomized Controlled Trials in Critical Care Medicine: An International Two-Center Observational Study.

We conducted this study to determine the generalizability of information gained from randomized controlled trials in critically ill patients by assessing the incidence of eligibility for each trial. Prospective, observational cohort study. We identified the 15 most highly cited randomized controlled trials in critical care medicine published between 1998 and 2008. We examined the inclusion and exclusion criteria for each randomized controlled trial and then assessed the eligibility of each patient admitted to a study ICU for each randomized controlled trial and calculated rates of potential trial eligibility in the cohort. Three ICUs in two academic medical centers in Canada and the United States. Adults admitted to participating medical or surgical ICU in November 2010 or July 2011. Among the 15 trials, the most common trial inclusion criteria were clinical criteria for sepsis (six trials) or acute respiratory distress syndrome (four trials), use of invasive mechanical ventilation (five trials) or related to ICU type or duration of ICU stay (five trials). Of the 93 patients admitted to a study ICU, 52% of patients (n = 48) did not meet enrollment criteria for any studied randomized controlled trial and 30% (n = 28) were eligible for only one of the 15. Trial ineligibility was mostly due to failure to meet inclusion criteria (87% of screening assessments) rather than meeting specific exclusion criteria (52% of screening assessments). Of the positive screening assessments, 85% occurred on the first day of ICU admission. Slightly more than half of the patients assessed were not eligible for enrollment in any of 15 major randomized controlled trials in critical care, most often due to the absence of the specific clinical condition of study. The majority of patients who met criteria for a randomized controlled trial did so on the first day of ICU admission.

Reporting of critical care trial abstracts: a comparison before and after the announcement of CONSORT guideline for abstracts

BackgroundAn extension of the Consolidated Standards of Reporting Trials (CONSORT) statement provides a checklist of items to improve the reporting quality of abstracts of randomized controlled trials (RCTs). However, authors of abstracts in some fields have poorly adhered to this guideline. We did an extensive literature survey to examine the quality of reporting trial abstracts in major critical care journals before and after announcement of the CONSORT guideline for abstracts.MethodsWe reviewed abstracts of RCTs published in four major critical care journals with publication dates ranging from 2006 to 2007 (pre-CONSORT) and from 2011 to 2012 (post-CONSORT): Intensive Care Medicine (ICM), Critical Care (CC), American Journal of Respiratory and Critical Care Medicine (AJRCCM), and Critical Care Medicine (CCM). For each item in the CONSORT guideline for abstracts, we considered that an abstract was well-reported when it reported a relevant item and adhered to the guideline. Our primary outcomes were to describe the proportion of abstracts that adhered to the guideline for each item in each period and the changes between the two periods. Pearson’s chi-square analysis was performed to compare adherence to the guideline between the two periods.ResultsOur inclusion criteria yielded 185 and 166 abstracts from pre- and post-CONSORT periods, respectively. Less than 50% of abstracts adequately reported trial design (16.3%), participants (44.0%), outcomes in methods (49.4%), randomization (1.8%), blinding (4.2%), numbers randomized (37.4%) and analyzed (8.4%), recruitment (4.2%), outcomes in results (16.9%), harms (27.7%), trial registration (42.2%), and funding (13.9%) in the recent period. There was significant improvement in reporting title, primary outcomes in both methods and results, interventions, harms, trial registration, and funding between the two periods (p < 0.05). Improvements were seen in reporting of participants in the Methods sections in CCM, as well as in outcomes in results and trial registration in AJRCCM and CCM, between the two periods. A significant decline was noted in reporting of interventions in Methods sections in AJRCCM and ICM, as well as the numbers randomized in Results sections in CC, over time.ConclusionsReporting of some items in abstracts for critical care trials improved over time, but the adherence to the CONSORT guideline for abstracts was still suboptimal.

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.

The Impact of Clinical Trials Conducted by Research Networks in Pediatric Critical Care.

Research networks in adult and neonatal critical care have demonstrated collaborative and successful execution of clinical trials. Such networks appear to have been relatively recently established in the field of pediatric critical care. The objective of this study was to evaluate the productivity and impact of randomized controlled trials conducted by pediatric critical care research networks, compared with nonnetwork trials. We searched multiple online databases including MEDLINE, reference lists of randomized controlled trials, and relevant systematic reviews. Independent pairs of reviewers identified published randomized controlled trials administering any intervention to children in a PICU and abstracted data. A research network was defined as a formal consortium or collaborative research group established for the purpose of conducting clinical research. Data were independently abstracted in duplicate. There were 288 pediatric critical care randomized controlled trials published in English between 1986 and July 2015, of which 15 randomized controlled trials (5.2%) were conducted by a total of five research networks. Network randomized controlled trials were more often multicentered, multinational, and larger in size (p < 0.001), compared with nonnetwork randomized controlled trials. Accordingly, their trials took longer to complete (median, 36 vs 21 mo; p < 0.001). Early stopping occurred in 46.7% of network randomized controlled trials (46.7%) and 27% of nonnetwork randomized controlled trials (p = 0.14), most commonly for futility. None of the network, but 45% of the nonnetwork trials found a significant difference in their primary outcome (p < 0.001). Network trials were more frequently cited (median, 6 vs 2 citations per year) and published in higher impact journals (median impact factor, 21.8 vs 3; p < 0.001). Research networks have conducted a minority of randomized controlled trials in pediatric critical care. They infrequently demonstrate significant differences in their primary outcomes. Despite this, network trials are cited more frequently and appear to have greater impact. There are important lessons to learn from both individual researchers as well as research networks that may guide the successful conduct of collaborative, high-quality randomized controlled trials in critically ill children.

Resuscitation Prior to Emergency Endotracheal Intubation: Results of a National Survey.

IntroductionRespiratory failure is a common problem in emergency medicine (EM) and critical care medicine (CCM). However, little is known about the resuscitation of critically ill patients prior to emergency endotracheal intubation (EETI). Our aim was to describe the resuscitation practices of EM and CCM physicians prior to EETI.MethodsA cross-sectional survey was developed and tested for content validity and retest reliability by members of the Canadian Critical Care Trials Group. The questionnaire was distributed to all EM and CCM physician members of three national organizations. Using three clinical scenarios (trauma, pneumonia, congestive heart failure), we assessed physician preferences for use and types of fluid and vasopressor medication in pre-EETI resuscitation of critically ill patients.ResultsIn total, 1,758 physicians were surveyed (response rate 50.2%, 882/1,758). Overall, physicians would perform pre-EETI resuscitation using either fluids or vasopressors in 54% (1,193/2,203) of cases. Most physicians would “always/often” administer intravenous fluid pre-EETI in the three clinical scenarios (81%, 1,484/1,830). Crystalloids were the most common fluid physicians would “always/often” administer in congestive heart failure (EM 43%; CCM 44%), pneumonia (EM 97%; CCM 95%) and trauma (EM 96%; CCM 96%). Pre-EETI resuscitation using vasopressors was uncommon (4.9%). Training in CCM was associated with performing pre-EETI resuscitation (odds ratio, 2.20; 95% CI, [1.44–3.36], p<0.001).ConclusionPre-EETI resuscitation is common among Canadian EM and CCM physicians. Most physicians use crystalloids pre-EETI as a resuscitation fluid, while few would give vasopressors. Physicians with CCM training were more likely to perform pre-EETI resuscitation.

Different Mortality Time Points in Critical Care Trials: Current Practice and Influence on Effect Estimates in Meta-Analyses.

Mortality is frequently used as an outcome in critical care trials, being a patient-orientated variable and robust against information/selection bias. Mortality frequency, however, should be measured at a defined time point of follow-up. Practice of meta-analysis shows that follow-up times of trials in critical care medicine differ substantially. This may have substantial implications on potential pooling of effect estimates. We aimed to describe the current practice of mortality follow-up time definitions in a representative sample of published critical care randomized controlled trials and to analyze the influence of different follow-up times on subsequently pooled effect estimates. Cochrane CENTRAL, EMBASE, MEDLINE, PASCAL Biomed, and PsycINFO. Databases were searched for critical care randomized controlled trials published after 2000. A random sample of 50% was drawn for further review. Study characteristics were extracted, as well as the number and time points of mortality ascertainment. Additional data were extracted from Kaplan-Meier plots, as available. Meta-regression and multilevel mixed-effects linear regression were used to analyze the influence of follow-up time (independent variable) on deviation of pooled risk ratios from study baseline (dependent variable). From 9,246 retrieved references, we included 106 studies representing 63,713 participants. Among these, 45 studies (43%) reported more than one time point, with 24 different time points at all, only three (28, 30, and 90 d) being reported in more than 10% of studies. Limiting meta-analyses to only one predefined time point would reduce the number of eligible studies by at least 60%. No influence of time points on meta-analytic summary effect estimates was found. In a large sample of critical care randomized controlled trials, numerous different mortality time points are reported. Mortality time points did not influence pooled point estimates of the effects. Consequently, it seems possible to pool effect estimates, which in turn will increase the precision of these effect estimates.

The Fragility Index in Multicenter Randomized Controlled Critical Care Trials.

Recent literature has drawn attention to the potential inadequacy of frequentist analysis and threshold p values as tools for reporting outcomes in clinical trials. The fragility index, which is a measure of how many events the statistical significance of a result depends on, has been suggested as a means to aid the interpretation of trial results. This study aimed to calculate the fragility index of clinical trials in critical care medicine reporting a statistically significant effect on mortality (increasing or decreasing mortality). Literature search (PubMed/MEDLINE) to identify all multicenter randomized controlled trials in critical care medicine. We identified 862 trials; of which 56 fulfilled eligibility criteria and were included in our analysis. Calculation of fragility index for trials reporting a statistically significant effect on mortality, and analysis of the relationship between trial characteristics and fragility index. The median fragility index was 2 (interquartile range, 1-3.5), and greater than 40% of trials had a fragility index of less than or equal to 1. 12.5% of trials reported loss to follow-up greater than their fragility index. Trial sample size was positively correlated, and reported p value was negatively correlated, with fragility index. In critical care trials reporting statistically significant effects on mortality, the findings often depend on a small number of events. Critical care clinicians should be wary of basing decisions on trials with a low fragility index. We advocate the reporting of fragility index for future trials in critical care to aid interpretation and decision making by clinicians.

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.

Challenging orthodoxy in critical care trial design: physiological responsiveness

Research involving critically ill adults poses unique challenges in addition to the usual difficulties involved in conducting quality, replicable scientific research. The critical care research community has responded admirably to these challenges by rigorously conducting numerous large and often multicenter randomized controlled trials (RCTs) of putative therapies for critical illnesses. Yet in spite of two decades of work, few incontrovertibly efficacious therapies have resulted from this herculean effort (1). The reasons for this are unsettled, but several categories of problems have emerged. The first problem is that of “positive” trials that cannot be replicated (2-15). Since the clinical trial is in essence a diagnostic test of a hypothesis (16), these non-replicable studies represent “false positives.” False positive trials are due to type I errors which are increased by selection of a conventional and lax statistical significance threshold (e.g., α=0.05) (17,18), bias in the study at any stage of design, conduct, analysis and reporting (19), and fraud (20). Recently, the center for open science collaboration demonstrated that the majority of 100 “positive” psychological research studies could not be replicated, suggesting a false positive rate of 63% in that field (21). The generalizability of this result to medicine is uncertain, but the problems of non-replicability and false positives are not.

Designing phase 3 sepsis trials: application of learned experiences from critical care trials in acute heart failure.

Substantial attention and resources have been directed to improving outcomes of patients with critical illnesses, in particular sepsis, but all recent clinical trials testing various interventions or strategies have failed to detect a robust benefit on mortality. Acute heart failure is also a critical illness, and although the underlying etiologies differ, acute heart failure and sepsis are critical care illnesses that have a high mortality in which clinical trials have been difficult to conduct and have not yielded effective treatments. Both conditions represent a syndrome that is often difficult to define with a wide variation in patient characteristics, presentation, and standard management across institutions. Referring to past experiences and lessons learned in acute heart failure may be informative and help frame research in the area of sepsis. Academic heart failure investigators and industry have worked closely with regulators for many years to transition acute heart failure trials away from relying on dyspnea assessments and all-cause mortality as the primary measures of efficacy, and recent trials have been designed to assess novel clinical composite endpoints assessing organ dysfunction and mortality while still assessing all-cause mortality as a separate measure of safety. Applying the lessons learned in acute heart failure trials to severe sepsis and septic shock trials might be useful to advance the field. Novel endpoints beyond all-cause mortality should be considered for future sepsis trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s40560-016-0151-6) contains supplementary material, which is available to authorized users.

Trials in adult critical care that show increased mortality of the new intervention: Inevitable or preventable mishaps?

Several promising therapies assessed in the adult critically ill in large, multicenter randomized controlled trials (RCTs) were associated with significantly increased mortality in the intervention arms. Our hypothesis was that there would be wide ranges in sponsorship (industry or not), type(s) of intervention(s), use of DSMBs, presence of interim analyses and early stopping rules, absolute risk increase (ARI), and whether or not adequate prior proof-of-principle Phase II studies were done of RCTs that found increased mortality rates of the intervention compared to control groups. We reviewed RCTs that showed a statistically significant increased mortality rate in the intervention compared to control group(s). We recorded source of sponsorship, sample sizes, types of interventions, mortality rates, ARI (as well as odds ratios, relative risks and number needed to harm), whether there were pre-specified interim analyses and early stopping rules, and whether or not there were prior proof-of-principle (also known as Phase II) RCTs. Ten RCTs (four industry sponsored) of many interventions (high oxygen delivery, diaspirin cross-linked hemoglobin, growth hormone, methylprednisolone, hetastarch, high-frequency oscillation ventilation, intensive insulin, NOS inhibition, and beta-2 adrenergic agonist, TNF-α receptor) included 19,126 patients and were associated with wide ranges of intervention versus control group mortality rates (25.7–59 %, mean 29.9 vs 17–49 %, mean 25 %, respectively) yielding ARIs of 2.6–29 % (mean 5 %). All but two RCTs had pre-specified interim analyses, and seven RCTs were stopped early. All RCTs were preceded by published proof-of-principle RCT(s), two by the same group. Seven interventions (except diaspirin cross-linked hemoglobin and the NOS inhibitor) were available for use clinically at the time of the pivotal RCT. Common, clinically available interventions used in the critically ill were associated with increased mortality in large, pivotal RCTs even though safety was often addressed by interim analyses and early stopping rules.

Stress ulcer prophylaxis in critical illness: a Canadian survey.

Stress ulcer prophylaxis (SUP) using histamine-2-receptor antagonists has been a standard of care in intensive care units (ICUs) for four decades. Proton pump inhibitors (PPIs) are increasingly used despite apparently lower background rates of gastrointestinal bleeding and growing concerns about PPI-associated complications. Our objective was to understand the views and prescribing habits amongst Canadian physicians regarding SUP in the ICU and to gauge interest in a future randomized-controlled trial (RCT). We created a short self-administered survey about SUP for critically ill adults, evaluated its clinical sensibility, and pilot tested the instrument. We surveyed all physician members of the Canadian Critical Care Trials Group (CCCTG) by e-mail and sent reminders three and five weeks later. We received 94 of 111 (85%) surveys from the validated respondent pool between May and June, 2015. Respondents reported use of SUP most commonly in patients 1) receiving invasive mechanical ventilation (62, 66%), 2) expected to be ventilated for ≥ two days (25, 27%), or 3) receiving mechanical ventilation but nil per os (NPO) (20, 21%). Stress ulcer prophylaxis is discontinued when patients no longer receive mechanical ventilation (75%), no longer are NPO (22%), or are discharged from the ICU (19%). Stress ulcer prophylaxis involves PPIs in 68% of centres. Most respondents endorsed the need for a large rigorous RCT of PPI vs placebo to understand the risks and benefits of this practice. Stress ulcer prophylaxis is reportedly used primarily for the duration of mechanical ventilation. The CCCTG physicians believe that a placebo-controlled RCT is needed to evaluate the effectiveness and safety of contemporary SUP with PPIs.

Canadian Guidelines for the use of targeted temperature management (therapeutic hypothermia) after cardiac arrest: A joint statement from The Canadian Critical Care Society (CCCS), Canadian Neurocritical Care Society (CNCCS), and the Canadian Critical Care Trials Group (CCCTG)

Canadian Guidelines for the use of targeted temperature management (therapeutic hypothermia) after cardiac arrest: A joint statement from The Canadian Critical Care Society (CCCS), Canadian Neurocritical Care Society (CNCCS), and the Canadian Critical Care Trials Group (CCCTG)

Premature Discontinuation of Randomized Trials in Critical and Emergency Care: A Retrospective Cohort Study.

Randomized clinical trials that enroll patients in critical or emergency care (acute care) setting are challenging because of narrow time windows for recruitment and the inability of many patients to provide informed consent. To assess the extent that recruitment challenges lead to randomized clinical trial discontinuation, we compared the discontinuation of acute care and nonacute care randomized clinical trials. Retrospective cohort of 894 randomized clinical trials approved by six institutional review boards in Switzerland, Germany, and Canada between 2000 and 2003. Randomized clinical trials involving patients in an acute or nonacute care setting. We recorded trial characteristics, self-reported trial discontinuation, and self-reported reasons for discontinuation from protocols, corresponding publications, institutional review board files, and a survey of investigators. Of 894 randomized clinical trials, 64 (7%) were acute care randomized clinical trials (29 critical care and 35 emergency care). Compared with the 830 nonacute care randomized clinical trials, acute care randomized clinical trials were more frequently discontinued (28 of 64, 44% vs 221 of 830, 27%; p = 0.004). Slow recruitment was the most frequent reason for discontinuation, both in acute care (13 of 64, 20%) and in nonacute care randomized clinical trials (7 of 64, 11%). Logistic regression analyses suggested the acute care setting as an independent risk factor for randomized clinical trial discontinuation specifically as a result of slow recruitment (odds ratio, 4.00; 95% CI, 1.72-9.31) after adjusting for other established risk factors, including nonindustry sponsorship and small sample size. Acute care randomized clinical trials are more vulnerable to premature discontinuation than nonacute care randomized clinical trials and have an approximately four-fold higher risk of discontinuation due to slow recruitment. These results highlight the need for strategies to reliably prevent and resolve slow patient recruitment in randomized clinical trials conducted in the critical and emergency care setting.

The Development of a Critical Care Resident Research Curriculum: A Needs Assessment.

Background. Conducting research is expected from many clinicians' professional profile, yet many do not have advanced research degrees. Research training during residency is variable amongst institutions and research education needs of trainees are not well understood. Objective. To understand needs of critical care trainees regarding research education. Methods. Canadian critical care trainees, new critical care faculty, program directors, and research coordinators were surveyed regarding research training, research expectations, and support within their programs. Results. Critical care trainees and junior faculty members highlighted many gaps in research knowledge and skills. In contrast, critical care program directors felt that trainees were prepared to undertake research careers. Major differences in opinion amongst program directors and other respondent groups exist regarding preparation for designing a study, navigating research ethics board applications, and managing a research budget. Conclusion. We demonstrated that Canadian critical care trainees and junior faculty reported gaps in knowledge in all areas of research. There was disagreement amongst trainees, junior faculty, research coordinators, and program directors regarding learning needs. Results from this needs assessment will be used to help redesign the education program of the Canadian Critical Care Trials Group to complement local research training offered for critical care trainees.

Nurse Research Experiences and Attitudes Toward the Conduct of Intensive Care Research: A Questionnaire Study.

To characterize ICU nurses' research experience, work environments, and attitudes toward clinical research in critically ill adults and children. Cross-sectional survey. Eight (seven adult and one pediatric) academic ICUs affiliated with the Canadian Critical Care Trials Group. Four hundred eighty-two ICU nurses. None. Response rate was 56%. Most participants had over 6 years of ICU experience (61%) and held a baccalaureate nursing degree (57%). Most participants (63%) had provided care for patients receiving research study procedures more than five times in the past 12 months and agreed that research leads to improved care for the critically ill (78%) and eligible patients should be approached for research participation (78%). Few perceived practicalities of nursing care are considered in study design (20%); 41% agreed that research studies increases nursing workload. Few participants reported receiving adequate information about study progress (24%) or findings (26%). Principal factor analysis identified three factors each in the environmental and attitudinal domains. Linear regression models demonstrated that positive relationships between researchers and clinicians were associated with favorable perceptions of research impact on nursing care (p < 0.001), ICU research acceptability (p < 0.001), and nursing engagement in research (p < 0.05). Nurses with more formal education reported more favorable attitudes toward nursing engagement in research (p < 0.01) and research acceptability (p < 0.01). Lack of experience in study protocol development and/or data analysis was associated with less favorable attitudes about nursing engagement in research (p < 0.01) and impact of research on nursing care (p < 0.01). In these research-intensive ICUs, nurses frequently care for research participants and believe ICU research is important. Inclusion of nurses in study protocol development, improved communication of study progress and findings, and investigation of research-related nursing workload are warranted. Such interventions will support intervention fidelity and data reliability during study conduct and translation of evidence into practice on study completion.

Barriers and Facilitators to Initiating and Completing Time-Limited Trials in Critical Care.

A time-limited trial is an agreement between clinicians and patients or surrogate decision makers to use medical therapies over a defined period of time to see if the patient improves or deteriorates according to agreed-upon clinical milestones. Although time-limited trials are broadly advocated, there is little empirical evidence of the benefits and risks of time-limited trials, when they are initiated, when and why they succeed or fail, and what facilitates completion of them. Our study objectives were to 1) identify the purposes for which clinicians use time-limited trials and 2) identify barriers and facilitators to initiating and completing time-limited trials. Semistructured interviews: We analyzed interviews using qualitative description with constant comparative techniques. Nine hundred-bed, academic, tertiary hospital in Houston, Texas. Interviewees were from open medical, surgical, neurosurgical, and cardiovascular ICUs. Thirty healthcare professionals were interviewed (nine surgeons, 16 intensivists, three nurse practitioners, and two "other" clinicians). None. Interviewees reported initiating time-limited trials for three different purposes: to prepare surrogates and clinicians for discussion and possible shifts toward comfort-care only therapies, build consensus, and refine prognostic information. The main barriers to initiating time-limited trials involve clinicians' or surrogate decision makers' disagreement on setting a time limit. Barriers to completing time-limited trials include 1) requesting more time; 2) communication breakdowns because of rotating call schedules; and 3) changes in clinical course. Finally, facilitators to completing time-limited trials include 1) having defined goals about what could be achieved during an ICU stay, either framed in narrow, numeric terms or broad goals focusing on achievable activities of daily living; 2) applying time-limited trials in certain types of cases; and 3) taking ownership to ensure completion of the trial. An understanding of barriers and facilitators to initiating and completing time-limited trials is an essential first step toward appropriate utilization of time-limited trials in the ICUs, as well as developing educational or communication interventions with clinicians to facilitate time-limited trial use. We provide practical suggestions on patient populations in whom time-limited trials may be successful, the setting, and clinicians likely to benefit from educational interventions, allowing clinicians to have a fuller sense of when and how to use time-limited trials.

Is critical care ready for an economic surrogate endpoint?

Intensive care is expensive, and thus a body of research has focused on strategies to reduce its costs. However, efforts to reduce the total cost of intensive care have met with limited success, partly because of the challenges of calculating how much a day in the ICU actually costs. We discuss these challenges and introduce the concept of total cost savings as an outcome of critical care trials, assuming statistically negative effects on mortality and quality of life.