Dataset Information

Heterogeneity in design and analysis of ICU delirium randomized trials: a systematic review.

ABSTRACT:

Background

There is a growing number of randomized controlled trials (RCTs) evaluating interventions to prevent or treat delirium in the intensive care unit (ICU). Efforts to improve the conduct of delirium RCTs are underway, but none address issues related to statistical analysis. The purpose of this review is to evaluate heterogeneity in the design and analysis of delirium outcomes and advance methodological recommendations for delirium RCTs in the ICU.

Methods

Relevant databases, including PubMed and Embase, were searched with no restrictions on language or publication date; the search was conducted on July 8, 2019. RCTs conducted on adult ICU patients with delirium as the primary outcome were included where trial results were available. Data on frequency and duration of delirium assessments, delirium outcome definitions, and statistical methods were independently extracted in duplicate. The review was registered with PROSPERO (CRD42020141204).

Results

Among 65 eligible RCTs, 44 (68%) targeted the prevention of delirium. The duration of follow-up varied, with 31 (48%) RCTs having ≤7 days of follow-up, and only 24 (37%) conducting delirium assessments after ICU discharge. The incidence of delirium was the most common outcome (50 RCTs, 77%) for which 8 unique statistical methods were applied. The most common method, applied to 51 of 56 (91%) delirium incidence outcomes, was the two-sample test comparing the proportion of patients who ever experienced delirium. In the presence of censoring of patients at ICU discharge or death, this test may be misleading. The impact of censoring was also not considered in most analyses of the duration of delirium, as evaluated in 24 RCTs, with 21 (88%) delirium duration outcomes analyzed using a non-parametric test or two-sample t test. Composite outcomes (e.g., rank-based delirium- and coma-free days), used in 11 (17%) RCTs, seldom explicitly defined how ICU discharge, and death were incorporated into the definition and were analyzed using non-parametric tests (11 of 13 (85%) composite outcomes).

Conclusions

To improve delirium RCTs, outcomes should be explicitly defined. To account for censoring due to ICU discharge or death, survival analysis methods should be considered for delirium incidence and duration outcomes; non-parametric tests are recommended for rank-based delirium composite outcomes.

Trial registration

PROSPERO CRD42020141204 . Registration date: 7/3/2019.

SUBMITTER: Colantuoni E

PROVIDER: S-EPMC8136095 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ObjectivesWe reviewed randomized trials of adult ICU patients of interventions hypothesized to reduce delirium burden to determine whether interventions that are more effective at reducing delirium duration are associated with a reduction in short-term mortality.Data sourcesWe searched CINHAHL, EMBASE, MEDLINE, and the Cochrane databases from 2001 to 2012.Study selectionCitations were screened for randomized trials that enrolled critically ill adults, evaluated delirium at least daily, compared a drug or nondrug intervention hypothesized to reduce delirium burden with standard care (or control), and reported delirium duration and/or short-term mortality (≤ 45 d).Data extractionIn duplicate, we abstracted trial characteristics and results and evaluated quality using the Cochrane risk of bias tool. We performed random effects model meta-analyses and meta-regressions.Data synthesisWe included 17 trials enrolling 2,849 patients which evaluated a pharmacologic intervention (n = 13) (dexmedetomidine [n = 6], an antipsychotic [n = 4], rivastigmine [n = 2], and clonidine [n = 1]), a multimodal intervention (n = 2) (spontaneous awakening [n = 2]), or a nonpharmacologic intervention (n = 2) (early mobilization [n = 1] and increased perfusion [n = 1]). Overall, average delirium duration was lower in the intervention groups (difference = -0.64 d; 95% CI, -1.15 to -0.13; p = 0.01) being reduced by more than or equal to 3 days in three studies, 0.1 to less than 3 days in six studies, 0 day in seven studies, and less than 0 day in one study. Across interventions, for 13 studies where short-term mortality was reported, short-term mortality was not reduced (risk ratio = 0.90; 95% CI, 0.76-1.06; p = 0.19). Across 13 studies that reported mortality, meta-regression revealed that delirium duration was not associated with reduced short-term mortality (p = 0.11).ConclusionsA review of current evidence fails to support that ICU interventions that reduce delirium duration reduce short-term mortality. Larger controlled studies are needed to establish this relationship.

Project description:IntroductionThe ideal measures to prevent postoperative delirium remain unestablished. We conducted this systematic review and meta-analysis to clarify the significance of potential interventions.MethodsThe PRISMA statement guidelines were followed. Two researchers searched MEDLINE, EMBASE, CINAHL and the Cochrane Library for articles published in English before August 2012. Additional sources included reference lists from reviews and related articles from 'Google Scholar'. Randomized clinical trials (RCTs) on interventions seeking to prevent postoperative delirium in adult patients were included. Data extraction and methodological quality assessment were performed using predefined data fields and scoring system. Meta-analysis was accomplished for studies that used similar strategies. The primary outcome measure was the incidence of postoperative delirium. We further tested whether interventions effective in preventing postoperative delirium shortened the length of hospital stay.ResultsWe identified 38 RCTs with interventions ranging from perioperative managements to pharmacological, psychological or multicomponent interventions. Meta-analysis showed dexmedetomidine sedation was associated with less delirium compared to sedation produced by other drugs (two RCTs with 415 patients, pooled risk ratio (RR)=0.39; 95% confidence interval (CI)=0.16 to 0.95). Both typical (three RCTs with 965 patients, RR=0.71; 95% CI=0.54 to 0.93) and atypical antipsychotics (three RCTs with 627 patients, RR=0.36; 95% CI=0.26 to 0.50) decreased delirium occurrence when compared to placebos. Multicomponent interventions (two RCTs with 325 patients, RR=0.71; 95% CI=0.58 to 0.86) were effective in preventing delirium. No difference in the incidences of delirium was found between: neuraxial and general anesthesia (four RCTs with 511 patients, RR=0.99; 95% CI=0.65 to 1.50); epidural and intravenous analgesia (three RCTs with 167 patients, RR=0.93; 95% CI=0.61 to 1.43) or acetylcholinesterase inhibitors and placebo (four RCTs with 242 patients, RR=0.95; 95% CI=0.63 to 1.44). Effective prevention of postoperative delirium did not shorten the length of hospital stay (10 RCTs with 1,636 patients, pooled SMD (standard mean difference)=-0.06; 95% CI=-0.16 to 0.04).ConclusionsThe included studies showed great inconsistencies in definition, incidence, severity and duration of postoperative delirium. Meta-analysis supported dexmedetomidine sedation, multicomponent interventions and antipsychotics were useful in preventing postoperative delirium.

Project description:BackgroundThe high prevalence of delirium among postoperative patients has increased morbidity and mortality. The kind of drug that can effectively reduce the incidence of delirium has become the focus of discussion in recent years. However, a consensus in this respect has yet to be reached.MethodsRandomized controlled trials (RCTs) were retrieved from the PubMed, Cochrane Library, ClinicalTrials.gov, and Embase databases from their inception through October 12, 2018. We included RCTs of pharmacological prevention for postoperative delirium in adults (at least 18 years), and the Cochrane risk of bias tool was used to evaluate the methodological quality of trials. The primary outcomes were the risk ratios (RRs) of incidence of postoperative delirium, and the secondary outcomes were the RRs of mortality and adverse events in the intervention and control groups.ResultsThirty-eight trials, which comprised 20302 patients and 18 different drugs, were included in the analysis. Of the 38 studies, 17 were rated as low risk with respect to methodological quality. Dexmedetomidine administration (RR 0.58, 95%CI 0.44-0.76, P<0.01) was associated with a significantly lower incidence of postoperative delirium than the control conditions. However, the findings from the studies with a low risk of bias did not show a significant difference in this beneficial effect (RR 0.64, 95%CI 0.39-1.04, P=0.07). The antipsychotic drugs olanzapine (RR 0.44, 95%CI 0.30- 0.65, P<0.01) and risperidone (RR 0.42, 95%CI 0.19-0.92, P=0.03) had promising effects, but there was a lack of sufficient evidence to obtain a definitive conclusion. The beneficial effect of other drugs, including haloperidol, methylprednisolone, dexamethasone, gabapentin, ketamine, cyproheptadine, donepezil, hypertonic saline, melatonin, nimodipine, ondansetron, pregabalin, rivastigmine, TJ-54, and tryptophan, was not proven on the basis of present evidence.ConclusionAmong the pharmacological prophylactic measures for postoperative delirium, dexmedetomidine, olanzapine, and risperidone showed higher efficacy than other drugs. However, more high-quality evidence is needed to confirm these results.

Project description:BackgroundAs an atypical antipsychotic drug, olanzapine is one of the most commonly used drugs for delirium control. There are no systematic evaluations or meta-analyses of the efficacy and safety of olanzapine for delirium control in critically ill adults.ObjectivesIn this meta-analysis, we evaluated the efficacy and safety of olanzapine for delirium control in critically ill adults in the intensive care unit (ICU).Data sources and methodsFrom inception to October 2022, 12 electronic databases were searched. We retrieved randomized controlled trials (RCTs) and retrospective cohort studies of critically ill adults with delirium that compared the effects of olanzapine and other interventions, including routine care (no intervention), nonpharmaceutical interventions and pharmaceutical interventions. The main outcome measures were the (a) relief of delirium symptoms and (b) a decrease in delirium duration. Secondary outcomes were ICU and in-hospital mortality, ICU and hospital length of stay, incidence of adverse events, cognitive function, sleep quality, quality of life, mechanical ventilation time, endotracheal intubation rate and delirium recurrence rate. We applied a random effects model.ResultsData from 10 studies (four RCTs and six retrospective cohort studies) involving 7076 patients (2459 in the olanzapine group and 4617 in the control group) were included. Olanzapine did not effectively relieve delirium symptoms (OR = 1.36, 95% CI [0.83, 2.28], p = 0.21), nor did it shorten the duration of delirium [standardized mean difference (SMD) = 0.02, 95% CI [-1.04, 1.09], p = 0.97] when compared with other interventions. Pooled data from three studies showed that the use of olanzapine reduced the incidence of hypotension (OR = 0.44, 95% CI [0.20, 0.95], p = 0.04) compared with other pharmaceuticals. There was no significant difference in other secondary outcomes, including ICU or hospital length of stay, in-hospital mortality, extrapyramidal reactions, QTc interval prolongation, or overall incidence of other adverse reactions. The number of included studies was not sufficient for performing a comparison between olanzapine and no intervention.ConclusionCompared with other interventions, olanzapine has no advantage in alleviating delirium symptoms and shortening delirium duration in critically ill adults. However, there is some evidence that the rate of hypotension was lower in patients who received olanzapine than in those who received other pharmaceutical interventions. There was a nonsignificant difference in the length of ICU or hospital stay, in-hospital mortality, and other adverse reactions. This study provides reference data for delirium research and clinical drug intervention strategies in critically ill adults.RegistrationProspective Register of Systematic Reviews (PROSPERO; registration number CRD42021277232).

Project description:IntroductionWhile numerous randomized controlled trials (RCTs) have been conducted in the field of trauma, a substantial portion of them are yielding negative results. One potential contributing factor to this trend could be the lack of agreement regarding the chosen definitions across different trials. The primary objective was to identify the terminology and definitions utilized for the characterization of multiple trauma patients within randomized controlled trials (RCTs).MethodsA systematic review of the literature was performed in MEDLINE, EMBASE and clinicaltrials.gov between January 1, 2002, and July 31, 2022. RCTs or RTCs protocols were eligible if they included multiple trauma patients. The terms employed to characterize patient populations were identified, and the corresponding definitions for these terms were extracted. The subsequent impact on the population recruited was then documented to expose clinical heterogeneity.ResultsFifty RCTs were included, and 12 different terms identified. Among these terms, the most frequently used were "multiple trauma" (n = 21, 42%), "severe trauma" (n = 8, 16%), "major trauma" (n = 4, 8%), and trauma with hemorrhagic shock" (n = 4, 8%). Only 62% of RCTs (n = 31) provided a definition for the terms used, resulting a total of 21 different definitions. These definitions primarily relied on the injury severity score (ISS) (n = 15, 30%), displaying an important underlying heterogeneity. The choice of the terms had an impact on the study population, affecting both the ISS and in-hospital mortality. Eleven protocols were included, featuring five different terms, with "severe trauma" being the most frequent, occurring six times (55%).ConclusionThis systematic review uncovers an important heterogeneity both in the terms and in the definitions employed to recruit trauma patients within RCTs. These findings underscore the imperative of promoting the use of a unique and consistent definition.

Project description:Background/objectivesDelirium manifests clinically in varying ways across settings. More than 40 instruments currently exist for characterizing the different manifestations of delirium. We evaluated all delirium identification instruments according to their psychometric properties and frequency of citation in published research.DesignWe conducted the systematic review by searching Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, Excerpta Medica Database (Embase), PsycINFO, PubMed, and Web of Science from January 1, 1974, to January 31, 2020, with the keywords "delirium" and "instruments," along with their known synonyms. We selected only systematic reviews, meta-analyses, or narrative literature reviews including multiple delirium identification instruments.MeasurementsTwo reviewers assessed the eligibility of articles and extracted data on all potential delirium identification instruments. Using the original publication on each instrument, the psychometric properties were examined using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) framework.ResultsOf 2,542 articles identified, 75 met eligibility criteria, yielding 30 different delirium identification instruments. A count of citations was determined using Scopus for the original publication for each instrument. Each instrument underwent methodological quality review of psychometric properties using COSMIN definitions. An expert panel categorized key domains for delirium identification based on criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM)-III through DSM-5. Four instruments were notable for having at least two of three of the following: citation count of 200 or more, strong validation methodology in their original publication, and fulfillment of DSM-5 criteria. These were, alphabetically, Confusion Assessment Method, Delirium Observation Screening Scale, Delirium Rating Scale-Revised-98, and Memorial Delirium Assessment Scale.ConclusionFour commonly used and well-validated instruments can be recommended for clinical and research use. An important area for future investigation is to harmonize these measures to compare and combine studies on delirium.

Project description:BackgroundPostoperative delirium (POD) not only increases the medical burden but also adversely affects patient prognosis. Although some cases of delirium can be avoided by early intervention, there is no clear evidence indicating whether any of these measures can effectively prevent POD in specific patient groups.ObjectiveThe aim of this meta-analysis was to compare the efficacy and safety of the existing preventive measures for managing POD.MethodsThe PubMed, OVID (Embase and MEDLINE), Web of Science, and the Cochrane Library databases were searched for articles published before January 2020. The relevant randomized controlled trials (RCTs) were selected based on the inclusion and exclusion criteria. Data extraction and methodological quality assessment were performed according to a predesigned data extraction form and scoring system, respectively. The interventions were compared on the basis of the primary outcome like incidence of POD, and secondary outcomes like duration of delirium and the length of intensive care unit and hospital stay.ResultsSixty-three RCTs were included in the study, covering interventions like surgery, anesthesia, analgesics, intraoperative blood glucose control, cholinesterase inhibitors, anticonvulsant drugs, antipsychotic drugs, sleep rhythmic regulation, and multi-modal nursing. The occurrence of POD was low in 4 trials that monitored the depth of anesthesia with bispectral index during the operation (P < .0001). Two studies showed that supplementary analgesia was useful for delirium prevention (P = .002). Seventeen studies showed that perioperative sedation with α2-adrenergic receptor agonists prevented POD (P = .0006). Six studies showed that both typical and atypical antipsychotic drugs can reduce the incidence of POD (P = .002). Multimodal nursing during the perioperative period effectively reduced POD in 6 studies (P < .00001). Furthermore, these preventive measures can reduce the duration of delirium, as well as the total and postoperative length of hospitalized stay for non-cardiac surgery patients. For patients undergoing cardiac surgery, effective prevention can only reduce the length of intensive care unit stay.ConclusionMeasures including intraoperative monitoring of bispectral index, supplemental analgesia, α2-adrenergic receptor agonists, antipsychotic drugs, and multimodal care are helpful to prevent POD effectively. However, larger, high-quality RCTs are needed to verify these findings and develop more interventions and drugs for preventing postoperative delirium.