Directions: please follow explicitly *** primarily this assignment is filling in the tables- attached all articles to use **** Use the attached "Literature Evaluation Table to complete this assignme

Copyright © 2020 The Author(s).

Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution- Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. OBJECTIVE: To evaluate the impact of bundle interventions on ICU de- lirium prevalence, duration, and other patients’ adverse outcomes.

DATA SOURCES: The Cochrane Library, PubMed, CINAHL, EMBASE, PsychINFO, and MEDLINE from January 2000 to July 2020. The protocol of the study was registered in International prospective register of sys\�tem- atic reviews (CRD42020163147).

STUDY SELECTION: Randomized clinical trials or cohort studies that examined the following outcomes were included in the current study: ICU delirium prevalence and duration, proportion of patient-days with coma, \� ventilator-free days, mechanical ventilation days, ICU or hospital length of stay, and ICU or inhospital or 28-day mortality.

DATA EXTRACTION: Using a standardized data-collection form, two authors screened the studies and extracted the data independently, and assessed the studies’ quality using the Modified Jadad Score Scale \�for ran- domized clinical trials and the Newcastle-Ottawa Scale for cohort studies.

DATA SYNTHESIS: Eleven studies with a total of 26,384 adult partici- pants were included in the meta-analysis. Five studies (three randomized clinical trials and two cohort studies) involving 18,638 patients demon- strated that ICU delirium prevalence was not reduced (risk ratio = 0.92; 95% CI, 0.68–1.24). Meta-analysis showed that the use of bundle inter- ventions was not associated with shortening the duration of ICU delirium (mean difference = –1.42 d; 95% CI, –3.06 to 0.22; two randomized clin- ical trials and one cohort study), increasing ventilator-free days (me\�an dif- ference = 1.56 d; 95% CI, –1.56 to 4.68; three randomized clinical trials), decreasing mechanical ventilation days (mean difference = –0.83 d; 95% CI, –1.80 to 0.14; four randomized clinical trials and two cohort studies), ICU length of stay (mean difference = –1.08 d; 95% CI, –2.16 to 0.00; seven randomized clinical trials and two cohort studies), and inhospital mortality (risk ratio = 0.86; 95% CI, 0.70–1.06; five randomized clinical trials and four cohort studies). However, bundle interventions are effective in reducing the proportion of patient-days experiencing coma (risk rati\�o = 0.47; 95% CI, 0.39–0.57; two cohort studies), hospital length of stay (mean difference = –1.47 d; 95% CI, –2.80 to –0.15; four randomized clinical trials and one cohort study), and 28-day mortality by 18% (risk ratio = 0.82; 95% CI, 0.69–0.99; three randomized clinical trials).

CONCLUSIONS: This meta-analysis fails to support that bundle interven- tions are effective in reducing ICU delirium prevalence and duration, but supports that bundle interventions are effective in reducing the propor- tion of patient-days with coma, hospital length of stay, and 28-day mor- tality. Larger randomized clinical trials are needed to evaluate the impact of bundle interventions on ICU delirium and other clinical outcomes. Shan Zhang, PhD 1 Yuan Han, MD 1 Qian Xiao, PhD 1 Haibin Li, PhD 2 Ying Wu, PhD, RN, ACNP, ANP, NFESC 1 Effectiveness of Bundle Interventions on ICU Delirium: A Meta-Analysis* LW W Zhang et al 336 www.ccmjournal.org February 2021 • Volume 49 • Number 2 KEY WORDS: bundle interventions; delirium; intensive care unit; meta-analysis D elirium is a common but mostly preventable complication among patients in the ICUs, with the incidence ranged as high as 70–87% (1, 2). ICU patients complicated with delirium have been identified with prolonged mechanical ventilation (MV), longer hospital stay, and increased mortality (2, 3). The severity of adverse outcomes was also associated with delirium duration, the longer the duration, and the worse the adverse outcomes (3, 4). Therefore, pre- vention of delirium from its happening or early man- agement to reverse ICU delirium is critical to minimize the adverse effects on clinical outcomes associated with ICU delirium among identified patients (5–7). Although the pathogenesis of ICU delirium is not completely clear, it is proposed that multiple risk factors collectively contributed to the onset and persistence of ICU delirium (7, 8). Therefore, clinical guidelines, in- cluding the pain, agitation, delirium, immobility, and sleep (PADIS) guidelines, have recommended to use a bundle approach, such as the “ABCDEF bundle” to target on eliminating multiple modifiable risk factors of ICU delirium to reduce the chances of or shorten the duration of delirium to be occurred in critically ill adults (6, 9). Among the different components of the ABCDEF bundle, A stands for Assess, prevent, and manage pain, which is a major risk factor of ICU de- lirium; B represents Both spontaneous awakening trials (SATs) for sedative patients and spontaneous breathing trials (SBTs) if patients were on mechanical ventilators; C refers to the Choice of analgesics and sedatives, as the use of analgesics and sedatives is a major risk factor of ICU delirium; D denotes for Delirium monitoring or management, which includes reorientation, improv- ing sleep and wakefulness, as well as reducing hearing and/or visual impairment, etc; E implies Early exercise/ mobility as immobility is a major risk factor of ICU de- lirium; and F refers to Family engagement and empow- erment (restrictive ICU visit is a major risk factor of ICU delirium) (9). Not every ICU patient has all the above-mentioned risk factors; therefore, the appro- priate subset of interventions from the ABCDEF bundle should be tailored to patients’ specific risk factors. It has been proposed that the ABCDEF bundle maybe more effective than any single-component strategy in preventing and managing ICU delirium with its evidence largely driven from before-after stud- ies (10–13) or pilot studies (14, 15). After the PADIS Guidelines were released, a number of well-designed robust randomized clinical trials (RCTs) (16–18) have been conducted to evaluate the bundle interventions in minimizing modifiable risk factors related to ICU delirium, therefore reducing its prevalence or dura- tion. However, their findings have been inconsistent or even contradictory among different studies (19–21).

Therefore, we conducted a meta-analysis to assess the overall effectiveness of bundle interventions on the prevalence and duration of ICU delirium, and other important adverse outcomes, such as the hospital length of stay (LOS) and mortality.

MATERIALS AND METHODS The meta-analysis was conducted and reported in ac- cordance with the criteria identified by the preferred reporting items for systematic reviews and meta-anal- yses (PRISMA) guidelines (Appendix File 1, http:// links.lww.com/CCM/G21) (22). The current study was a retrospective analysis of published research litera- ture only, and no human were involved. Therefore, the Institution Review Board approval was not required based on the institutional policies. The protocol of the study was registered in International prospective reg- ister of systematic reviews (CRD42020163147).

Search Strategy We performed a comprehensive literature search to identify RCTs and cohort studies related to delirium bundle interventions between January 2000 and July 2020. Following a preliminary PubMed search using combined key terms (delirium OR ICU delirium) AND (intervention OR critical care), the earliest published work by Slomka et al (23) relevant to the topic of this meta-analysis was identified in the year of 2000; there- fore, the year of 2000 was chosen as the starting point to search available relevant published works. Databases including the Cochrane Library, PubMed, CINAHL, EMBASE, PsychINFO, and MEDLINE were searched for published articles with no language restriction applied. The search terms included a combination of key terms related to delirium: (delirium OR confusion OR acute confusional syndrome OR postoperative de- lirium OR cognitive dysfunction OR ICU delirium OR ICU psychosis OR ICU syndrome OR deliri*) AND Review Articles Critical Care Medicine www.ccmjournal.org 337 (ABCDE bundle OR ABCDEF bundle OR bundle OR PAD OR critical care* OR intensive care* OR preven- tion OR intervention). We also searched ongoing and unpublished trials using the clinicaltrials.gov data- bases. Additional relevant articles were identified by manually reviewing the reference lists of all included research articles as well as published review articles and meta-analyses. The authors of original studies were also contacted to acquire missed data to be in- cluded in the final analysis.

Study Selection The title and abstract of all articles were screened ini- tially, and the full text of potential studies was retrieved and further reviewed by two reviewers (S.Z. and Y.H.) independently to assess the eligibility. Articles were eli- gible for inclusion in the meta-analysis if they met all of the following inclusion criteria: 1) RCTs or cohort stud- ies, (the Cochrane Handbook for Systematic Reviews of Interventions, Version 6.0 [24], identifies that the re- view may include nonrandomized studies, such as co- hort studies, when the question of interest cannot be answered by RCTs), 2) study participants were adults (18 years old or older) administered in the ICUs, and 3) application of at least three of the components identified in the ABCDEF bundle, which includes assessment and pain management, SAT or SAT plus SBT for patients supported by ventilator, choice of analgesia and seda- tion, delirium monitoring/management, early exercise/ mobility, and family engagement and empowerment.

Articles were excluded if they were presented with any of the following reasons: 1) nonrelevant topics, 2) study protocols or case reports, 3) commentary or meta-anal- ysis and systemic review, and 4) nonhuman study. For articles that met the above initial criteria, the following second-level inclusion criteria were applied: 1) study must be designed with control groups, 2) ICU delirium was measured by validated instruments including the diagnostic and statistical methods IV criteria, confu- sion assessment method (CAM), CAM for the ICU (CAM-ICU), or the intensive care delirium screening checklist (ICDSC), and 3) the study reported selected clinical outcomes of our interest (Fig. 1).

Outcome Measures The primary endpoint assessed in this study was the prevalence and duration of ICU delirium. The prevalence of ICU delirium was defined as the presence of delirium among patients at the end of follow-up, and the duration of ICU delirium is defined as the total hospital days in which the patient was diagnosed with ICU delirium. The secondary endpoints included pro- portion of patient-days with coma, ICU and hospital LOS, number of ventilator-free days (VFDs) and MV days, as well as the ICU, inhospital, and 28-day mor - talities (Supplementary File 2 , http://links.lww.com/ CCM/G22).

Quality Assessment The quality of RCT studies was examined by two reviewers (S.Z. and Y.H.) separately, using the Modified Jadad Scale (25). The score on the Modified Jadad Scale was ranged from 0 to 7, with a score of greater than or equal to 4 being defined as high-quality stud- ies. The quality of cohort studies was examined using the Newcastle-Ottawa Scale (NOS) (26). The score on the NOS was ranged from 0 to 9 with a score of greater than or equal to 6 being identified as an acceptable methodological design. Risk of bias of each study was further assessed based on the six domains identified by the “Cochrane Handbook for Systematic Reviews of Interventions” (27).

Data Collection Using a predesigned standardized data-collection form, relevant data from original studies were extracted and collected independently by two researchers (S.Z.

and Y.H.), including study characteristics (primary au- thor, publication year, study design, and sample size), participant demographics (age and gender), interven- tions and comparisons, as well as information on the intended outcome variables. For each outcome, the reviewers extracted the means (sd s) of the variable or number of patients in each study.

Statistical Analysis Meta-analysis was performed using the Review Manager (RevMan) Version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark). Heterogeneity among studies was assessed using the chi- square test, and Ι 2 values were used to deter - mine heterogeneity across studies, attributing to Zhang et al 338 www.ccmjournal.org February 2021 • Volume 49 • Number 2 the proportion of total variation, in which the Ι 2 > 50% indicated substantial heterogeneity of effects and random-effects models were applied. If the Ι 2 < 50% was identified, which represented homogeneity, fixed-effects models were selected. For continuous data, mean difference (MD) and 95% CI were used for outcomes pooled. For dichotomous outcomes, risk ratios (RRs) with 95% CI were evaluated in ac- cordance with intent-to-treat principles. The for - est plot was applied to represent the meta-analysis results, and the funnel plots were constructed to identify publication bias using the Begg and Egger Figure 1. Flowchart of literature identification, review, and selection. Review Articles Critical Care Medicine www.ccmjournal.org 339 tests with Stata software (Stata/SE 12.0; StataCorp LP, College Station, TX). Sensitivity analysis was also performed by assessing whether random-effects and fixed-effects models would bring about the same re- sult. All statistical tests were two-tailed, and p value of less than 0.05 was considered statistically significant. RESULTS Study Identification Our initial search yielded 7,190 publications based on the defined search terms (Fig. 1). After screening of the titles and abstracts, 37 potential studies with TABLE 1.

Characteristics of Included Studies Source Study Type Setting Sample Size (n) Intervention Group/ Control Group ICU Delirium Assessment Tool Interventions Quality Assessment a Risk of Bias b Girard et al (29) (2008) RCT ICU 167/168 CAM-ICU 3/6 (A, B, D) 5 5/6 (A, C, S, R, O) Schweickert et al (30) (2009) RCT MICU 49/55CAM-ICU 4/6 (A, B, D, E) 7 6/6 (A, B, C, S, R, O) Mehta et al (28) (2012) RCT SICU and MICU 214/209 ICDSC 3/6 (A, B, D) 7 6/6 (A, B, C, S, R, O) Mansouri et al (31) (2013) RCT SICU and MICU 96/105 CAM-ICU 3/6 (A, C, D) 4 4/6 (A, C, S, O) Moon and Lee (18) (2015) RCT SICU and MICU 60/63 CAM-ICU 4/6 (A, C, D, E) 5 5/6 (A, C, S, R, O) Sosnowski et al (17) (2018) RCT ICU 15/15CAM-ICU 5/6 (A, B, C, D, E) 5 5/6 (A, C, S, R, O) Olsen et al (16) (2020) RCT ICU 351/349 CAM-ICU 5/6 (A, B, C, D, E) 5 4/6 (A, C, S, O) Barnes-Daly et al (32) (2017) CS MICU and SICU 6,064 CAM-ICU 5/6 (A, B, C, D, E) 8 3/6 (C, S, O) Hsieh et al (20) (2019) CS MICU 281/366 CAM-ICU 3/6 (B, D, E) 8 3/6 (C, S, O) Pun et al (21) (2019) CS ICU NACAM-ICU or ICDSC 6/6 (A, B, C, D, E, F) 8 3/6 (C, S, O) Trogrlić et al (19) (2019) CS SICU and MICU 1,194/ 1,337 CAM-ICU or ICDSC 5/6 (A, C, D, E, F) 8 3/6 (C, S, O) A = assess, prevent, and manage pain, B = both spontaneous awakening trials and spontaneous breathing trials, C = c\�hoice of analgesia and sedation, CAM-ICU = confusion assessment method for the ICU, CS = cohort study, D = delirium monitoring/management, E = early exercise/mobility, F = family engagement and empowerment, ICDSC = intensive care delirium screening checklist, MICU = medical ICU, NR = not report, RCT = randomized clinical trial, SICU = surgical ICU.

a The quality of included RCTs articles was examined using the Modified Jadad Scale (range, 0–7). The quality of included cohort studies was examined using the Newcastle-Ottawa Scale (range, 0–9).

b Risk of bias include the following: A = allocation concealment, B = blinding of participants, personnel, and outcome assessors, C = complet\�e- ness of outcome data, O = other sources of bias, R = random-sequence gen\�eration or balanced allocation, S = selective outcome reporting. Zhang et al 340 www.ccmjournal.org February 2021 • Volume 49 • Number 2 full-text were retrieved, in which 26 studies did not meet the second-level inclusion criteria. Therefore, a total of 11 studies (seven RCTs and four cohort stud- ies) were included in the final analysis according to the selection criteria (Ta b l e 1 ). Two datasets were ac- quired from the principal investigators of the original studies (16, 28) as the data included in the articles were inadequate for analysis.

Study Characteristics The 11 original studies included in the current study were published between 2008 and 2020, with a total of 26,384 adult participants. The reported ICU delirium prevalence varied from 20.49% (19) to 74.25% (29).

All studies (with supplementary data obtained from authors of two original studies) provided relevant data on one or more targeted outcomes that were suitable for final analysis (Table  1). The selected elements of the bundle intervention used in each study were listed in Supplementary Table 1 (http://links.lww.com/ CCM/G24).

Pooled Outcomes ICU Delirium Prevalence . Five studies (three RCTs and two cohort studies) reported on the prevalence of ICU delirium, which included a total of 18,638 patients in the meta-analysis (Ta b l e 2 ). A random- effect model showed that, when compared with con- trol groups, the bundle interventions lowered the odds of ICU delirium prevalence by 8% (RR = 0.92; 95% CI, 0.68–1.24; p = 0.57), but not statistically sig- nificant (Fig. 2). The ICU delirium prevalence was stratified by the study design, with three RCTs com- prising 441 ICU patients in intervention groups and 440 in control groups, and the pooled result showed that the bundle interventions had no effect on low- ering the odds of ICU delirium (RR = 1.01; 95% CI, 0.91–1.13; p = 0.81) (Table 2). The two cohort stud- ies that applied bundle interventions lowered the ICU delirium prevalence by 8% (RR = 0.92; 95% CI, 0.40–2.11; p = 0.84) (Table 2), but no significant dif- ferences were detected. ICU Delirium Duration . There was no difference identified on the length of ICU delirium between the par - ticipants in the bundle-intervention group (n = 1,410) and usual care (n = 1,560) group (three studies [two RCTs and one cohort study]; MD = –1.42 d; 95% CI, –3.06 to 0.22; p = 0.09) (Table  2; and Supplementary Fig. 1, http://links.lww.com/CCM/G23). Proportion of Patient-Days With Coma. Patients in the bundle-intervention group were associated with lower likelihood on the proportion of patient-days experiencing coma (RR = 0.47; 95% CI, 0.39–0.57; p < 0.001; two cohort studies; fixed-effects model) (Table  2; and Supplementary Fig. 2, http://links.lww.

com/CCM/G23). Mechanical Ventilation Days and Ventilator-Free Days . The length of MV was 0.83 days shorter among 1,849 ICU patients who received the bundle interven- tions (MD = –0.83 d; 95% CI, –1.80 to 0.14; p = 0.09; six studies [four RCTs and two cohort studies]) (Table  2; and Supplementary Fig. 3, http://links.lww.com/ CCM/G23) compared with those in the control group (n = 2,087), but the outcome was not statistically sig- nificant. Regarding VFDs, no difference was found be- tween the intervention group (n = 567) and the control group ( n = 572) (MD = 1.56 d; 95% CI, –1.56 to 4.68; p = 0.33; three RCTs) (Table  2; and Supplementary Fig. 4, http://links.lww.com/CCM/G23). ICU and Hospital Length of Stay. There were nine studies (seven RCTs and two cohort studies) re- porting results on the ICU LOS. With a total of 5,184 ICU patients included in the meta-analysis using a random-effects model, the pooled result showed that the MD was 1.08 days shorter (95% CI, –2.16 to 0.00; p = 0.05) (Table  2; and Supplementary Fig. 5, http:// links.lww.com/CCM/G23) among patients in the in- tervention group compared with those in the control group. In addition, five studies (four RCTs and one co- hort study) measured hospital LOS (Table  2), and the meta-analysis using a fixed-effects model (I 2 = 42%; p = 0.14) found that the MD of hospital LOS was 1.47 (95% CI, –2.80 to –0.15; p = 0.03) days shorter among 726 ICU patients in the intervention group compared with patients in the control group (Table 2; and Supplementary Fig. 6, http://links.lww.com/ CCM/G23). Mortality . Two (one RCT and one cohort study), nine (five RCTs and four cohort studies), and three (all RCTs) studies reported results on the ICU, inhos- pital, and 28-day mortalities, respectively (Table  2; and Supplementary Figs. 7–9, http://links.lww.com/ CCM/G23). Meta-analysis using a fixed-effects model (I 2 = 0%; p = 0.61) found that the bundle interven- tions did not decrease ICU mortality (RR = 1.01; 95% Review Articles Critical Care Medicine www.ccmjournal.org 341 TABLE 2.

Meta-Analysis of the Effect of Bundle Interventions VariableStatistical Method Risk Ratio or Mean Difference (95% CI) I 2 Value (%)p ICU delirium prevalence RCTs (18, 28, 29) (3) M-H, fixed1.01 (0.91–1.13) 310.81 Cohort studies (19, 21) (2) M-H, random0.92 (0.40–2.11) 980.84 Combined M-H, random0.92 (0.68–1.24) 910.57 ICU delirium duration RCTs (29, 30) (2) IV, random–0.89 (–2.82 to 1.06) 790.37 Cohort studies (19) (1) IV, random–2.30 (–2.83 to –1.77) NA< 0.001 Combined IV, random–1.42 (-–3.06 to 0.22) 900.09 Coma RCTs (0) NANANANA Cohort studies (19, 21) (2) M-H, fixed0.47 (0.39–0.57) 47< 0.001 Combined M-H, fixed0.47 (0.39–0.57) 47< 0.001 Ventilator-free days RCTs (16, 29, 30) (3) IV, random1.56 (–1.56 to 4.68) 760.33 Cohort studies (0) NANANANA Combined IV, random1.56 (–1.56 to 4.68) 760.33 Mechanical ventilation days RCTs (17, 28, 30, 31) (4) IV, random–0.74 (–2.22 to 0.74) 790.33 Cohort studies (19, 20) (2) IV, random–0.94 (–2.99 to 1.12) 950.37 Combined IV, random–0.83 (–1.80 to 0.14) 860.09 ICU LOS RCTs (16–18, 28, 29–31) (7) IV, random–1.07 (–2.62 to 0.48) 630.18 Cohort studies (19, 20) (2) IV, random–0.96 (–2.72 to 0.80) 910.29 Combined IV, random–1.08 (–2.16 to 0.00) 740.05 Hospital LOS RCTs (17, 28, 29, 30) (4) IV, fixed–2.24 (–4.11 to –0.37) 470.02 Cohort studies (20) (1) IV, fixed–0.70 (–2.58 to 1.18) NA0.47 Combined IV, fixed–1.47 (–2.80 to –0.15) 420.03 ICU mortality RCTs (28) (1) M-H, fixed0.94 (0.67–1.32) NA0.72 Cohort studies (19) (1) M-H, fixed1.05 (0.83–1.32) NA0.71 Combined M-H, fixed1.01 (0.84–1.23) 00.89 Inhospital mortality RCTs (17, 18, 28, 30, 31) (5) M-H, random0.73 (0.45–1.17) 530.19 Cohort studies (19–21, 32 (4) M-H, random0.92 (0.71–1.19) 800.52 Combined M-H, random0.86 (0.70–1.06) 670.16 28-d mortality RCTs (16, 18, 29) (3) M-H, fixed0.83 (0.71–0.98) 110.02 Cohort studies (0) NANANANA Combined M-H, fixed0.83 (0.71–0.98) 110.02 IV = inverse variance, LOS = length of stay, M-H = Mantel-Haenszel, NA = not applicable, RCT = randomized clinical trial. Zhang et al 342 www.ccmjournal.org February 2021 • Volume 49 • Number 2 CI, 0.84–1.23; p = 0.89) among 2,954 ICU patients.

Additionally, the RR for inhospital mortality was 0.86 (95% CI, 0.70–1.06; p = 0.16) among 25,349 ICU patients, with nonsignificant findings. However, the 28-day mortality was decreased by 18% (RR = 0.82; 95% CI, 0.69–0.99; p = 0.04) among 1,158 ICU patients in the intervention group. Sensitivity Analysis . In the sensitivity analysis on the ICU delirium prevalence, there was still heterogeneity among studies (p < 0.001; I 2 = 93%) after excluding the study from Mehta et al (28), which used the ICDSC to assess ICU delirium. The RRs obtained by the random- effect model were 0.89 (95% CI, 0.59–1.33), Z = 0.59, and p = 0.56, with no substantial changes observed in the results. Meanwhile, the sensitivity analysis was also per - formed by excluding the study from Pun et al(21), which underwent extensive modeling and adjusted for 18 confounding factors, and therefore could have af- fected the result on ICU delirium prevalence. However, the result was similar to the general pooled analysis (RR = 1.08; 95% CI, 0.87–1.34; p = 0.49). The ICU delirium duration was stratified based on the number of bundle interventions, which was dichot- omized using the median of 4 as the cutoff point and was divided into two groups among patients received the intervention (Supplementary Table 2 , http://links.

lww.com/CCM/G24). In patients who received inter - ventions with equal or less than four elements iden- tified in the bundle approach (two studies), the MD obtained by the random-effect model was –0.89 (95% CI, –2.83 to 1.06; p = 0.37), and the MD was –2.30 (95% CI, –2.83 to –1.77; p < 0.01) among those who received more than four elements of the bundle interventions (one study). In the sensitivity analysis on inhospital mortality, heterogeneity was still identified among studies ( I 2 = 69%; p = 0.002) after excluding the study from Sosnowski et al (17), which is a pilot study reported with very high inhospital mortality in the interven- tion group. The result was in line with that from the general pooled data (RR = 0.85; 95% CI, 0.70–1.04; p = 0.12).

The sensitivity analysis shows that regardless of which effect model was applied, the outcomes remained similar. Publication Bias . As shown in Supplementary Fig. 10 (http://links.lww.com/CCM/G23), the funnel plot is generally symmetric, which implied no pub- lication bias existed for the ICU delirium prevalence (Egger test, p = 0.66; Begg test, p = 0.46). Similar find- ings were observed for ICU LOS, MV days, hospital LOS, and inhospital mortality (Supplementary Figs.

11–14, http://links.lww.com/CCM/G23). However, the number of studies reported on the relationship of bundle interventions with other outcomes was too small and a funnel plot analysis was not performed. Association Between Quality Ratings and Effectiveness. The quality assessment based on the Modified Jadad Scale showed that seven RCTs were rated as high-quality study designs (Modified Jadad Score 4–7) (Table 1). The four cohort studies were also identified with high quality, among which the NOSs score were ranged from 6 to 8 (Table 1). No significant difference was observed between the score on risk of bias and the effectiveness of bundle interventions. DISCUSSION In this meta-analysis, we included 11 studies with a total of 26,384 adult ICU patients to evaluate the ef- fectiveness of bundle interventions on either pre- vention and/or management of ICU delirium. Our findings failed to provide evidence in supporting that Figure 2. Meta-analysis of ICU delirium prevalence. RR = risk ratio. Review Articles Critical Care Medicine www.ccmjournal.org 343 the bundle interventions were effective measures on reducing either ICU delirium prevalence or duration.

However, the result should be interpreted with cau- tion, as there was substantial heterogeneity among studies even though sensitivity analysis was applied in terms of the result on ICU delirium prevalence and duration, but the results were not changed from the pooled effects. To the best of our knowledge, this is the first meta-analysis conducted to evaluate the effect of the ABCDEF bundle on ICU delirium prevalence and duration and other related adverse outcomes. The PADIS Guidelines have recommended to use all components of the ABCDEF bundle to reduce the modifiable risk factors (e.g., pain, deep sedation, use of MV, analgesics and sedatives, and immobility) relevant to the development of the ICU delirium. However, the majority of the studies in the current analysis only used selected elements from the bundle. Among all the studies included, four studies used three elements, two studies used four elements, another four studies used five elements, and only one study reported the use of all ABCDEF bundle elements. This indicates that most of the interventions described by authors may not tailor to patients’ every specific risk factors targeted by the ABCDEF bundle. Our meta-analysis found that there were no signif- icant differences in reducing the prevalence and dura- tion of ICU delirium between the bundle-intervention group and the control group in the pooled analysis.

These findings may be explained by the following pos- sible reasons. First, the majority of the included studies in this meta-analysis did not focus on all the elements identified in the ABCDEF bundle, so not all modifiable ICU delirium risk factors were appropriately addressed by the interventions applied. For example, the PADIS Guidelines recommend to use nonbenzodiazepine seda- tives (e.g., dexmedetomidine) over benzodiazepines for sedation in ICU patients (9, 33). However, as identified by authors in three of the included studies (28, 29, 30), benzodiazepines were commonly prescribed for seda- tion in patients in the ICU. In addition, one study (19) used five elements of the bundle interventions, which significantly decreased the ICU delirium duration by 2.30 days among patients in the intervention group.

However, the result must be interpreted with caution, as only one study used interventions that included more than four elements of the bundle approach among those examined the effects of the intervention on ICU delirium duration. In addition, the cohort study conducted by Pun et al (21) used all ABCDEF bundle elements and demonstrated that the bundle approach significantly reduced the delirium prevalence and improved selected outcomes such as coma and MV use. However, there is a lack of sufficient evidence from RCTs to support the effectiveness of ABCDEF bundle in improving ICU de- lirium prevalence and duration. Future well-designed RCTs are needed to evaluate the effects of all the ABCDEF bundle components as a whole intervention on ICU delirium. Second, due to the complexity of the ABCDEF bundle approach, the adoption and adherence of the bundle interventions were suboptimal among included studies (28, 34). Healthcare providers were often reluc- tant to implement fully the bundle interventions in ICU patients, concerning practical difficulty, patient safety, workload burden, etc (5, 35); therefore, even the bundle interventions were implemented and they were not executed in their full extent (such as the dosage of sedatives is not adequately titrated) (28). The proportion of patient-days experiencing coma was reduced by 53% in the bundle-intervention group.

Although only two cohort studies (19, 21) reported the proportion of patient-days with coma in the current meta-analysis, there are one RCT study and two cohort studies revealed that the bundle intervention signifi- cantly shortened the duration of coma, decreased the proportion of patients with coma, or experienced more days free of coma, respectively. However, we failed to combine these coma-related outcomes due to incon- sistent data formats among studies (20, 29, 32). The pos- sible effect of bundle approach on coma improvement may be explained in part by the application of bundle intervention targeting on daily awakening, which attempts to stimulate the reticular activating system in the brain of comatose patient, and therefore promoted arousal (36, 37). Evidences have shown that the awak- ening trial is necessary for sustaining cortical arousal, which promoted further recovery of the nervous system and improved functional efficiency of the brain (36, 38).

In addition, as demonstrated in previous research, pas- sive range-of-motion activities (the “E” element) could also stimulate the brain activities that might have con- tributed to the decrease in the proportion of patient- days with coma (39, 40). Further studies are necessary to verify this result. The improvement of coma by the Zhang et al 344 www.ccmjournal.org February 2021 • Volume 49 • Number 2 bundle intervention may also explained our result on decreased LOS (1.47 d) in the current analysis. As indicated by the results on mortality, the 28-day mortality was reduced after implementation of the bundle intervention but not with the ICU or inhospital mortality. The possible reason may be that the preva- lence and duration of delirium were not changed in patients receiving the bundle intervention in the cur - rent meta-analysis; therefore, it could not reverse the adverse effect of delirium such as ICU and inhospital mortality. The other reason may be that none of the in- cluded studies were designed to test the effectiveness of bundle intervention on ICU mortality as primary out- comes; therefore, they were not powered to test the dif- ferences between the groups. However, a longer follow up period, such as 28 days, will increase the power to test the differences on 28-day mortality (1, 29). One of the strengths of this study is that our meta- analysis strictly followed the PRISMA statement and used a comprehensive search strategy to identify po- tential studies in all available databases to ensure the generalizability of the results. Meanwhile, we included a relevantly large number of studies in the meta-anal- ysis to extend the conclusion beyond the population contained in previous meta-analyses and systematic reviews. In our meta-analysis, bundle interventions were applied in all 11 studies that were identified as methodologically high-quality studies. Therefore, our findings appear to be largely driven by the findings from high-quality RCTs, allowing us to draw more re- liable and valid conclusions. In addition, we avoided publication bias by following comprehensive search strategies that included studies with a large sample size. Several limitations should be noted in this meta- analysis. First, we included both RCT and cohort studies in the current analysis, and heterogeneity was identified among studies in terms of results on the ICU delirium prevalence and duration, MV days, ICU, or hospital LOS. These could be due to differentiation existed in terms of study designs and inconsistent in- clusion and exclusion criteria among studies; these all restricted the power to draw conclusions. However, we rigorously limited the heterogeneity by including only high-quality studies in the analysis and used sensi- tivity analysis that applied random-effects models and fixed-effects models simultaneously to examine the effect of bundle interventions. In addition, the results of the sensitivity analyses on related outcomes showed no different findings from the pooled effects. Second, the number of studies included in the current analysis reporting outcomes on ICU mortality is small, which may have insufficient power to assess the differences and limited the interpretation of our pooled data.

Third, although some studies reported coma-related outcomes, we failed to combine these data for anal- ysis due to different presented data formats. Although authors of the original studies were contacted several times, no responses were obtained. Therefore, this lim- ited the reliability when interpreting this result. Finally, as majority of the studies in this analysis did not in- clude all elements of the bundle approach, the modi- fiable risk factors identified by the PADIS Guidelines are not fully addressed in the interventions. Therefore, it is limited to draw conclusions on the collective effect of the full bundle approach with current evidence.

Further studies are needed to examine the full imple- mentation of the ABCDEF bundle on the prevalence and duration of ICU delirium in the future. Despite these limitations, the results of this meta-analysis are clinically relevant and reliable for the prevention and management of delirium in the ICU settings.

CONCLUSIONS The current meta-analysis did not support the effects of bundle interventions on decreasing the prevalence and shortening the duration of ICU delirium, although there is clear evidence in supporting that the bundle interventions are effective in reducing the proportion of patient-days with coma, hospital LOS, and 28-day mortality in ICU patients. The modifiable risk factors for ICU delirium were not fully addressed by interven- tions in the majority of the included studies, which may limit the effectiveness of bundle interventions to be shown on ICU delirium prevalence and duration.

Future studies, especially well and rigorously designed RCTs and full implementation of ABCDEF bundle in- tervention, should be considered to test the effect of bundle interventions on ICU delirium prevalence and duration, as well as other related adverse outcomes.

ACKNOWLEDGMENTS We thank for the support from Karen V. Lamb (Associate Professor, College of Nursing, Rush University, United States) and Meihua Ji (Associate Professor, School of Nursing, Capital Medical University, Beijing, China) Review Articles Critical Care Medicine www.ccmjournal.org 345 for her editing assistance. We also thank Prof. Palle Toft (Department of Anaesthesiology and Intensive Care, Odense University Hospital) and Prof. Sangeeta Mehta (Medical Surgical ICU, Mount Sinai Hospital) for providing additional dataset on related outcomes.

1 Department of Adult Care, School of Nursing, Capital Medical University, Beijing, China.

2 Department of Epidemiology and Health Statistics, School of Public Heath, Capital Medical University, Beijing, China.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

The funding source had no role in the study design, data collec- tion, data analysis, data explanation, or article writing.

Dr. Wu is receiving a grant (#71661167008) from “the National Natural Science Foundation of China.” The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: [email protected].

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