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

2Department of Public Health, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.

3Department of Intensive Care, Albert Schweitzer Hospital, Dordrecht, The Netherlands.

4Department of Intensive Care, Ikazia Hospital, Rotterdam, The Nether-lands.

5Department of Intensive Care, IJsselland Hospital, Rotterdam, The Neth-erlands.

6Department of Intensive Care, Franciscus Gasthuis & Vlietland, Rot-terdam, The Netherlands.

7Department of Intensive Care, Maasstad Hospital, Rotterdam, The Neth-erlands.

8Department of Pulmonology and Critical Care, New York University - Langone, New York, NY.

9Department of Pulmonology and Critical Care, Columbia University Med-ical Center - New York Presbyterian, New York, NY.

10Department of Intensive Care, Pontificia Universidad Catolica de Chile, Santiago, Chile.

11Department of Pediatric Surgery, Intensive Care Unit, Erasmus MC - Sophia Children’s Hospital University Medical Center Rotterdam, Rot- terdam, The Netherlands.

Drs. van der Jagt and Ista supervised the study and contributed equally.

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

Supported, in part, by grant No. 171203008 from The Netherlands Orga- nization for Health Research and Development (ZonMw). ZonMw had no role in the statistical analyses or publication decisions.

This work was performed at Department of Intensive Care Adults, Erasmus MC University Medical Center Rotterdam; Department of Intensive Care, Albert Schweitzer Hospital Dordrecht; Department of Intensive Care, Ika- zia Hospital Rotterdam; Department of Intensive Care, IJsselland Hospital Rotterdam; Department of Intensive Care, Sint Franciscus Gasthuis Rot- terdam; and Department of Intensive Care, Maasstad Hospital Rotterdam, all in the Netherlands. Drs. Trogrlic’s and van der Jagt’s institutions received funding from The Netherlands Organization for Health Research and Development (ZonMw) with the grant number: 171203008 awarded to Drs. van der Jagt and Ista.

Drs. Verbrugge’s and Bakker’s institutions received funding from ZonMW.

The remaining authors have disclosed that they do not have any potential \ conflicts of interest.

Address requests for reprints to: Zoran Trogrlić , RN, MSc, Department of Intensive Care Adults, Erasmus MC University Medical Center Rotterdam‘s Gravendijkwal 230, P.O. Box 2040, 3000CA Rotterdam, the Netherlands, office: Ne-405. E-mail: [email protected] Objectives: Implementation of delirium guidelines at ICUs is sub- optimal. The aim was to evaluate the impact of a tailored mul- tifaceted implementation program of ICU delirium guidelines on processes of care and clinical outcomes and draw lessons re- garding guideline implementation.

Design: A prospective multicenter, pre-post, intervention study.

Setting: ICUs in one university hospital and five community hospitals.

Patients: Consecutive medical and surgical critically ill patients were enrolled between April 1, 2012, and February 1, 2015.

Interventions: Multifaceted, three-phase (baseline, delirium screening, and guideline) implementation program of delirium guidelines in adult ICUs.

Measurements and Main Results: The primary outcome was adherence changes to delirium guidelines recommendations, based on the Pain, Agitation and Delirium guidelines. Secondary outcomes were brain dysfunction (delirium or coma), length of ICU stay, and hospital mortality. A total of 3,930 patients were included. Improvements after the implementation pertained to delirium screening (from 35% to 96%; p < 0.001), use of benzodiazepines for continuous sedation (from 36% to 17%; p < 0.001), light sedation of ventilated patients (from 55% to 61%; p < 0.001), physiotherapy (from 21% to 48%; p < 0.001), and early mobilization (from 10% to 19%; p < 0.001). Brain dys- function improved: the mean delirium duration decreased from 5.6 to 3.3 days (–2.2 d; 95% CI, –3.2 to –1.3; p < 0.001), and DOI: 10.1097/CCM.0000000000003596 Improved Guideline Adherence and Reduced Brain Dysfunction After a Multicenter Multifaceted Implementation of ICU Delirium Guidelines in 3,930 Patients Zoran Trogrlić, RN, MSc 1; Mathieu van der Jagt, MD, PhD 1; Hester Lingsma, PhD 2; Diederik Gommers, MD, PhD 1; Huibert H. Ponssen, MD 3; Jeannette F. J. Schoonderbeek, MD, PhD 4; Frodo Schreiner, MD 5; Serge J. Verbrugge, MD, PhD 6; Servet Duran, MD 7; Jan Bakker, MD, PhD 1,8,9,10 ; Erwin Ista, RN, PhD 11 Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. 420 www.ccmjournal.org March 2019 • Volume 47 • Number 3 coma days decreased from 14% to 9% (risk ratio, 0.5; 95% CI, 0.4–0.6; p < 0.001). Other clinical outcome measures, such as length of mechanical ventilation, length of ICU stay, and hospital mortality, did not change.

Conclusions: This large pre-post implementation study of delir- ium-oriented measures based on the 2013 Pain, Agitation, and Delirium guidelines showed improved health professionals’ adher- ence to delirium guidelines and reduced brain dysfunction. Our findings provide empirical support for the differential efficacy of the guideline bundle elements in a real-life setting and provide les- sons for optimization of guideline implementation programs. (Crit Care Med 2019; 47 :419–427) Key Words: critical care; delirium; guideline adherence; intensive care units D elirium is a common form of vital organ dysfunc- tion in critically ill adults, associated with increased morbidity, mortality, and long-term cognitive deteri- oration (1–3). Adequate delirium management is therefore an important component of intensive care—as substantiated in the Pain, Agitation, and Delirium (PAD) guidelines (4). Suc- cessful implementation of guidelines into daily practice is chal- lenging (5) although multifaceted implementation programs have the potential to facilitate success (6). Implementation of the PAD guidelines has had beneficial effects on pain, brain dysfunction, durations of mechanical ventilation and ICU stay, early mobilization, long-term cognitive dysfunction, func- tional recovery, and mortality in the critically ill (7–9). Still, “real-life” prospective multicenter implementation studies fo- cused on these delirium-oriented guidelines in hospitals with low use of the guidelines at baseline are needed to bring clinical evidence into practice on a wider scale, given the suboptimal implementation of these guidelines worldwide (10). We therefore performed the prospective multicenter “ICU DElirium in Clinical PracTice Implementation Evaluation” study (11), designed to evaluate the effectiveness of a multifac- eted implementation program tailored to improving adherence to delirium guidelines and to study patient-related benefits. MATERIALS AND METHODS Study Design and Participants We conducted a prospective, multicenter, before-after imple- mentation study in six ICUs in the Netherlands—one uni- versity and five community hospitals (three teaching and two nonteaching hospitals) (11). The size of the units varied be- tween eight and 32 ICU beds. Consecutive ICU patients 18 years old or older were included. Exclusion criteria were a primary neurologic diagnosis, home mechanical ventilation for chronic respiratory insufficiency, and burn injuries. The intervention, an implementation program focused at the im- plementation of the delirium-oriented recommendations de- rived from Dutch ICU Delirium Guidelines (12), and the PAD guidelines of the Society of Critical Care Medicine (4) was aimed at all ICU physicians and nurses. Results of this study were reported using the Standards for Quality Improvement Reporting Excellence guidelines (13). The study protocol was reviewed by the Medical Ethical Committees of participating hospitals (MEC-2012–063). Patients’ informed consent was not necessary according to Dutch legislation (14). The study was registered at ClinicalTrials.gov (Identifier: Nct01952899 2017).

Procedures, Outcomes, and Data Collection The study duration was 36 months and consisted of three measurement periods between April 2012 and February 2015 (Fig. 1). The Implementation Model of Change of Grol and Wensing (15) was used to structure the guideline implemen- tation. This model is a seven steps approach and starts with identifying the problem and defining the aim of change fol- lowed by identification of potential barriers and facilitators for implementation; development of an implementation plan based on these barriers and facilitators; and finally execution, evaluation, and sustaining of the implementation plan.

Phase I. The baseline phase started with a 4-month data collection period. To avoid the Hawthorne effect (11), staff of the participating ICUs were not informed about the study during data collection, with the exception of the local inten- sivist (principal investigator) and research nurses. Next, we performed an analysis of barriers and facilitators for delirium guideline adherence by means of a survey (16) and focus group interviews with stakeholders and development of the imple- mentation program (Fig. 1). We identified more than 30 bar - riers and facilitators for guideline adherence, to which we then tailored the implementation program following the model of Grol and Wensing and change theories (6, 11, 17) (Supple- mental Digital Content 1 and 2, http://links.lww.com/CCM/ E227). Important facilitators were realizing that delirium is a major problem, that treatment is essential, and that delirium is often underdiagnosed. The most important barriers were in- sufficient knowledge for screening, no integral delirium pro- tocol with a link to screening results (16). The implementation program consisted of different implementation strategies in accordance to the Effective Practice and Organization of Care (EPOC) group classification, mainly on organizational and professionals levels (18, 19). See details in Table 1 and Figure 1.

Phase II. This phase was dedicated to reliable delirium screening, for which all nurses and physicians compulsory completed an e-learning program. We formally appointed an intensivist and research nurse at each site to act as local champions during this and subsequent phases and encour - aged them to involve other ICU nurses or ICU physicians as “ambassadors”. Additional clinical lessons and bedside educa- tion were provided by the local implementation teams, which also performed delirium screening spot checks. Three of the ICUs preferred the Confusion Assessment Method for the ICU (CAM-ICU) (20); the other three preferred the Intensive Care Delirium Screening Checklist (ICDSC) (21). All implementa- tion elements are briefly explained in Table 1 and were catego- rized according to the Cochrane EPOC (18) and study phase.

Trogrli et al Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.Neurologic Critical Care Critical Care Medicine www.ccmjournal.org 421 Phase III. This phase consisted of 8 months of implemen- tation followed by 4 months of data collection (Fig. 1). The nurses and physicians now completed a second e-learning pro- gram focused on the guideline. Everyone received a laminated pocket card summarizing the integrated measures based on the PAD guidelines (Supplemental Digital Content 3, a and b, http://links.lww.com/CCM/E227). Throughout the implementation phase, we regularly did bedside reliability spot checks on delirium screening, distrib- uted delirium screening adherence feedback posters, issued newsletters on study progression and practical experiences, assessed the perceived level of implementation of bundle elements, and the deployment of implementation elements as another feedback tool to the local implementation teams.

Furthermore, experiences with the implementation program were shared in repeated focus group sessions.

Outcomes The primary outcome was changes in adherence to guideline recommendations from before to after implementation. Sec- ondary outcomes were presence of brain dysfunction defined as days with delirium or coma, duration of mechanical venti- lation, ICU length of stay (LOS), ICU and hospital mortality. Study data were prospectively collected by research nurses at each site, using a data handling protocol (Supplemental Digital Content 4, http://links.lww.com/CCM/E227). Guideline ad- herence was measured using seven performance indicators ( Supplemental Digital Content 5, http://links.lww.com/CCM/ E227). During phase I, the presence of delirium was defined as treatment with any antipsychotic drug or documentation of a de- lirium diagnosis in the medical or nursing chart. During phases II and III, delirium was diagnosed with the CAM-ICU or ICDSC (20, 21). Coma was defined as a sedation level compatible with a Richmond Agitation-Sedation Scale (RASS) score (22) of –4 or –5 or a Ramsay Sedation Scale score (23) less than 5 or a Critically Ill Assessment score (24) less than 7. A “delirium day” was defined as at least one recorded delirium diagnosis in a 24-hour period.

A coma day was defined as documented presence of coma with absence of documented delirium during a 24-hour period.

Statistical Analysis Demographics are presented as numbers and percentages, medi- ans and interquartile ranges (IQRs), or means and sds where ap- propriate. differences in guideline adherence between the three phases, as expressed by crude numbers and percentages, were assessed with a chi-square test. To examine between-group dif- ferences, we used Kruskal-Wallis test for nonparametric analyses.

differences in clinical outcomes between the three phases were assessed with adjusted regression models. Poisson regression was used for count data (e.g., number of delirium assessments per day), logistic regression for binary outcomes, and linear re- gression for continuous outcomes. Guideline adherence and presence of brain dysfunction were analyzed on day level, with random effect models with a random intercept for patient. du- ration of mechanical ventilation, ICU LOs, ICU and hospital mortality were analyzed on patient level with xed effect models.

The adjusted models used severity of illness score Acute Phys- iology and Chronic Health Evaluation-II, hospital, age and ad- mission diagnosis (elective or acute surgery vs medical diagnosis) as covariables. differences between the periods were expressed as adjusted rate ratios, adjusted odds ratios (ORs), or betas. Miss- ing baseline data were imputed using single imputation with the Figure 1. Timeline ICU DElirium in Clinical PracTice Implementation Evaluation Study. See text for further details. Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. 422 www.ccmjournal.org March 2019 • Volume 47 • Number 3 AregImpute function in R. Two-sided p values less than 0.05 were considered statistically significant. All analyses were performed with computer software programs R (extension packages: for - eign, lme4, and rms; R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org/) and IBM SPSS Sta- tistics Version 23.0 (IBM Corp., Armonk, NY).

RESULTS In total 4,853 patients were admitted during the three data col- lection periods. As 923 patients had to be excluded (Supple- mental Digital Content 6, http://links.lww.com/CCM/E227), data of 3,930 patients, with a total of 18,288 patient-days, were analyzed. Demographics are presented in Table 2. The e-learn- ing programs in phases II and III were completed by 90% of physicians (73/81) and 91% of nurses (374/409).

Primary Outcomes—Guideline Adherence Figure 2 and Supplemental Digital Content 7 (http://links.

lww.com/CCM/E227) show the crude performance indicator metrics presented as percentages. Delirium screening increased from 35% to 93% (p < 0.001) to 96% (p < 0.001). Contin- uous IV benzodiazepine sedation decreased from 36% to 31% TABLE 1. Description of Implementation Strategies Used, According to Effective Practice and Organization of Care classification Implementation Strategy InterventionPhase IIPhase III Audit and feedback Repeated evaluation of implementation process strategies used and level \ of perceived adherence to guideline recommendations. + a + Monitoring the performance of the delivery of healthcare Posters with delirium screening adherence and delirium incidence.

++ Educational materials Reader development and dissemination; interactive website e-learning (with instructional videos, e.g., on the\ use of screening instruments Confusion Assessment Method for ICU/ Intensive Care Delirium Screening Checklist). + + Educational meetings Education of expert teams at each hospital/ICU Education sessions. + + Educational outreach visits or academic detailing Interactive workshop sessions: education about the severity and impact of delirium on patient outcomes on short and long term. The importance of why screening for delirium is important and what may work as pre- ventive measures. + + Clinical Practice Guidelines Construction of general delirium guideline protocol by several “con- sensus group”—meetings with representatives from each ICU (physi- cians, nurses). During the sessions, various local protocols (if any)\ from each ICU would be made visible when discussing the interpretation and translation of the guideline into a workable and widely endorsed protocol among participating centers. – b + Interprofessional education Spot checks for screening were first done by expert-team members, but later by all nurses, checking and discussing each other’s delirium assessments. + – Local consensus processes Yes, see previous point under “Clinical Practice Guidelines”. –+ Local opinion leaders Medical and nursing stakeholders were recruited and involved in the stud\ y and its execution. They had the task to appeal to people, encourag- ing colleagues to work according to the guidelines (e.g., during daily \ rounds/visits). We appointed one participating intensivist and a dedi- cated research nurse as local opinion leaders/champion. + + Patient-mediated interventions Family involvement was encouraged:

Delirium information poster and info booklet placed in family room.

Instructions by nurses to family members on participation in daily care and communication in case of delirium. – + Reminders Operationalization of existing PDMS for integration of delirium guideline protocol. Reminders for screening was preferentially incorporated. One of the hospitals did not have a digital PDMS system which hampered the implementation process. + + Tailored interventions Yes: based on preimplementation assessment of barriers and facilitators. ++ PDMS = Patient Data Management System. a Plus (+) and and b minus (–) signs indicate whether individual implementation strategies were used (+) or not used (–) during: the phase \ II or phase III (Fig. 1).

Trogrli et al Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.Neurologic Critical Care Critical Care Medicine www.ccmjournal.org 423 (p < 0.001) to 17% (p < 0.001). Administration of daily inter - mittent benzodiazepines boluses had not consistently increased over the three phases. The amounts given (mean of 0.22– 0.48 mg/d of diazepam equivalent; see legend of Supplemental Digital Content 7, http://links.lww.com/CCM/E227) seemed negligible compared with usual daily dosages of continuous IV benzodiazepines. Although the daily use of midazolam, fen- tanyl, and morphine had decreased, that of propofol, dexme- detomidine, and remifentanil had increased (Supplemental Digital Content 8, http://links.lww.com/CCM/E227). Applica- tion of physical therapy (PT), early mobilization of patients, sedation assessments, and light sedation improved signifi- cantly. The medians of all available daily maximum RASS scores in mechanically ventilated patients were significantly different between the study phases (p < 0.001), indicating less deep sedation after the implementation (Supplemental Dig- ital Content 9, http://links.lww.com/CCM/E227). Supplemental Digital Content 10 (http://links.lww.com/ CCM/E227) shows the adjusted effect changes of the per - formance indicators. Implementation of delirium screening resulted in a significant improvement in adherence to delirium screening, sedation assessments, light sedation, less use of continuous IV benzodiazepine sedation, and performing PT compared with the baseline period. These ORs indicate, for example, that for a random patient on a random admission day, the odds of getting sedated with continuous IV benzodi- azepines was 0.5 (or two times smaller) after implementation of delirium screening. These improvements in adherences rel- ative to the baseline period were maintained after implemen- tation of the guideline. Early mobilization (as opposed to PT) only improved after guideline implementation but not after screening implementation. Guideline implementation resulted in additional improvements compared with the screening im- plementation phase for delirium screening, use of benzodi- azepines, performing PT, and performing early mobilization when feasible.

Secondary Outcomes—Clinical Outcomes Table 3 shows crude and adjusted clinical outcomes changes per study phase. The duration of delirium decreased over three periods from 5.6 days to 2.9 days (Beta: – 2.6 d; 95% CI, –3.5 to –1.6 d; p < 0.001) and to 3.3 days after guideline implementation TABLE 2. Patient Demographics and Baseline Clinical Characteristics Characteristics Data Collection Period a Phase I: Baseline Phase II: Screening Implementation Phase III: Guideline Implementation Number of patients, n 1,337 1,399 1,194 Number of ICU days, n 6,527 6,086 5,675 Gender, n (%) Male 775 (58)789 (56) 710 (60) Female 562 (42)610 (44) 484 (40) Age (yr), median (IQR) 66 (54–75)66 (53–75) 65 (5–74) Admission status, n (%) Elective surgery 401 (30)432 (31) 339 (28) Emergency surgery 188 (14)200 (14) 167 (14) Medical 748 (56)767 (55) 688 (58) Acute Physiology and Chronic Health Evaluation -II b, median (IQR) 16 (11–22)15 (10–21) 16 (11–21) Mechanically ventilated patients, n (%) 560 (42) 541 (39) 593 (50) Hospital, n (%) 1 145 (11)155 (11) 195 (16) 2 247 (19)248 (18) 242 (20) 3 231 (17)251 (18) 249 (18) 4 158 (12)166 (12) 76 (6) 5 251 (19)271 (19) 216 (18) 6 305 (23)308 (22) 216 (18) IQR = interquartile range .a See Figure 1 for further explanation.b Acute Physiology and Chronic Health Evaluation-II range is 0–71. Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. 424 www.ccmjournal.org March 2019 • Volume 47 • Number 3 (Beta: –2.2 d; 95% CI, –3.2 to –1.3 d; p < 0.001). Implemen- tation of delirium screening resulted in 6% more patients detected with delirium in the third study period compared with the baseline period (OR, 1.4; 95% CI, 1.2–1.7; p < 0.001). Sup- plemental Digital Content 11 (http://links.lww.com/CCM/ E227) shows the cumulative proportions of delirium- and coma(-free) days as changes in percentages for the three study periods. In the adjusted analysis (Supplemental Digital Con- tent 12, http://links.lww.com/CCM/E227), only the coma days were significantly reduced in phases II and III relative to phase I (from 14% to 12%; OR, 0.6; 95% CI, 0.4–0.8; p < 0.001, and from 14% to 9%; OR, 0.5; 95% CI, 0.4–0.6; p < 0.001). There were no significant changes for the other study outcomes.

DISCUSSION In this study, the implementation of delirium monitoring and other elements of delirium care recommended in the 2013 PAD guideline recommendations was associated with modest, although significant, improvements in six of the seven studied care processes, corresponding with fewer delirium or coma days. On the assumption that the participating ICUs already applied light sedation practices in general, we decided not to focus strongly on safety screens for Spontaneous Awakening Trials (SATs) and Spontaneous Breathing Trials (SBTs), which may have precluded improvements of the secondary outcomes, such as length of ventilation, ICU stay, or mortality. We found that delirium screening resulted in slightly higher delirium detection rates, probably on account of the phe- nomenon that the use of a vali- dated delirium screening tool increases the detection rate, es- pecially of hypoactive delirium (25). This may also explain that the cumulative number of de- lirium and coma free days in the entire population did not decrease significantly in spite of decreased mean duration of delirium and days with coma per patient. Several previous studies on delirium screening implementation (26–29) and PAD guidelines (7, 30–32) also have reported improvement in delirium screening adherence.

Further, a recent systematic re- view reported that adherence to delirium screening was assessed in 15 of 21 implementation studies, 13 of which found improved adherence, with rates ranging from 14% to 92% (6). In a previous trial (SLEAP trial), SATs/SBTs did not have additional benefit for LOS or mortality in settings with rel- atively light sedation practices (33). The sedation levels we found (RASS –1 [IQR, –3 to 0) more closely resembled those of patients in the SLEAP trial (RASS between –2 and –1) than those of patients in the Awakening and Breathing Controlled trial (RASS between –4 and –1), which indeed found a positive effect on mortality (34). On the other hand, the implementa- tion studies by Balas et al (7, 35), that bared many methodo- logical similarities to our study, but was a single-center study, also had a mean RASS of –1 indicating light sedation rates, but still established lower length of mechanical ventilation, apply- ing awakening and breathing trials. Our lack of focus on SATs and SBTs may also be illustrative for the tension between the premises of the PAD guidelines (with moderate emphasis on SATs/SBTs), the Assess, Prevent, and Manage Pain, Both SAT and SBT, Choice of analgesia and sedation, Delirium: Assess, Prevent, and Manage, Early mobility and Exercise, and Family engagement concept (with strong emphasis) and more recent insights such as provided by the SLEAP study and as substanti- ated in the early Comfort using Analgesia, minimal Sedatives and maximal Humane care (eCASH) concept that has even questioned the value of daily sedation stops as opposed to goal- directed sedation (36). Furthermore, our results on patient outcomes are in line with a recent meta-analysis reporting that interventions that reduced delirium duration did not neces- sarily translate into reduced short-term mortality (37).

Figure 2. Adherence to guideline recommendations. This figure graph shows adherence percentage per performance indicator for the three data collection periods. See Supplem\ ental Digital Content 7 (http://links.

lww.com/CCM/E227) for crude numbers. *Indicates a significant change relative to the baseline period.

#Indicates a significant change after guideline implementation relative to the screening implement\ ation period.

For adjusted analyses: see Supplemental Digital Content 10 (http://links\ .lww.com/CCM/E227). LOS = length of stay, PT = physical therapy.

Trogrli et al Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.Neurologic Critical Care Critical Care Medicine www.ccmjournal.org 425 From an implementation perspective, we learned several lessons on evidence-to-practice translation. First, our implicit assumption that other improvements such as SATs and SBTs would follow next to our efforts to implement delirium-ori- ented measures, not specifically aimed at safety screens, has been falsified. Second, ICU teams less experienced with use of the guideline bundles or relying solely on “local champions” rather than interprofessional implementation teams should not try to implement all PAD/ABCDE bundle elements “si- multaneously” within a limited time frame. Of note, our study deployed one or two local champions (intensivist or research nurse), but limited funding precluded appointment of full interprofessional teams (IPTs), existing of all relevant stakeholders, such as residents, respiratory therapists, physical therapists, and other dedicated healthcare workers. Deploying such IPTs has been shown in other implementation studies to be essential for multibundle implementation within a limited timeframe (7, 38, 39). A graded or phased implementation seems much more feasible in such relatively resource-limited settings, and we learned that “integration” of bundle elements should not be confused with their “simultaneous” adoption.

Third, not only the caregivers but also the dedicated “role models” have a learning curve for providing education and the feedback, so patience is of the essence. Fourth, successful im- plementation of bundle elements requires taking into account the baseline situation and contextual issues, such as existing barriers and facilitators, because many have been identified and not all are pertinent to all settings (40).

The strengths of our study include the prospective design, use of tailored multifaceted implementation strategies, the largest cohort to date outside of the United States, and the representative mix of ICU types supporting the translatability of our findings. Further, we deployed a pragmatic approach:

implementation as part of daily clinical practice instead of deployment in a controlled research setting, which is also in contrast to most published studies. Several limitations need to be addressed. First, the Hawthorne effect was not avoided, seeing that delirium screening implementation alone resulted in improved adherence to several guideline recommendations.

Second, duration of delirium might be a doubtful outcome pa- rameter due to the difference between a clinical diagnosis as assessed by chart review at baseline compared with the second and third phases (based on validated screening instruments).

Long-term outcomes, such as cognition or posttraumatic stress disorder, may be more relevant outcomes. Last, certain changes over time may have been overestimated in the pres- ence of secular trends (41). In conclusion, this largest pre-post implementation study outside of the United States of delirium-oriented measures based on the 2013 PAD guidelines showed that implementa- tion had improved health professionals’ adherence to delirium guidelines, which was linked to reduced brain dysfunction. TABLE 3. Secondary (Clinical) Outcomes Outcomes Crude analysis Adjusted a Effect Values Phase I:

Baseline Phase II:

Screening Implementation Phase III: Guideline Implementation Adjusted OR/Rate Ratio/Beta a (95% CI; p) a) Phase I vs Phase II b) Phase I vs Phase III c) Phase II vs Phase III Patients (n) Patients (n) Patients (n) Delirium duration (d), mean ( sd) 2 74 5.6 (8.6) 3002.9 (3.3) 3193.3 (4.5) a) 2.6 3.5 to 1.6; p < 0.001) b) –2.2 (–3.2 to –1.3; p < 0.001) c) 0.3 (–0.6 to 1.2; p = 0.46) Patients with delirium during ICU admission, n (%) 1,337 274 (21) 1,399300 (21) 1,194319 (27) a) 1.2 (0.9–1.4; p = 0.16) b) 1.4 (1.2–1.7; p < 0.001) c) 1.2 (1.0–1.5; p = 0.25) Duration of mechanical ventilation (d), mean ( sd) 560 4.6 (8.2) 5414.9 (6.4) 5934.7 (6.5) a) 0.5 0.3 to 1.3; p = 0.23) b) 0.4 (–0.4 to 1.2; p = 0.36) c) –0.1 (–0.9 to 0.7; p = 0.75) ICU length of stay (d), mean ( sd) 1,337 4.9 (6.9) 1,3994.3 (6.0) 1,1944.8 (5.9) a) 0.3 0.8 to 0.1; p = 0.19) b) –0.1 (–0.6 to 0.3; p = 0.56) c) 0.2 (–0.3 to 0.6; p = 0.49) ICU mortality, n (%) 1,337 135 (10.1) 1,399140 (10.0) 1,194126 (10.6) a) 1.3 (1.0–1.7; p = 0.08) b) 1.3 (0.9–1.7; p = 0.13) c) 1.0 (0.7–1.3; p = 0.88) Hospital mortality, n (%) 1,337 216 (16.2) 1,399226 (16.2) 1,194194 (16.2) a) 1.3 (1.0–1.6; p = 0.057) b) 1.1 (0.9–1.5; p = 0.31) c) 0.9 (0.7–1.1; p = 0.39) OR = odds ratio.a Differences are expressed as adjusted OR or adjusted rate ratios with the Phase I: Baseline (for a and b) and Phase II: After screening implementation (for c) as the reference. Adjusted for Acute Physiology and Chronic Health Evaluati\ on-II, hospital, age, and admission type. Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. 426 www.ccmjournal.org March 2019 • Volume 47 • Number 3 Our data add to existing implementation literature due to the non-U.S. setting, strongly enhancing translatability of findings.

Furthermore, implementation lessons learned that are unique for our study pertain to 1) the feasibility of staggered versus simultaneous implementation of bundle elements, that seem strongly dependent on local resources (e.g., “local champions” vs interprofessional implementation teams or level of previous experience with the guidelines), and 2) the fact that our “error of omission” of daily safety screens for SATs and SBTs may have precluded concurrently improved clinical outcomes, adding strong empirical support from a “real-life setting” for effective- ness of individual ABCDE bundle elements.

ACKNOWLEDGMENTS The authors thank the coordinating nurses: A. van Wijk van Brievingh, I. van Doremalen, T. Schravesande, H. van Embden, and M. Campo; ICU pharmacist N. Hunfeld; psy- chiatrist R.J. Osse; all those who have contributed to data collection, all nurses and physicians for participating in ed- ucation; all site data managers; and all those who provided help during the study. The authors thank Ko Hagoort for editing the article.

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