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Abstract The primary aim of this study was to evaluate computed tomography (CT)-based bone density analysis at the level of thoracic vertebra 12 (Th12) as a screening method for decreased bone density in patients admitted to the intensive care unit (ICU). Interobserver variability was analyzed. Secondary aims were to assess the prevalence of CT-based low bone density upon ICU admission in a cohort of COVID-19 patients and to assess the potential effect of long-term ICU stay on bone density in these patients. Retrospective single-center cohort study. ICU of the Leiden University Medical Center (LUMC), the Netherlands. Patients admitted to the ICU of the LUMC between March 1st, 2020 and February 1st, 2022 with a diagnosis of COVID-19, and a length of ICU stay of ≥ 21 days. In the included patients both baseline chest CT scans (obtained upon ICU admission) and follow-up chest CT scans (obtained ≥ 21 days after ICU admission) were available for analysis. A total of 118 CT scans in 38 patients were analyzed. There was a good interobserver variability, with an overall mean absolute difference (between measurements of three observers) of 9.7 Hounsfield Units (HU) and an intraclass correlation coefficient (ICC) of 0.93 (95% CI 0.88–0.96). The effect of intravenous contrast administration on bone density measurements was small (+ 7.5 HU (95% CI 3.4–11.5 HU)) higher in contrast enhanced CT images compared to non contrast enhanced CT images). Thirty-seven percent of patients had a bone density

Abstract Heart surgery may be complicated by acute lung injury and adult respiratory distress syndrome. Expression and release of mucins MUC5AC and MUC5B in the lungs has been reported to be increased in acute lung injury. The aim of our study was to [1] investigate the perioperative changes of MUC5AC, MUC5B and other biomarkers in mini-bronchoalveolar lavage (minBAL), and [2] relate these to clinical outcomes after cardiac surgery. In this prospective cohort study in 49 adult cardiac surgery patients pre- and post-surgery non-fiberscopic miniBAL fluids were analysed for MUC5AC, MUC5B, IL-8, human neutrophil elastase, and neutrophils. All measured biomarkers increased after surgery. Perioperative MUC5AC-change showed a significant negative association with postoperative P/F ratio (p = 0.018), and a positive association with ICU stay (p = 0.027). In conclusion, development of lung injury after cardiac surgery and prolonged ICU stay are associated with an early increase of MUC5AC as detected in mini-BAL.

Summary: Background: The circadian timing system coordinates daily cycles in physiological functions, including glucose metabolism and insulin sensitivity. Here, the aim was to characterise the 24-h variation in glucose levels in critically ill patients during continuous enteral nutrition after controlling for potential sources of bias. Methods: Time-stamped clinical data from adult patients who stayed in the Intensive Care Unit (ICU) for at least 4 days and received enteral nutrition were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Linear mixed-effects and XGBoost modelling were used to determine the effect of time of day on blood glucose values. Findings: In total, 207,647 glucose measurements collected during enteral nutrition were available from 6,929 ICU patients (3,948 males and 2,981 females). Using linear mixed-effects modelling, time of day had a significant effect on blood glucose levels (p

Introduction: Immune checkpoint inhibitors (ICIs) represent the standard therapy for metastatic melanoma. However, a few patients do not respond to ICIs and reliable predictive biomarkers are needed.Methods: This pilot study investigates the association between mRNA levels of programmed cell death-1 (PD-1) ligand 1 (PD-L1), interferon-gamma (IFN-γ), and transforming growth factor-β (TGF-β) in circulating extracellular vesicles (EVs) and survival in 30 patients with metastatic melanoma treated with first line anti-PD-1 antibodies. Blood samples were collected at baseline and RNA extracted from EVs; the RNA levels of PD-L1, IFN-γ, and TGF-β were analysed by digital droplet PCR (ddPCR). A biomarker-radiomic correlation analysis was performed in a subset of patients.Results: Patients with high TGF-β expression (cut-off fractional abundance [FA] >0.19) at baseline had longer median progression-free survival (8.4 vs. 1.8 months; p = 0.006) and overall survival (17.9 vs. 2.63 months; p = 0.0009). Moreover, radiomic analysis demonstrated that patients with high TGF-β expression at baseline had smaller lesions (2.41 ± 3.27 mL vs. 42.79 ± 101.08 mL, p < 0.001) and higher dissimilarity (12.01 ± 28.23 vs. 5.65 ± 8.4; p = 0.018).Discussion: These results provide evidence that high TGF-β expression in EVs is associated with a better response to immunotherapy. Further investigation on a larger patient population is needed to validate the predictive power of this potential biomarker of response to ICIs.

Extragonadal androgens play a pivotal role in prostate cancer disease progression on androgen receptor signaling inhibitors (ARSi), including abiraterone and enzalutamide. We aimed to investigate if germline variants in genes involved in extragonadal androgen synthesis contribute to resistance to ARSi and may predict clinical outcomes on ARSi. We included ARSi naive metastatic prostate cancer patients treated with abiraterone or enzalutamide and determined 18 germline variants in six genes involved in extragonadal androgen synthesis. Variants were tested in univariate and multivariable analysis for the relation with overall survival (OS) and time to progression (TTP) by Cox regression, and PSA response by logistic regression. A total of 275 patients were included. From the investigated genes CYP17A1, HSD3B1, CYP11B1, AKR1C3, SRD5A1 and SRD5A2, only rs4736349 in CYP11B1 in homozygous form (TT), present in 54 patients (20%), was related with a significantly worse OS (HR = 1.71, 95% CI 1.09 – 2.68, p = 0.019) and TTP (HR = 1.50, 95% CI 1.08 – 2.09, p = 0.016), and was related with a significantly less frequent PSA response (OR = 0.48, 95% CI 0.24 – 0.96, p = 0.038) on abiraterone or enzalutamide in a multivariable analysis. The frequent germline variant rs4736349 in CYP11B1 is, as homozygote, an independent negative prognostic factor for treatment with abiraterone or enzalutamide in ARSi naive metastatic prostate cancer patients. Our findings warrant prospective investigation of this potentially important predictive biomarker.

Summary: Background: Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated (EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFRm+ NSCLC patients. Methods: Patients who started treatment with osimertinib for EGFRm+ NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. Findings: From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11–0.73; p = 0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0% versus 16.5%; p = 0.010). Interpretation: ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment. Funding: No funding was received for this trial.

Abstract Background Treatment and the clinical course during Emergency Department (ED) stay before Intensive Care Unit (ICU) admission may affect predicted mortality risk calculated by the Acute Physiology and Chronic Health Evaluation (APACHE)-IV, causing lead-time bias. As a result, comparing standardized mortality ratios (SMRs) among hospitals may be difficult if they differ in the location where initial stabilization takes place. The aim of this study was to assess to what extent predicted mortality risk would be affected if the APACHE-IV score was recalculated with the initial physiological variables from the ED. Secondly, to evaluate whether ED Length of Stay (LOS) was associated with a change (delta) in these APACHE-IV scores. Methods An observational multicenter cohort study including ICU patients admitted from the ED. Data from two Dutch quality registries were linked: the Netherlands Emergency department Evaluation Database (NEED) and the National Intensive Care Evaluation (NICE) registry. The ICU APACHE-IV, predicted mortality, and SMR based on data of the first 24 h of ICU admission were compared with an ED APACHE-IV model, using the most deviating physiological variables from the ED or ICU. Results A total of 1398 patients were included. The predicted mortality from the ICU APACHE-IV (median 0.10; IQR 0.03–0.30) was significantly lower compared to the ED APACHE-IV model (median 0.13; 0.04–0.36; p 3.9 h was associated with a slight increase in delta APACHE-IV of 1.6 (95% CI 0.4–2.8) compared to ED LOS

Abstract Background INTELLiVENT–Adaptive Support Ventilation (ASV) is a fully automated closed-loop mode of ventilation for use in critically ill patients. Evidence for benefit of INTELLiVENT–ASV in comparison to ventilation that is not fully automated with regard to duration of ventilation and quality of breathing is largely lacking. We test the hypothesis that INTELLiVENT–ASV shortens time spent on a ventilator and improves the quality of breathing. Methods The “Effects of Automated Closed–loop VenTilation versus Conventional Ventilation on Duration and Quality of Ventilation” (ACTiVE) study is an international, multicenter, two-group randomized clinical superiority trial. In total, 1200 intensive care unit (ICU) patients with an anticipated duration of ventilation of > 24 h will be randomly assigned to one of the two ventilation strategies. Investigators screen patients aged 18 years or older at start of invasive ventilation in the ICU. Patients either receive automated ventilation by means of INTELLiVENT–ASV, or ventilation that is not automated by means of a conventional ventilation mode. The primary endpoint is the number of days free from ventilation and alive at day 28; secondary endpoints are quality of breathing using granular breath-by-breath analysis of ventilation parameters and variables in a time frame of 24 h early after the start of invasive ventilation, duration of ventilation in survivors, ICU and hospital length of stay (LOS), and mortality rates in the ICU and hospital, and at 28 and 90 days. Discussion ACTiVE is one of the first randomized clinical trials that is adequately powered to compare the effects of automated closed-loop ventilation versus conventional ventilation on duration of ventilation and quality of breathing in invasively ventilated critically ill patients. The results of ACTiVE will support intensivist in their choices regarding the use of automated ventilation. Trial registration ACTiVE is registered in clinicaltrials.gov (study identifier: NCT04593810 ) on 20 October 2020.

Abstract Appropriate interpretation of blood tests is important for risk stratification and guidelines used in the Emergency Department (ED) (such as SIRS or CURB-65). The impact of abnormal blood test values on mortality may change with increasing age due to (patho)-physiologic changes. The aim of this study was therefore to assess the effect of age on the case-mix adjusted association between biomarkers of renal function and homeostasis, inflammation and circulation and in-hospital mortality. This observational multi-center cohort study has used the Netherlands Emergency department Evaluation Database (NEED), including all consecutive ED patients ≥ 18 years of three hospitals. A generalized additive logistic regression model was used to visualize the association between in-hospital mortality, age and five blood tests (creatinine, sodium, leukocytes, C-reactive Protein, and hemoglobin). Multivariable logistic regression analyses were used to assess the association between the number of abnormal blood test values and mortality per age category (18–50; 51–65; 66–80; > 80 years). Of the 94,974 included patients, 2550 (2.7%) patients died in-hospital. Mortality increased gradually for C-reactive Protein (CRP), and had a U-shaped association for creatinine, sodium, leukocytes, and hemoglobin. Age significantly affected the associations of all studied blood tests except in leukocytes. In addition, with increasing age categories, case-mix adjusted mortality increased with the number of abnormal blood tests. In summary, the association between blood tests and (adjusted) mortality depends on age. Mortality increases gradually or in a U-shaped manner with increasing blood test values. Age-adjusted numerical scores may improve risk stratification. Our results have implications for interpretation of blood tests and their use in risk stratification tools and acute care guidelines. Trial registration number Netherlands Trial Register (NTR) NL8422, 03/2020.

OBJECTIVES:. Mechanical power (MP) is a way of estimating the energy delivered by the ventilator to the patient. For both volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) methods have been described to calculate the MP. The pressure-volume (PV) loop, from which the MP is calculated, is different for VCV compared with PCV. We aimed to compare the MP of VCV with zero pause time (VCV-0), VCV with 10% pause time (VCV-10), and PCV within patients in different patient categories based on severity of lung injury. DESIGN:. In a proof-of-concept study, we enrolled 46 mechanically ventilated patients without spontaneous breathing efforts. Baseline measurements were done in pressure-controlled mode. Subsequently, measurements were done in VCV-0 and VCV-10. Tidal volume and all other settings were kept the same. SETTING:. ICU, single university medical center. PATIENTS:. Fifty-eight cases in 46 patients on controlled ventilation modes. INTERVENTIONS:. Comparison between the MP of PCV, VCV-0, and VCV-10. MEASUREMENT AND MAIN RESULTS:. The mean MP of VCV-0, VCV-10, and PCV was 19.30, 21.80, and 20.87 J/min, respectively (p < 0.05 for all comparisons). The transpulmonary MP of VCV-0, VCV-10, and PCV was 6.75, 8.60, and 7.99 J/min, respectively (p < 0.05 for all comparisons). CONCLUSIONS:. In patients ventilated in a controlled mode, VCV without pause time had the lowest MP followed by PCV. VCV with 10% pause time had the highest MP.

Abstract Background Lung ultrasound can adequately monitor disease severity in pneumonia and acute respiratory distress syndrome. We hypothesize lung ultrasound can adequately monitor COVID-19 pneumonia in critically ill patients. Methods Adult patients with COVID-19 pneumonia admitted to the intensive care unit of two academic hospitals who underwent a 12-zone lung ultrasound and a chest CT examination were included. Baseline characteristics, and outcomes including composite endpoint death or ICU stay > 30 days were recorded. Lung ultrasound and CT images were quantified as a lung ultrasound score involvement index (LUSI) and CT severity involvement index (CTSI). Primary outcome was the correlation, agreement, and concordance between LUSI and CTSI. Secondary outcome was the association of LUSI and CTSI with the composite endpoints. Results We included 55 ultrasound examinations in 34 patients, which were 88% were male, with a mean age of 63 years and mean P/F ratio of 151. The correlation between LUSI and CTSI was strong (r = 0.795), with an overall 15% bias, and limits of agreement ranging − 40 to 9.7. Concordance between changes in sequentially measured LUSI and CTSI was 81%. In the univariate model, high involvement on LUSI and CTSI were associated with a composite endpoint. In the multivariate model, LUSI was the only remaining independent predictor. Conclusions Lung ultrasound can be used as an alternative for chest CT in monitoring COVID-19 pneumonia in critically ill patients as it can quantify pulmonary involvement, register changes over the course of the disease, and predict death or ICU stay > 30 days. Trial registration: NTR, NL8584. Registered 01 May 2020—retrospectively registered, https://www.trialregister.nl/trial/8584

Abstract Post cardiac arrest syndrome is associated with high morbidity and mortality, which is related not only to a poor neurological outcome but also to respiratory and cardiovascular dysfunctions. The control of gas exchange, and in particular oxygenation and carbon dioxide levels, is fundamental in mechanically ventilated patients after resuscitation, as arterial blood gases derangement might have important effects on the cerebral blood flow and systemic physiology. In particular, the pathophysiological role of carbon dioxide (CO2) levels is strongly underestimated, as its alterations quickly affect also the changes of intracellular pH, and consequently influence metabolic energy and oxygen demand. Hypo/hypercapnia, as well as mechanical ventilation during and after resuscitation, can affect CO2 levels and trigger a dangerous pathophysiological vicious circle related to the relationship between pH, cellular demand, and catecholamine levels. The developing hypocapnia can nullify the beneficial effects of the hypothermia. The aim of this review was to describe the pathophysiology and clinical consequences of arterial blood gases and pH after cardiac arrest. According to our findings, the optimal ventilator strategies in post cardiac arrest patients are not fully understood, and oxygen and carbon dioxide targets should take in consideration a complex pattern of pathophysiological factors. Further studies are warranted to define the optimal settings of mechanical ventilation in patients after cardiac arrest.

Abstract Background There are many prognostic models and scoring systems in use to predict mortality in ICU patients. The only general ICU scoring system developed and validated for patients after cardiac surgery is the APACHE-IV model. This is, however, a labor-intensive scoring system requiring a lot of data and could therefore be prone to error. The SOFA score on the other hand is a simpler system, has been widely used in ICUs and could be a good alternative. The goal of the study was to compare the SOFA score with the APACHE-IV and other ICU prediction models. Methods We investigated, in a large cohort of cardiac surgery patients admitted to Dutch ICUs, how well the SOFA score from the first 24 h after admission, predict hospital and ICU mortality in comparison with other recalibrated general ICU scoring systems. Measures of discrimination, accuracy, and calibration (area under the receiver operating characteristic curve (AUC), Brier score, R2, and Ĉ-statistic) were calculated using bootstrapping. The cohort consisted of 36,632 Patients from the Dutch National Intensive Care Evaluation (NICE) registry having had a cardiac surgery procedure for which ICU admission was necessary between January 1st, 2006 and June 31st, 2018. Results Discrimination of the SOFA-, APACHE-IV-, APACHE-II-, SAPS-II-, MPM24-II - models to predict hospital mortality was good with an AUC of respectively: 0.809, 0.851, 0.830, 0.850, 0.801. Discrimination of the SOFA-, APACHE-IV-, APACHE-II-, SAPS-II-, MPM24-II - models to predict ICU mortality was slightly better with AUCs of respectively: 0.809, 0.906, 0.892, 0.919, 0.862. Calibration of the models was generally poor. Conclusion Although the SOFA score had a good discriminatory power for hospital- and ICU mortality the discriminatory power of the APACHE-IV and SAPS-II was better. The SOFA score should not be preferred as mortality prediction model above traditional prognostic ICU-models.

Abstract Background Vasoplegia is a severe complication which may occur after cardiac surgery, particularly in patients with heart failure. It is a result of activation of vasodilator pathways, inactivation of vasoconstrictor pathways and the resistance to vasopressors. However, the precise etiology remains unclear. The aim of the Vasoresponsiveness in patients with heart failure (VASOR) study is to objectify and characterize the altered vasoresponsiveness in patients with heart failure, before, during and after heart failure surgery and to identify the etiological factors involved. Methods This is a prospective, observational study conducted at Leiden University Medical Center. Patients with and patients without heart failure undergoing cardiac surgery on cardiopulmonary bypass are enrolled. The study is divided in two inclusion phases. During phase 1, 18 patients with and 18 patients without heart failure are enrolled. The vascular reactivity in response to a vasoconstrictor (phenylephrine) and a vasodilator (nitroglycerin) is assessed in vivo on different timepoints. The response to phenylephrine is assessed on t1 (before induction), t2 (before induction, after start of cardiotropic drugs and/or vasopressors), t3 (after induction), t4 (15 min after cessation of cardiopulmonary bypass) and t5 (1 day post-operatively). The response to nitroglycerin is assessed on t1 and t5. Furthermore, a sample of pre-pericardial fat tissue, containing resistance arteries, is collected intraoperatively. The ex vivo vascular reactivity is assessed by constructing concentrations response curves to various vasoactive substances using isolated resistance arteries. Next, expression of signaling proteins and receptors is assessed using immunohistochemistry and mRNA analysis. Furthermore, the groups are compared with respect to levels of organic compounds that can influence the cardiovascular system (e.g. copeptin, (nor)epinephrine, ANP, BNP, NTproBNP, angiotensin II, cortisol, aldosterone, renin and VMA levels). During inclusion phase 2, only the ex vivo vascular reactivity test is performed in patients with (N = 12) and without heart failure (N = 12). Discussion Understanding the difference in vascular responsiveness between patients with and without heart failure in detail, might yield therapeutic options or development of preventive strategies for vasoplegia, leading to safer surgical interventions and improvement in outcome. Trial registration The Netherlands Trial Register (NTR), NTR5647. Registered 26 January 2016.

Abstract Background Audit and feedback (A&F) is more effective if it facilitates action planning, but little is known about how best to do this. We developed an electronic A&F intervention with an action implementation toolbox to improve pain management in intensive care units (ICUs); the toolbox contained suggested actions for improvement. A head-to-head randomised trial demonstrated that the toolbox moderately increased the intervention’s effectiveness when compared with A&F only. Objective To understand the mechanisms through which A&F with action implementation toolbox facilitates action planning by ICUs to increase A&F effectiveness. Methods We extracted all individual actions from action plans developed by ICUs that received A&F with (n = 10) and without (n = 11) toolbox for 6 months and classified them using Clinical Performance Feedback Intervention Theory. We held semi-structured interviews with participants during the trial. We compared the number and type of planned and completed actions between study groups and explored barriers and facilitators to effective action planning. Results ICUs with toolbox planned more actions directly aimed at improving practice (p = 0.037) and targeted a wider range of practice determinants compared to ICUs without toolbox. ICUs with toolbox also completed more actions during the study period, but not significantly (p = 0.142). ICUs without toolbox reported more difficulties in identifying what actions they could take. Regardless of the toolbox, all ICUs still experienced barriers relating to the feedback (low controllability, accuracy) and organisational context (competing priorities, resources, cost). Conclusions The toolbox helped health professionals to broaden their mindset about actions they could take to change clinical practice. Without the toolbox, professionals tended to focus more on feedback verification and exploring solutions without developing intentions for actual change. All feedback recipients experienced organisational barriers that inhibited eventual completion of actions. Trial registration ClinicalTrials.gov, NCT02922101. Registered on 26 September 2016.

Abstract Background While influenza-like-illness (ILI) surveillance is well-organized at primary care level in Europe, few data are available on more severe cases. With retrospective data from intensive care units (ICU) we aim to fill this current knowledge gap. Using multiple parameters proposed by the World Health Organization we estimate the burden of severe acute respiratory infections (SARI) in the ICU and how this varies between influenza epidemics. Methods We analyzed weekly ICU admissions in the Netherlands (2007–2016) from the National Intensive Care Evaluation (NICE) quality registry (100% coverage of adult ICUs in 2016; population size 14 million) to calculate SARI incidence, SARI peak levels, ICU SARI mortality, SARI mean Acute Physiology and Chronic Health Evaluation (APACHE) IV score, and the ICU SARI/ILI ratio. These parameters were calculated both yearly and per separate influenza epidemic (defined epidemic weeks). A SARI syndrome was defined as admission diagnosis being any of six pneumonia or pulmonary sepsis codes in the APACHE IV prognostic model. Influenza epidemic periods were retrieved from primary care sentinel influenza surveillance data. Results Annually, an average of 13% of medical admissions to adult ICUs were for a SARI but varied widely between weeks (minimum 5% to maximum 25% per week). Admissions for bacterial pneumonia (59%) and pulmonary sepsis (25%) contributed most to ICU SARI. Between the eight different influenza epidemics under study, the value of each of the severity parameters varied. Per parameter the minimum and maximum of those eight values were as follows: ICU SARI incidence 558–2400 cumulated admissions nationwide, rate 0.40–1.71/10,000 inhabitants; average APACHE score 71–78; ICU SARI mortality 13–20%; ICU SARI/ILI ratio 8–17 cases per 1000 expected medically attended ILI in primary care); peak-incidence 101–188 ICU SARI admissions in highest-incidence week, rate 0.07–0.13/10,000 population). Conclusions In the ICU there is great variation between the yearly influenza epidemic periods in terms of different influenza severity parameters. The parameters also complement each other by reflecting different aspects of severity. Prospective syndromic ICU SARI surveillance, as proposed by the World Health Organization, thereby would provide insight into the severity of ongoing influenza epidemics, which differ from season to season.

Abstract Background Audit and feedback aims to guide health professionals in improving aspects of their practice that need it most. Evidence suggests that feedback fails to increase accuracy of professional perceptions about clinical performance, which likely reduces audit and feedback effectiveness. This study investigates health professionals’ perceptions about their clinical performance and the influence of feedback on their intentions to change practice. Methods We conducted an online laboratory experiment guided by Control Theory with 72 intensive care professionals from 21 units. For each of four new pain management indicators, we collected professionals’ perceptions about their clinical performance; peer performance; targets; and improvement intentions before and after receiving first-time feedback. An electronic audit and feedback dashboard provided ICU’s own performance, median and top 10% peer performance, and improvement recommendations. The experiment took place approximately 1 month before units enrolled into a cluster-randomised trial assessing the impact of adding a toolbox with suggested actions and materials to improve intensive care pain management. During the experiment, the toolbox was inaccessible; all participants accessed the same version of the dashboard. Results We analysed 288 observations. In 53.8%, intensive care professionals overestimated their clinical performance; but in only 13.5%, they underestimated it. On average, performance was overestimated by 22.9% (on a 0–100% scale). Professionals similarly overestimated peer performance, and set targets 20.3% higher than the top performance benchmarks. In 68.4% of cases, intentions to improve practice were consistent with actual gaps in performance, even before professionals had received feedback; which increased to 79.9% after receiving feedback (odds ratio, 2.41; 95% CI, 1.53 to 3.78). However, in 56.3% of cases, professionals still wanted to improve care aspects at which they were already top performers. Alternatively, in 8.3% of cases, they lacked improvement intentions because they did not consider indicators important; did not trust the data; or deemed benchmarks unrealistic. Conclusions Audit and feedback helps health professionals to work on aspects for which improvement is recommended. Given the abundance of professionals’ prior good improvement intentions, the limited effects typically found by audit and feedback studies are likely predominantly caused by barriers to translation of intentions into actual change in clinical practice. Trial registration ClinicalTrials.gov NCT02922101. Registered 26 September 2016.

Abstract Background Audit and feedback is often used as a strategy to improve quality of care, however, its effects are variable and often marginal. In order to learn how to design and deliver effective feedback, we need to understand their mechanisms of action. This theory-informed study will investigate how electronic audit and feedback affects improvement intentions (i.e. information–intention gap), and whether an action implementation toolbox with suggested actions and materials helps translating those intentions into action (i.e. intention–behaviour gap). The study will be executed in Dutch intensive care units (ICUs) and will be focused on pain management. Methods and design We will conduct a laboratory experiment with individual ICU professionals to assess the impact of feedback on their intentions to improve practice. Next, we will conduct a cluster randomised controlled trial with ICUs allocated to feedback without or feedback with action implementation toolbox group. Participants will not be told explicitly what aspect of the intervention is randomised; they will only be aware that there are two variations of providing feedback. ICUs are eligible for participation if they submit indicator data to the Dutch National Intensive Care Evaluation (NICE) quality registry and agree to allocate a quality improvement team that spends 4 h per month on the intervention. All participating ICUs will receive access to an online quality dashboard that provides two functionalities: gaining insight into clinical performance on pain management indicators and developing action plans. ICUs with access to the toolbox can develop their action plans guided by a list of potential barriers in the care process, associated suggested actions, and supporting materials to facilitate implementation of the actions. The primary outcome measure for the laboratory experiment is the proportion of improvement intentions set by participants that are consistent with recommendations based on peer comparisons; for the randomised trial it is the proportion of patient shifts during which pain has been adequately managed. We will also conduct a process evaluation to understand how the intervention is implemented and used in clinical practice, and how implementation and use affect the intervention’s impact. Discussion The results of this study will inform care providers and managers in ICU and other clinical settings how to use indicator-based performance feedback in conjunction with an action implementation toolbox to improve quality of care. Within the ICU context, this study will produce concrete and directly applicable knowledge with respect to what is or is not effective for improving pain management, and under which circumstances. The results will further guide future research that aims to understand the mechanisms behind audit and feedback and contribute to identifying the active ingredients of successful interventions. Trial registration ClinicalTrials.gov NCT02922101 . Registered 26 September 2016.

Abstract Background Mechanical ventilation and hyperoxia have the potential to independently promote lung injury and inflammation. Our purpose was to study both time- and dose-dependent effects of supplemental oxygen in an experimental model of mechanically ventilated mice. Methods Healthy male C57Bl/6J mice, aged 9–10 weeks, were intraperitoneally anesthetized and randomly assigned to the mechanically ventilated group or the control group. In total, 100 mice were tracheotomized and mechanically ventilated for either 8 or 12 h after allocation to different settings for the applied fractions of inspired oxygen (FiO2, 30, 50, or 90%) and tidal volumes (7.5 or 15 ml/kg). After euthanisation arterial blood, bronchoalveolar lavage fluid (BALf) and tissues were collected for analyses. Results Mechanical ventilation significantly increased the lung injury score (P

IntroductionExtensive antibiotic use makes the intensive care unit (ICU) an important focus for antibiotic stewardship programs. The aim of this study was to develop a set of actionable quality indicators for appropriate antibiotic use at ICUs and an implementation toolbox, which can be used to assess and improve the appropriateness of antibiotic use in the treatment of adult patients at an ICU.MethodsA four round modified-RAND Delphi procedure was used. Potential indicators were identified by a multidisciplinary panel of 15 Dutch experts, from international literature and guidelines. Using an online survey, the identified indicators were rated on three criteria: relevance, actionability and feasibility. Experts discussed and rated the indicators for the second time during a face-to-face consensus meeting. During a final consensus meeting the toolbox was developed, containing potential barriers and improvement strategies which were identified using a validated checklist by Flottorp et al., and if available also containing supporting material.ResultsThe first round resulted in 24 potential indicators. After the final meeting a set of three process indicators, one structure indicator and one quantity metric remained: 1) perform at least two sets of blood cultures before start of empirical systemic therapy; 2) perform therapeutic drug monitoring in patients treated with vancomycin or aminoglycosides; 3) perform surveillance cultures if selective digestive or oropharyngeal decontamination is applied at the ICU; 4) biannual face-to-face meetings between ICU and microbiology staff in which local resistance rates are discussed; and 5) quantitative antibiotic use at the ICU expressed in days of therapy (DOT). The toolbox contains 24 unique barriers and 37 improvement strategies.ConclusionsOur study identified a set of four actionable quality indicators and one quantity metric, together with an implementation toolbox, to improve appropriate antibiotic use at ICUs.

PURPOSE:To assess and improve the effectiveness of ICU care, in-hospital mortality rates are often used as principal quality indicator for benchmarking purposes. Two other often used, easily quantifiable, quality indicators to assess the efficiency of ICU care are based on readmission to the ICU and ICU length of stay. Our aim was to examine whether there is an association between case-mix adjusted outcome-based quality indicators in the general ICU population as well as within specific subgroups. MATERIALS AND METHODS:We included patients admitted in 2015 of all Dutch ICUs. We derived the standardized in-hospital mortality ratio (SMR); the standardized readmission ratio (SRR); and the standardized length of stay ratio (SLOSR). We expressed association through Pearson's correlation coefficients. RESULTS:The SMR ranged from 0.6 to 1.5; the SRR ranged from 0.7 to 2.1; and the SLOSR ranged from 0.7 to 1.3. For the total ICU population we found no significant associations. We found a positive, non-significant, association between SMR and SLOSR for admissions with low-mortality risk, (r = 0.25; p = 0.024), and a negative association between these indicators for admissions with high-mortality risk (r = -0.49; p

Intensive care units (ICUs) are increasingly interested in assessing and improving their performance. ICU Length of Stay (LoS) could be seen as an indicator for efficiency of care. However, little consensus exists on which prognostic method should be used to adjust ICU LoS for case-mix factors. This study compared the performance of different regression models when predicting ICU LoS. We included data from 32,667 unplanned ICU admissions to ICUs participating in the Dutch National Intensive Care Evaluation (NICE) in the year 2011. We predicted ICU LoS using eight regression models: ordinary least squares regression on untransformed ICU LoS,LoS truncated at 30 days and log-transformed LoS; a generalized linear model with a Gaussian distribution and a logarithmic link function; Poisson regression; negative binomial regression; Gamma regression with a logarithmic link function; and the original and recalibrated APACHE IV model, for all patients together and for survivors and non-survivors separately. We assessed the predictive performance of the models using bootstrapping and the squared Pearson correlation coefficient (R2), root mean squared prediction error (RMSPE), mean absolute prediction error (MAPE) and bias. The distribution of ICU LoS was skewed to the right with a median of 1.7 days (interquartile range 0.8 to 4.0) and a mean of 4.2 days (standard deviation 7.9). The predictive performance of the models was between 0.09 and 0.20 for R2, between 7.28 and 8.74 days for RMSPE, between 3.00 and 4.42 days for MAPE and between -2.99 and 1.64 days for bias. The predictive performance was slightly better for survivors than for non-survivors. We were disappointed in the predictive performance of the regression models and conclude that it is difficult to predict LoS of unplanned ICU admissions using patient characteristics at admission time only.