Emergency Department Triage, Transfer Times, and Hospital Mortality of Patients Admitted to the ICU: A Retrospective Replication and Continuation Study.

OBJECTIVES: This study aimed to provide new insights into the impact of emergency department (ED) to ICU time on hospital mortality, stratifying patients by academic and nonacademic teaching (NACT) hospitals, and considering Acute Physiology and Chronic Health Evaluation (APACHE)-IV probability and ED-triage scores. DESIGN, SETTING, AND PATIENTS: We conducted a retrospective cohort study (2009-2020) using data from the Dutch National Intensive Care Evaluation registry. Patients directly admitted from the ED to the ICU were included from four academic and eight NACT hospitals. Odds ratios (ORs) for mortality associated with ED-to-ICU time were estimated using multivariable regression, both crude and after adjusting for and stratifying by APACHE-IV probability and ED-triage scores. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 28,455 patients were included. The median ED-to-ICU time was 1.9 hours (interquartile range, 1.2-3.1 hr). No overall association was observed between ED-to-ICU time and hospital mortality after adjusting for APACHE-IV probability (p = 0.36). For patients with an APACHE-IV probability greater than 55.4% (highest quintile) and an ED-to-ICU time greater than 3.4 hours the adjusted OR (ORsadjApache) was 1.24 (95% CI, 1.00-1.54; p < 0.05) as compared with the reference category (< 1.1 hr). In the academic hospitals, the ORsadjApache for ED-to-ICU times of 1.6-2.3, 2.3-3.4, and greater than 3.4 hours were 1.21 (1.01-1.46), 1.21 (1.00-1.46), and 1.34 (1.10-1.64), respectively. In NACT hospitals, no association was observed (p = 0.07). Subsequently, ORs were adjusted for ED-triage score (ORsadjED). In the academic hospitals the ORsadjED for ED-to-ICU times greater than 3.4 hours was 0.98 (0.81-1.19), no overall association was observed (p = 0.08). In NACT hospitals, all time-ascending quintiles had ORsadjED values of less than 1.0 (p < 0.01). CONCLUSIONS: In patients with the highest APACHE-IV probability at academic hospitals, a prolonged ED-to-ICU time was associated with increased hospital mortality. We found no significant or consistent unfavorable association in lower APACHE-IV probability groups and NACT hospitals. The association between longer ED-to-ICU time and higher mortality was not found after adjustment and stratification for ED-triage score.

Exploring bone density analysis on routine CT scans as a tool for opportunistic osteoporosis screening.

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 < 140 HU, suggestive of osteoporosis. No significant difference was found between bone density upon ICU admission and bone density at follow-up (≥ 21 days after ICU admission). Vertebral CT-based bone density analysis using routine CT scans is an easily applicable method to identify ICU patients with decreased bone density, which could enable enrollment in osteoporosis prevention programs. A high prevalence of low bone density was found in our cohort of ICU patients. There were no changes observed in bone density between baseline and follow-up measurements.

Daily variation in blood glucose levels during continuous enteral nutrition in patients on the intensive care unit: a retrospective observational study.

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 < 0.001), with a peak of 9.6 [9.5-9.6; estimated marginal means, 95% CI] mmol/L at 10:00 in the morning and a trough of 8.6 [8.5-8.6] mmol/L at 02:00 at night. A similar impact of time of day on glucose levels was found with the XGBoost regression model. INTERPRETATION: These results revealed marked 24-h variation in glucose levels in ICU patients even during continuous enteral nutrition. This 24-h pattern persists after adjustment for potential sources of bias, suggesting it may be the result of endogenous biological rhythmicity. FUNDING: This work was supported by a VENI grant from the Netherlands Organisation for Health Research and Development (ZonMw), an institutional project grant, and by the Dutch Research Council (NWO).

TGF-ß mRNA levels in circulating extracellular vesicles are associated with response to anti-PD1 treatment in metastatic melanoma.

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-ß (TGF-ß) 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-ß were analysed by digital droplet PCR (ddPCR). A biomarker-radiomic correlation analysis was performed in a subset of patients. Results: Patients with high TGF-ß 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-ß 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-ß 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.

Clinical Utility of Circulating Tumor DNA in Patients With Advanced KRASG12C-Mutated NSCLC Treated With Sotorasib.

INTRODUCTION: For patients with KRASG12C-mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and on-treatment circulating tumor DNA (ctDNA) and treatment-emergent alterations on disease progression. METHODS: Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372). Plasma samples were collected before sotorasib treatment, at first-response evaluation and at disease progression. The TruSight Oncology 500 panel was used for ctDNA and variant allele frequency analysis. Tumor response and progression-free survival were assessed per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Pretreatment KRASG12C ctDNA was detected in 50 of 66 patients (76%). Patients with detectable KRASG12C had inferior progression-free survival (hazard ratio [HR] 2.13 [95% confidence interval [CI]: 1.06-4.30], p = 0.031) and overall survival (HR 2.61 [95% CI: 1.16-5.91], p = 0.017). At first-response evaluation (n = 40), 29 patients (73%) had a molecular response. Molecular nonresponders had inferior overall survival (HR 3.58 [95% CI: 1.65-7.74], p = 0.00059). The disease control rate was significantly higher in those with a molecular response (97% versus 64%, p = 0.015). KRAS amplifications were identified as recurrent treatment-emergent alterations. CONCLUSIONS: Our data suggest detectable pretreatment KRASG12C ctDNA as a marker for poor prognosis and on-treatment ctDNA clearance as a marker for treatment response. We identified KRAS amplifications as a potential recurring resistance mechanism to sotorasib. Identifying patients with superior prognosis could aid in optimizing time of treatment initiation, and identifying patients at risk of early progression could allow for earlier treatment decisions.

MUC5AC concentrations in lung lavage fluids are associated with acute lung injury after cardiac surgery.

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.

The effect of computerised decision support alerts tailored to intensive care on the administration of high-risk drug combinations, and their monitoring: a cluster randomised stepped-wedge trial.

BACKGROUND: Drug-drug interactions (DDIs) can harm patients admitted to the intensive care unit (ICU). Yet, clinical decision support systems (CDSSs) aimed at helping physicians prevent DDIs are plagued by low-yield alerts, causing alert fatigue and compromising patient safety. The aim of this multicentre study was to evaluate the effect of tailoring potential DDI alerts to the ICU setting on the frequency of administered high-risk drug combinations. METHODS: We implemented a cluster randomised stepped-wedge trial in nine ICUs in the Netherlands. Five ICUs already used potential DDI alerts. Patients aged 18 years or older admitted to the ICU with at least two drugs administered were included. Our intervention was an adapted CDSS, only providing alerts for potential DDIs considered as high risk. The intervention was delivered at the ICU level and targeted physicians. We hypothesised that showing only relevant alerts would improve CDSS effectiveness and lead to a decreased number of administered high-risk drug combinations. The order in which the intervention was implemented in the ICUs was randomised by an independent researcher. The primary outcome was the number of administered high-risk drug combinations per 1000 drug administrations per patient and was assessed in all included patients. This trial was registered in the Netherlands Trial Register (identifier NL6762) on Nov 26, 2018, and is now closed. FINDINGS: In total, 10 423 patients admitted to the ICU between Sept 1, 2018, and Sept 1, 2019, were assessed and 9887 patients were included. The mean number of administered high-risk drug combinations per 1000 drug administrations per patient was 26·2 (SD 53·4) in the intervention group (n=5534), compared with 35·6 (65·0) in the control group (n=4353). Tailoring potential DDI alerts to the ICU led to a 12% decrease (95% CI 5-18%; p=0·0008) in the number of administered high-risk drug combinations per 1000 drug administrations per patient, after adjusting for clustering and prognostic factors. INTERPRETATION: This cluster randomised stepped-wedge trial showed that tailoring potential DDI alerts to the ICU setting significantly reduced the number of administered high-risk drug combinations. Our list of high-risk drug combinations can be used in other ICUs, and our strategy of tailoring alerts based on clinical relevance could be applied to other clinical settings. FUNDING: ZonMw.

Perspectives of ICU Patients on Deferred Consent in the Context of Post-ICU Quality of Life: A Substudy of a Randomized Clinical Trial.

OBJECTIVES: Deferred consent enables research to be conducted in the ICU when patients are unable to provide consent themselves, and there is insufficient time to obtain consent from surrogates before commencing (trial) treatment. The aim of this study was to evaluate how former ICU patients reflect on their participation in a study with deferred consent and examine whether their opinions are influenced by the quality of life (QoL) following hospital discharge. DESIGN: Survey study by questionnaire. SETTING: Eight ICUs in The Netherlands. PATIENTS: Former ICU patients who participated in the ICONIC trial, a multicenter randomized clinical trial that evaluated oxygenation targets in mechanically ventilated ICU patients. INTERVENTIONS: Participants enrolled in the ICONIC trial in one of the eight participating centers in The Netherlands received a questionnaire 6 months after randomization. The questionnaire included 12 close-ended questions on their opinion about the deferred consent procedure. QoL was measured using the EQ-5D-5L questionnaire. By calculating the EQ-5D index, patients were divided into four QoL quartiles, where Q1 reflects the lowest and Q4 is the highest. MEASUREMENTS AND MAIN RESULTS: Of 362 participants who were contacted, 197 responded (54%). More than half of the respondents (59%) were unaware of their participation in the ICONIC study. In total 61% were content with the deferred consent procedure, 1% were not content, 25% neutral, 9% did not know, and 9% answered "other." Those with a higher QoL were more likely to be content ( p = 0.02). In all QoL groups, the legal representative was the most often preferred individual to provide consent. CONCLUSIONS: Former ICU patients who participated in the ICONIC study often did not remember their participation but were predominantly positive regarding the use of deferred consent. Those with a higher QoL were most likely to be content.

Adverse drug events caused by three high-risk drug-drug interactions in patients admitted to intensive care units: A multicentre retrospective observational study.

AIMS: Knowledge about adverse drug events caused by drug-drug interactions (DDI-ADEs) is limited. We aimed to provide detailed insights about DDI-ADEs related to three frequent, high-risk potential DDIs (pDDIs) in the critical care setting: pDDIs with international normalized ratio increase (INR+ ) potential, pDDIs with acute kidney injury (AKI) potential, and pDDIs with QTc prolongation potential. METHODS: We extracted routinely collected retrospective data from electronic health records of intensive care units (ICUs) patients (≥18 years), admitted to ten hospitals in the Netherlands between January 2010 and September 2019. We used computerized triggers (e-triggers) to preselect patients with potential DDI-ADEs. Between September 2020 and October 2021, clinical experts conducted a retrospective manual patient chart review on a subset of preselected patients, and assessed causality, severity, preventability, and contribution to ICU length of stay of DDI-ADEs using internationally prevailing standards. RESULTS: In total 85 422 patients with ≥1 pDDI were included. Of these patients, 32 820 (38.4%) have been exposed to one of the three pDDIs. In the exposed group, 1141 (3.5%) patients were preselected using e-triggers. Of 237 patients (21%) assessed, 155 (65.4%) experienced an actual DDI-ADE; 52.9% had severity level of serious or higher, 75.5% were preventable, and 19.3% contributed to a longer ICU length of stay. The positive predictive value was the highest for DDI-INR+ e-trigger (0.76), followed by DDI-AKI e-trigger (0.57). CONCLUSION: The highly preventable nature and severity of DDI-ADEs, calls for action to optimize ICU patient safety. Use of e-triggers proved to be a promising preselection strategy.

Acute kidney injury associated with nephrotoxic drugs in critically ill patients: a multicenter cohort study using electronic health record data.

Background: Nephrotoxic drugs frequently cause acute kidney injury (AKI) in adult intensive care unit (ICU) patients. However, there is a lack of large pharmaco-epidemiological studies investigating the associations between drugs and AKI. Importantly, AKI risk factors may also be indications or contraindications for drugs and thereby confound the associations. Here, we aimed to estimate the associations between commonly administered (potentially) nephrotoxic drug groups and AKI in adult ICU patients whilst adjusting for confounding. Methods: In this multicenter retrospective observational study, we included adult ICU admissions to 13 Dutch ICUs. We measured exposure to 44 predefined (potentially) nephrotoxic drug groups. The outcome was AKI during ICU admission. The association between each drug group and AKI was estimated using etiological cause-specific Cox proportional hazard models and adjusted for confounding. To facilitate an (independent) informed assessment of residual confounding, we manually identified drug group-specific confounders using a large drug knowledge database and existing literature. Results: We included 92 616 ICU admissions, of which 13 492 developed AKI (15%). We found 14 drug groups to be associated with a higher hazard of AKI after adjustment for confounding. These groups included established (e.g. aminoglycosides), less well established (e.g. opioids) and controversial (e.g. sympathomimetics with α- and ß-effect) drugs. Conclusions: The results confirm existing insights and provide new ones regarding drug associated AKI in adult ICU patients. These insights warrant caution and extra monitoring when prescribing nephrotoxic drugs in the ICU and indicate which drug groups require further investigation.

A common germline variant in CYP11B1 is associated with adverse clinical outcome of treatment with abiraterone or enzalutamide.

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.

Conservative versus Liberal Oxygenation Targets in Intensive Care Unit Patients (ICONIC): A Randomized Clinical Trial.

Rationale: Supplemental oxygen is widely administered to ICU patients, but appropriate oxygenation targets remain unclear. Objectives: This study aimed to determine whether a low-oxygenation strategy would lower 28-day mortality compared with a high-oxygenation strategy. Methods: This randomized multicenter trial included mechanically ventilated ICU patients with an expected ventilation duration of at least 24 hours. Patients were randomized 1:1 to a low-oxygenation (PaO2, 55-80 mm Hg; or oxygen saturation as measured by pulse oximetry, 91-94%) or high-oxygenation (PaO2, 110-150 mm Hg; or oxygen saturation as measured by pulse oximetry, 96-100%) target until ICU discharge or 28 days after randomization, whichever came first. The primary outcome was 28-day mortality. The study was stopped prematurely because of the COVID-19 pandemic when 664 of the planned 1,512 patients were included. Measurements and Main Results: Between November 2018 and November 2021, a total of 664 patients were included in the trial: 335 in the low-oxygenation group and 329 in the high-oxygenation group. The median achieved PaO2 was 75 mm Hg (interquartile range, 70-84) and 115 mm Hg (interquartile range, 100-129) in the low- and high-oxygenation groups, respectively. At Day 28, 129 (38.5%) and 114 (34.7%) patients had died in the low- and high-oxygenation groups, respectively (risk ratio, 1.11; 95% confidence interval, 0.9-1.4; P = 0.30). At least one serious adverse event was reported in 12 (3.6%) and 17 (5.2%) patients in the low- and high-oxygenation groups, respectively. Conclusions: Among mechanically ventilated ICU patients with an expected mechanical ventilation duration of at least 24 hours, using a low-oxygenation strategy did not result in a reduction of 28-day mortality compared with a high-oxygenation strategy. Clinical trial registered with the National Trial Register and the International Clinical Trials Registry Platform (NTR7376).

THE ASSOCIATION BETWEEN SYSTOLIC BLOOD PRESSURE AND HEART RATE IN EMERGENCY DEPARTMENT PATIENTS: A MULTICENTER COHORT STUDY.

BACKGROUND: Guidelines and textbooks assert that tachycardia is an early and reliable sign of hypotension, and an increased heart rate (HR) is believed to be an early warning sign for the development of shock, although this response may change by aging, pain, and stress. OBJECTIVE: To assess the unadjusted and adjusted associations between systolic blood pressure (SBP) and HR in emergency department (ED) patients of different age categories (18-50 years; 50-80 years; > 80 years). METHODS: A multicenter cohort study using the Netherlands Emergency department Evaluation Database (NEED) including all ED patients ≥ 18 years from three hospitals in whom HR and SBP were registered at arrival to the ED. Findings were validated in a Danish cohort including ED patients. In addition, a separate cohort was used including ED patients with a suspected infection who were hospitalized from whom measurement of SBP and HR were available prior to, during, and after ED treatment. Associations between SBP and HR were visualized and quantified with scatterplots and regression coefficients (95% confidence interval [CI]). RESULTS: A total of 81,750 ED patients were included from the NEED, and a total of 2358 patients with a suspected infection. No associations were found between SBP and HR in any age category (18-50 years: -0.03 beats/min/10 mm Hg, 95% CI -0.13-0.07, 51-80 years: -0.43 beats/min/10 mm Hg, 95% CI -0.38 to -0.50, > 80 years: -0.61 beats/min/10 mm Hg, 95% CI -0.53 to -0.71), nor in different subgroups of ED patient. No increase in HR existed with a decreasing SBP during ED treatment in ED patients with a suspected infection. CONCLUSION: No association between SBP and HR existed in ED patients of any age category, nor in ED patients who were hospitalized with a suspected infection, even during and after ED treatment. Emergency physicians may be misled by traditional concepts about HR disturbances because tachycardia may be absent in hypotension.

Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer.

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.

Leucocyte and platelet activation in cardiac surgery patients with and without lung injury: A prospective cohort study.

OBJECTIONS: Development of acute lung injury after cardiac surgery is associated with an unfavourable outcome. Acute respiratory distress syndrome in general is, besides cytokine and interleukin activation, associated with activation of platelets, monocytes and neutrophils. In relation to pulmonary outcome after cardiac surgery, leucocyte and platelet activation is described in animal studies only. Therefore, we explored the perioperative time course of platelet and leucocyte activation in cardiac surgery and related these findings to acute lung injury assessed via PaO2/FiO2 (P/F) ratio measurements. METHODS: A prospective cohort study was performed, including 80 cardiac surgery patients. At five time points, blood samples were directly assessed by flow cytometry. For time course analyses in low (< 200) versus high (≥200) P/F ratio groups, repeated measurement techniques with linear mixed models were used. RESULTS: Already before the start of the operation, platelet activatability (P = 0.003 for thrombin receptor-activator peptide and P = 0.017 for adenosine diphosphate) was higher, and the expression of neutrophil activation markers was lower (CD18/CD11; P = 0.001, CD62L; P = 0.013) in the low P/F group. After correction for these baseline differences, the peri- and postoperative thrombin receptor-activator peptide-induced thrombocyte activatability was decreased in the low P/F ratio group (P = 0.008), and a changed pattern of neutrophil activation markers was observed. CONCLUSIONS: Prior to surgery, an upregulated inflammatory state with higher platelet activatability and indications for higher neutrophil turnover were demonstrated in cardiac surgery patients who developed lung injury. It is difficult to distinguish whether these factors are mediators or are also aetiologically related to the development of lung injury after cardiac surgery. Further research is warranted. TRIAL REGISTRATION: Clinical Registration number: ICTRP: NTR 5314, 26-05-2015.

Development and External Validation of the International Early Warning Score for Improved Age- and Sex-Adjusted In-Hospital Mortality Prediction in the Emergency Department.

OBJECTIVES: Early Warning Scores (EWSs) have a great potential to assist clinical decision-making in the emergency department (ED). However, many EWS contain methodological weaknesses in development and validation and have poor predictive performance in older patients. The aim of this study was to develop and externally validate an International Early Warning Score (IEWS) based on a recalibrated National Early warning Score (NEWS) model including age and sex and evaluate its performance independently at arrival to the ED in three age categories (18-65, 66-80, > 80 yr). DESIGN: International multicenter cohort study. SETTING: Data was used from three Dutch EDs. External validation was performed in two EDs in Denmark. PATIENTS: All consecutive ED patients greater than or equal to 18 years in the Netherlands Emergency department Evaluation Database (NEED) with at least two registered vital signs were included, resulting in 95,553 patients. For external validation, 14,809 patients were included from a Danish Multicenter Cohort (DMC). MEASUREMENTS AND MAIN RESULTS: Model performance to predict in-hospital mortality was evaluated by discrimination, calibration curves and summary statistics, reclassification, and clinical usefulness by decision curve analysis. In-hospital mortality rate was 2.4% ( n = 2,314) in the NEED and 2.5% ( n = 365) in the DMC. Overall, the IEWS performed significantly better than NEWS with an area under the receiving operating characteristic of 0.89 (95% CIs, 0.89-0.90) versus 0.82 (0.82-0.83) in the NEED and 0.87 (0.85-0.88) versus 0.82 (0.80-0.84) at external validation. Calibration for NEWS predictions underestimated risk in older patients and overestimated risk in the youngest, while calibration improved for IEWS with a substantial reclassification of patients from low to high risk and a standardized net benefit of 5-15% in the relevant risk range for all age categories. CONCLUSIONS: The IEWS substantially improves in-hospital mortality prediction for all ED patients greater than or equal to18 years.

Detecting measurable residual disease beyond 10-4 by an IGHV leader-based NGS approach improves prognostic stratification in CLL.

The sensitivity of conventional techniques for reliable quantification of minimal/measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL) is limited to MRD 10-4. Measuring MRD <10-4 could help to further distinguish between patients with CLL with durable remission and those at risk of early relapse. We herein present an academically developed immunoglobulin heavy-chain variable (IGHV) leader-based next-generation sequencing (NGS) assay for the quantification of MRD in CLL. We demonstrate, based on measurements in contrived MRD samples, that the linear range of detection and quantification of our assay reaches beyond MRD 10-5. If provided with sufficient DNA input, MRD can be detected down to MRD 10-6. There was high interassay concordance between measurements of the IGHV leader-based NGS assay and allele-specific oligonucleotide quantitative polymerase chain reaction (PCR) (r = 0.92 [95% confidence interval {CI}, 0.86-0.96]) and droplet digital PCR (r = 0.93 [95% CI, 0.88-0.96]) on contrived MRD samples. In a cohort of 67 patients from the CLL11 trial, using MRD 10-5 as a cutoff, undetectable MRD was associated with superior progression-free survival (PFS) and time to next treatment. More important, deeper MRD measurement allowed for additional stratification of patients with MRD <10-4 but ≥10-5. PFS of patients in this MRD range was significantly shorter, compared with patients with MRD <10-5 (hazard ratio [HR], 4.0 [95% CI, 1.6-10.3]; P = .004), but significantly longer, compared with patients with MRD ≥10-4 (HR, 0.44 [95% CI, 0.23-0.87]; P = .018). These results support the clinical utility of the IGHV leader-based NGS assay.

Negative calcium balance despite normal plasma ionized calcium concentrations during citrate anticoagulated continuous venovenous hemofiltration (CVVH) in ICU patients.

BACKGROUND: Supplementation of calcium during continuous venovenous hemofiltration (CVVH) with citrate anticoagulation is usually titrated using a target blood ionized calcium concentration. Plasma calcium concentrations may be normal despite substantial calcium loss, by mobilization of calcium from the skeleton. Aim of our study is to develop an equation to calculate CVVH calcium and to retrospectively calculate CVVH calcium balance in a cohort of ICU-patients. METHODS: This is a single-center retrospective observational cohort study. In a subcohort of patients, all calcium excretion measurements in patients treated with citrate CVVH were randomly divided into a development set (n = 324 in 42 patients) and a validation set (n = 441 in 42 different patients). Using mixed linear models, we developed an equation to calculate calcium excretion from routinely available parameters. We retrospectively calculated calcium balance in 788 patients treated with citrate CVVH between 2014 and 2021. RESULTS: Calcium excretion (mmol/24 h) was - 1.2877 + 0.646*[Ca]blood,total * ultrafiltrate (l/24 h) + 0.107*blood flow (ml/h). The mean error of the estimation was - 1.0 ± 6.7 mmol/24 h, the mean absolute error was 4.8 ± 4.8 mmol/24 h. Calculated calcium excretion was 105.8 ± 19.3 mmol/24 h. Mean daily CVVH calcium balance was - 12.0 ± 20.0 mmol/24 h. Mean cumulative calcium balance ranged from - 3687 to 448 mmol. CONCLUSION: During citrate CVVH, calcium balance was negative in most patients, despite supplementation of calcium based on plasma ionized calcium levels. This may contribute to demineralization of the skeleton. We propose that calcium supplementation should be based on both plasma ionized calcium and a simple calculation of calcium excretion by CVVH.