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Background Acute kidney injury is a common complication in critically ill patients, often coinciding with the need for antibiotic therapy. The dose of beta-lactam antibiotics is frequently adjusted and often reduced based on estimated Glomerular Filtration Rate. However, early dose reductions may lead to underdosing, especially during the critical first 48 h of infection treatment, when acute kidney injury may be transient and adequate antibiotic treatment is critical. While some reviews suggest delaying dose reductions improves clinical outcomes, evidence remains limited. This scoping review evaluates the current literature on beta-lactam dosing strategies in critically ill patients with acute kidney injury, focusing on pharmacological and clinical outcomes. Methods We conducted a systematic scoping review following PRISMA-ScR guidelines. We searched Medline, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar from database inception through March 24, 2025. Two reviewers independently screened all articles and assessed study quality using ROB-2 and ROBINS-E tools. Eligible studies included critically ill adult patients with acute kidney injury, receiving beta-lactams, and reporting clinical or pharmacological outcomes. Data were extracted using a standardized template and categorized by pharmacological or clinical outcomes. Further stratification by antibiotic type or patient characteristics was not feasible. Results Out of the 1,436 screened articles, 11 studies involving 1,407 patients were included. The risk of bias was high in most studies. Most studies were observational; one was a randomized controlled trial. Seven studies reported beta-lactam plasma concentrations. Higher concentrations were generally observed in patients with acute kidney injury, even though dosages were oftentimes already reduced. One study associated early dose reductions with lower rates of neurotoxicity. One study reported higher rates of treatment failure with early dose reductions and three studies linked delayed dose reductions to reduced mortality. Conclusions Current evidence on beta-lactam dose reduction in critically ill patients with acute kidney injury is limited and of low quality. Delaying reductions may improve clinical outcomes, but further prospective studies are urgently needed. Trial registration The protocol for this scoping review was not prospectively registered.

Background Sepsis and septic shock are significant global healthcare challenges with high mortality rates. Effective management requires timely and adequate antimicrobial therapy. Beta-lactam antibiotics, commonly used in patients with sepsis, are crucial for treating these infections. However, standard dosing often leads to insufficient plasma levels due to dynamic physiological changes in critically ill patients. Previous randomized controlled trials highlighted the need for timely dose adjustments to improve clinical outcomes. This is the study protocol for the BULLSEYE trial in which we aim to optimize antibiotic treatment during the initial 48 h of sepsis by comparing standard to double dosing of beta-lactam antibiotics. Methods This open-label, multicenter, randomized controlled trial will compare standard to double dosing of beta-lactam antibiotics (cefuroxime, ceftazidime, ceftriaxone, cefotaxime, amoxicillin, amoxicillin/clavulanic acid, flucloxacillin, meropenem, and piperacillin/clavulanic acid) in critically ill patients with septic shock. Participants will be randomized into two arms: the control arm receiving standard care, and the intervention arm receiving double antibiotic doses for 48 h, irrespective of renal function. Following this period, all patients will receive standard doses as per local protocol. The primary outcome is all cause 28-day mortality, with secondary outcomes including 90-day, 365-day, hospital and ICU mortality, hospital and ICU length of stay, SOFA scores, time to shock reversal, microbiological eradication, clinical cure, pharmacodynamic target attainment, safety, quality of life, and medical consumption. Discussion The BULLSEYE trial aims to improve sepsis treatment in critically ill patients. Despite anticipated recruitment challenges, its large sample size ensures robust comparability. This pivotal trial could significantly impact sepsis treatment, leading to better clinical outcomes. Trial registration EU_CT 2024–512950-13–00. Protocol version 2.3, protocol date 09–12-2024. Prospectively registered on 09–01-2025 at Clinicaltrails.gov nr. NCT06766461.

The strong anti-oxidative properties of bilirubin largely explain its cardioprotective effects. Insulin resistance is featured by low circulating bilirubin. Thyroid hormone affects both bilirubin generation and its biliary transport, but it is unknown whether circulating bilirubin is associated with thyroid function in euthyroid subjects. Aim is to determine relationships of bilirubin with TSH, free T4 and free T3 in euthyroid subjects without type 2 diabetes mellitus (T2DM), and to assess whether such a relationship would be modified by the degree of insulin resistance. Total bilirubin, TSH, free T4, free T3, glucose, insulin, lipids and transaminases were measured in 1854 fasting euthyroid subjects without T2DM, recruited from the general population (PREVEND cohort). Insulin resistance was assessed by homeostasis model assessment. Bilirubin was positively related to free T4 (β = 0.116, P<0.001) and free T3 (β = 0.078, P = 0.001), but bilirubin was unrelated to TSH. The relationship of bilirubin with free T4 was modified by insulin resistance with a larger effect in more insulin resistant individuals (adjusted for age and sex: β = 0.043, P = 0.056 for interaction; additionally adjusted for smoking, alcohol intake, transaminases and total cholesterol (β = 0.044, P = 0.044 for interaction). The association of bilirubin with free T4 was also modified by high density lipoprotein cholesterol (age- and sex-adjusted: β = 0.040, P = 0.072). Low bilirubin relates to low free T4 in euthyroid non-diabetic subjects. Low normal free T4 may particularly confer low bilirubin in more insulin resistant individuals.

Background: Influenza can cause severe complications, especially in patients with specific risk factors or comorbidities associated with poor outcomes. Some patients are at increased risk of a complicated disease course, including secondary infections, ICU admission, and the need for mechanical ventilation. The first post–COVID-19 seasonal influenza season placed a substantial burden on Dutch ICUs. This study investigates the disease course and outcomes of ICU patients with influenza. Methods: A retrospective influenza registry study was conducted across 34 Dutch ICUs, including patients aged 18 and older admitted to the ICU with a positive influenza RT-PCR test, between 1 November 2023 and 17 March 2024. Data on demographic information, medical history, clinical symptoms, laboratory and imaging results, parameters of mechanical ventilation, additional treatments, length of hospital stay, and mortality was retrieved from the electronic patient record. Results: A total of 498 patients were included in the study. The median age was 64 (IQR: 55–72) years and 58.8% of the patients were men. The most common comorbidities were cardiovascular disease (34.1%), chronic obstructive pulmonary disease (COPD) (31.5%), and diabetes (22.3%). Bacterial co-infections were present in 37.6% of the patients. Invasive mechanical ventilation (IMV) was necessary in 46.0% of patients, 38.0% of those requiring IMV were treated in prone position. A substantial mortality rate was observed, with an ICU mortality rate of 21.9% and an additional hospital mortality rate of 5.2%. Conclusion: This study described the characteristics and course of disease of all patients with laboratory-confirmed influenza infection admitted to one of the 34 participating Dutch ICUs between November 2023 and March 2024. The major findings of this study are the substantial mortality rate, a high proportion of patients with bacterial co-infections, and a significant percentage of patients requiring IMV and prone position ventilation. Finally, patients without comorbidities that were admitted to the ICU with an influenza virus infection showed severe disease parameters but had a lower mortality than patients with comorbidities.

Background Bilirubin has been implicated in cardiovascular protection by virtue of its anti-inflammatory and anti-oxidative properties. The metabolic syndrome is featured by enhanced low-grade systemic inflammation and oxidative stress. Serum amyloid A (SAA) impairs anti-oxidative properties of high-density lipoprotein (HDL). We determined relationships of high sensitive C-reactive protein (hs-CRP) and SAA with bilirubin in subjects with and without metabolic syndrome (MetS). Methods Serum total bilirubin, hs-CRP, SAA and homeostasis model assessment- insulin resistance (HOMA-IR) were documented in 94 subjects with and in 73 subjects without MetS (26 and 54 subjects with type 2 diabetes mellitus (T2DM), respectively). Results Bilirubin was lower in MetS ( P  = 0.013), coinciding with higher hs-CRP ( P  < 0.001) and SAA levels ( P  = 0.002). In all subjects combined, hs-CRP was inversely related to bilirubin (r = −0.203, P  = 0.008), irrespective of the presence of MetS or T2DM (interaction terms: P  ≥ 0.75). The inverse relationship of bilirubin with SAA was confined to subjects without MetS (r = −0.267, P  = 0.009). Furthermore, the presence of either MetS or T2DM modified the relationship of bilirubin with SAA (interaction terms: β = 0.366, P  = 0.003 and β = 0.289, P  = 0.025, respectively) in age- and sex-adjusted analyses. Effect modification was also found for HOMA-IR (β = 0.790, P  = 0.020). Of the individual MetS components, the strongest interaction of bilirubin on SAA was observed with low HDL cholesterol (β = 0.435, P  < 0.001). Conclusions hs-CRP is inversely related to bilirubin, suggesting that low bilirubin is implicated in enhanced low-grade systemic inflammation. The inverse relationship of SAA with bilirubin was found to be absent in MetS, which could be attributable to MetS-associated abnormalities in HDL characteristics.