Christina Scharf

Introduction: Blood purification techniques are being investigated as adjunctive options in critically ill patients not only to treat severe inflammation but also to remove harmful substances such as myoglobin in rhabdomyolysis. Yet, the available evidence is limited, and further research is needed to clarify their clinical benefits. Methods: The international prospective COSMOS Registry (NCT05146336, 23 Nov 2021) tracks CytoSorb® (CS) utilization patterns and outcomes in critical care settings. Clinical assessment was performed before, during, and after CS treatment, with a 90-day follow-up. Device-related adverse effects were reported by investigators as the safety evaluation. Data were analyzed according to a pre-specified statistical plan using descriptive statistics and paired tests to compare pre- and post-treatment values, with subgroup and safety analyses performed. Results: A total of 300 adult patients (30.3% female, mean age 59 ± 15 years) from 22 sites were included in this analysis. The most common indications for CS therapy (multiple indications possible per patient) were septic shock (48.3%), rhabdomyolysis (12.8%), cardiogenic shock (11.5%), liver failure (11.5%), and acute respiratory distress syndrome (ARDS; 5.0%). On average, each patient received 3.3 ± 3.3 adsorbers, with 27.9% of patients receiving 4 or more adsorbers. CS was integrated in conjunction with kidney replacement therapy (75.6%), standalone hemoperfusion (7.1%), intermittent hemodialysis (IHD; 10.6%), extracorporeal membrane oxygenation (ECMO; 3.9%), and sustained low-efficiency daily dialysis (SLEDD; 4.9%). At baseline, median (interquartile range, IQR) APACHE II and SOFA scores were 24 [18, 30] and 12 [9, 15], respectively. Fluid balance improved from +1675 [141, 3348] mL pre-CS to +115 [−1100, 1495] mL post-CS, and norepinephrine requirements decreased from 0.21 [0.09, 0.40] µg/kg/min to 0.08 [0.02, 0.22] µg/kg/min ( p < 0.0001 for both). Ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration (P/F ratio) improved from 120 [72, 208] to 176 [115, 255] ( p < 0.0001). Platelet counts decreased from 123 [76, 185] to 72 [42, 118] × 10 ⁹ /L ( p < 0.0001), while albumin levels remained stable from 2.6 [2.3, 3.1] to 2.5 [2.3, 3.0] g/dL ( p = 0.112). ICU mortality was 33.1%, which was lower than mortality estimates historically associated with comparable APACHE II and SOFA scores. No serious adverse effects related to the device or device deficiencies were reported. Conclusions: Real-world CytoSorb® use as part of standard care in critically ill patients was associated with improvements in several clinical and laboratory parameters; however, these findings should be interpreted cautiously given the observational design and absence of a control group. Observed mortality was lower than mortality estimates historically associated with established severity scores.

Purpose An increasing number of critically ill patients receive slow extended daily dialysis (SLEDD) due to their pathophysiology while suffering from sepsis, necessitating effective and safe antibiotic therapy. Although SLEDD reduces meropenem exposure and increases treatment failure risk, effective and safe dosing regimens are unclear. We aimed to identify optimised meropenem dosing strategies for critically ill SLEDD patients through population pharmacokinetic (PK) modelling and PK/pharmacodynamic (PD)-based probability of target attainment (PTA) analysis. Methods Clinical data from a prospective study involving critically ill SLEDD patients receiving meropenem were monitored through routine therapeutic drug monitoring. A total of 178 blood samples from 13 patients (median 14 samples per patient) were analysed. A PK model was developed and utilised to evaluate 24 clinically relevant dosing regimens during SLEDD therapy (7-h on-SLEDD periods q24h) in PTA analyses. The PK/PD target window of minimum meropenem concentration between 8 mg/L (P. aeruginosa; R-breakpoint) and 44.45 mg/L (toxicity threshold) was used. Results A one-compartment PK model with linear elimination and total clearance (CL) split into renal (CL_REN; 45%) and SLEDD-associated (55%) CL well characterised the SLEDD data. Creatinine clearance (urine-collected; CLCR_urine) was identified as significant factor on CL_REN. Continuous infusions, specifically 2 g q24h for CLCR_urine 0–25 mL/min and 3 g q24h for CLCR_urine 25–40 mL/min, showed the highest PTA being effective and safe during SLEDD therapy. A comprehensive dosing nomogram was developed. Conclusion Our easy-to-use dosing nomogram presents a promising tool in optimising meropenem dosing regimens for critically ill SLEDD patients considering their kidney function in clinical practice. Trial registration Clinicaltrials.gov NCT03985605. Registered 14 June 2019. https://classic.clinicaltrials.gov/ct2/show/study/NCT03985605 Graphical abstract

Background/Objectives: Patients with shock suffer from hyperlactatemia, which can lead to endothelial dysfunction. The use of the adsorber Cytosorb^® (CS) is recommended in these patients as it may contribute to higher lactate clearance and hemodynamic stabilization. However, it is unclear whether CS can directly adsorb lactate and can therefore increase lactate clearance. Methods: The Cyto-SOLVE trial included patients undergoing continuous kidney replacement therapy combined with CS application. Patients with a lactate concentration > 2 mmol/L and measurements of lactate pre- and post-adsorber, as well as measurements in the blood 10 min and 1, 3, 6, and 12 h after initiation were selected. Lactate clearance was calculated using the following formula: bloodflow_(mL/min) × concentration_pre−post/concentration_pre. A t-test was used with the collected samples. Changes in the lactate concentration and vasopressor requirement were recorded before initiation and at the end of therapy. Results: Sixty-five lactate concentrations were measured pre- and post-CS application, as well as in patients’ blood, in a total of 14 patients (median age of 52 years, 10 males, median SAPS-II 67). There was no significant change in the lactate concentration pre- and post-CS application (mean pre-CS: 6.7 mmol/L, mean post-CS: 6.9 mmol/L, RR: −0.2, 95% confidence interval (CI): −0.4–0.1, p = 0.13, Cohen’s d: 0.90). The mean lactate clearance was −6 mL/min (standard deviation (SD): 21 mL/min), with no correlation with the initial lactate concentration or blood flow. In contrast, the mean lactate clearance measured using the dialyzer was 39 mL/min (SD: 28 mL/min). When comparing values before and after treatment, no significant change was observed in the lactate blood concentrations (mean of 9.0 vs. 8.5 mmol/L), nor in the requirement for vasopressin (median of 1.9 vs. 1.8 IE/h) or norepinephrine (mean of 2.7 vs. 2.6 mg/h). Conclusions: The adsorber CS cannot directly adsorb lactate, unlike kidney replacement therapy. Therefore, it is not suitable for achieving faster extracorporeal lactate elimination. Understanding the adsorption spectrum is of great relevance and should be considered when using CS in clinical practice.

Introduction: Angiopoietin II (Ang-II) plays a pivotal role in the development of microcirculatory dysfunction as it provokes endothelial barrier disruption in patients with sepsis or septic shock. In particular, those with acute kidney injury show high Ang-II concentrations. So far, it is unclear which covariates influence Ang-II concentration in the early phase of sepsis, especially if extracorporeal therapies also do. Methods: Ang-II concentrations were measured in 171 patients with sepsis after the first day of antibiotic treatment between 03/2013 and 01/2015. Ang-II was correlated with potential influencing factors (Spearman correlation). A multivariate model was established including the significant correlating parameters. The Mann–Whitney U test and the Kruskal–Wallis test were used to detect significant differences in Ang-II concentration. Results: The median Ang-II concentration was 8015 pg/mL (interquartile range (IQR): 5024–14,185). A total of forty patients were treated with kidney replacement therapy (KRT) and 20 were supported by venovenous extracorporeal membrane oxygenation (vv-ECMO). Sequential organ failure assessment (SOFA) score (r = 0.541), creatinine clearance (r = −0.467), urinary output (r = −0.289), interleukin (IL)-6 (r = 0.529), C-reactive protein (CRP) (r = 0.241), platelet count (r = −0.419), bilirubin (r = 0.565), lactate (r = 0.322), KRT (r = 0.451), and fluid balance (r = 0.373) significantly correlated with Ang-II concentration and were included in the multivariate model. There, creatinine clearance (p < 0.01, b = −26.3, 95% confidence interval (CI) −41.8–−10.8), fluid balance (p = 0.002, b = 0.92, 95% CI 0.33–1.51), and CRP (p = 0.004, b = 127.6, 95% CI 41.6–213.7) were associated with Ang-II concentration. Furthermore, patients with KRT (median: 15,219 pg/mL, IQR: 10,548–20,270) had significantly (p < 0.01) higher Ang-II concentrations than those with vv-ECMO support (median: 6412 pg/mL, IQR: 5246–10,257) or those without extracorporeal therapy (median: 7156 pg/mL, IQR: 4409–12,741). Conclusion: Increased CRP, positive fluid balance, and impaired kidney function were associated with higher Ang-II concentrations in critically ill patients in the early stage of sepsis in this post hoc analysis. In particular, patients with KRT had very high Ang-II concentrations, whereas the use of vv-ECMO was not related to higher Ang-II concentrations. The significance for clinical practice should be clarified by a prospective study with standardized measurements.

Background: Therapeutic drug monitoring (TDM) of anti-infectives such as linezolid is routinely performed in blood of intensive care unit (ICU) patients to optimize target attainment. However, the concentration at the site of infection is considered more important for a successful therapy. Until now, bronchoalveolar lavage (BAL) is the gold standard to measure intrapulmonary concentrations of anti-infective agents. However, it is an invasive method and unsuitable for regular TDM. The aim of this proof-of-concept study was to investigate whether it is possible to reliably determine the intrapulmonary concentration of linezolid from endotracheal aspiration (ENTA). Methods: Intubated ICU patients receiving 600 mg intravenous linezolid twice daily were examined in steady state. First, preliminary experiments were performed in six patients to investigate which patients are suitable for linezolid measurement in ENTA. In a second step, trough and peak linezolid concentrations of plasma and ENTA were determined in nine suitable patients. Results: Linezolid can validly be detected in ENTA with viscous texture and > 0.5 mL volume. The mean (SD) linezolid trough concentration was 2.02 (1.27) mg/L in plasma and 1.60 (1.36) mg/L in ENTA, resulting in a median lung penetration rate of 104%. The mean (SD) peak concentration in plasma and ENTA was 10.77 (5.93) and 4.74 (2.66) mg/L. Conclusions: Linezolid can validly be determined in ENTA with an adequate texture and volume. The penetration rate is comparable to already published BAL concentrations. This method might offer a simple and non-invasive method for TDM at the site of infection “lung”. Due to promising results of the feasibility study, comparison of ENTA and BAL in the same patient should be investigated in a further trial.