Target-Controlled Infusion of Cefepime in Critically Ill Patients:single center experience

Attainment of appropriate pharmacokinetic-pharmacodynamic (PK-PD) targets for antimicrobial treatment is challenging in critically ill patients, particularly for cefepime, which exhibits a relative narrow therapeutic-toxic window compared to other beta-lactam antibiotics. Target-controlled infusion (TCI) systems, which deliver drugs to achieve specific target drug concentrations, have successfully been implemented for improved dosing of sedatives and analgesics in anesthesia. We conducted a clinical trial in an intensive care unit (ICU) to investigate the performance of TCI for adequate target attainment of cefepime. Twenty-one patients treated with cefepime according to the standard of care were included. Cefepime was administered through continuous infusion using TCI for a median duration of 4.5 days. TCI was based on a previously developed population PK model incorporating the estimated creatinine clearance based on the Cockcroft-Gault formula as the input variable to calculate cefepime clearance. A cefepime blood concentration of 16 mg/liter was targeted. To evaluate the measured versus predicted plasma concentrations, blood samples were taken (median of 10 samples per patient), and total cefepime concentrations were measured using ultraperformance liquid chromatography-tandem mass spectrometry. The performance of the TCI system was evaluated using Varvel criteria. Half (50.3%) of the measured cefepime concentrations were within +/- 30% around the target value of 16 mg liter(-1). The wobble was 11.4%, the median performance error (MdPE) was 21.1%, the median absolute performance error (MdAPE) was 32.0%, and the divergence was -3.72% h(-1). Based on these results, we conclude that TCI is useful for dose optimization of cefepime in ICU patients

Management and outcomes in critically ill nonagenarian versus octogenarian patients.

BACKGROUND: Intensive care unit (ICU) patients age 90 years or older represent a growing subgroup and place a huge financial burden on health care resources despite the benefit being unclear. This leads to ethical problems. The present investigation assessed the differences in outcome between nonagenarian and octogenarian ICU patients. METHODS: We included 7900 acutely admitted older critically ill patients from two large, multinational studies. The primary outcome was 30-day-mortality, and the secondary outcome was ICU-mortality. Baseline characteristics consisted of frailty assessed by the Clinical Frailty Scale (CFS), ICU-management, and outcomes were compared between octogenarian (80-89.9 years) and nonagenarian (> 90 years) patients. We used multilevel logistic regression to evaluate differences between octogenarians and nonagenarians. RESULTS: The nonagenarians were 10% of the entire cohort. They experienced a higher percentage of frailty (58% vs 42%; p < 0.001), but lower SOFA scores at admission (6 + 5 vs. 7 + 6; p < 0.001). ICU-management strategies were different. Octogenarians required higher rates of organ support and nonagenarians received higher rates of life-sustaining treatment limitations (40% vs. 33%; p < 0.001). ICU mortality was comparable (27% vs. 27%; p = 0.973) but a higher 30-day-mortality (45% vs. 40%; p = 0.029) was seen in the nonagenarians. After multivariable adjustment nonagenarians had no significantly increased risk for 30-day-mortality (aOR 1.25 (95% CI 0.90-1.74; p = 0.19)). CONCLUSION: After adjustment for confounders, nonagenarians demonstrated no higher 30-day mortality than octogenarian patients. In this study, being age 90 years or more is no particular risk factor for an adverse outcome. This should be considered- together with illness severity and pre-existing functional capacity - to effectively guide triage decisions. TRIAL REGISTRATION: NCT03134807 and NCT03370692

A model-based analysis of the predictive performance of different renal function markers for cefepime clearance in the ICU

Several population pharmacokinetic models for cefepime in critically ill patients have been described, which all indicate that variability in renal clearance is the main determinant of the observed variability in exposure. The main objective of this study was to determine which renal marker best predicts cefepime clearance. A pharmacokinetic model was developed using NONMEM based on 208 plasma and 51 urine samples from 20 ICU patients during a median follow-up of 3 days. Four serum-based kidney markers (creatinine, cystatin C, urea and uromodulin) and two urinary markers [measured creatinine clearance (CLCR) and kidney injury molecule-1] were evaluated as covariates in the model. A two-compartment model incorporating a renal and non-renal clearance component along with an additional term describing haemodialysis clearance provided an adequate description of the data. The Cockcroft-Gault formula was the best predictor for renal cefepime clearance. Compared with the base model without covariates, the objective function value decreased from 1971.7 to 1948.1, the median absolute prediction error from 42.4% to 29.9% and the between-subject variability in renal cefepime clearance from 135% to 50%. Other creatinine- and cystatin C-based formulae and measured CLCR performed similarly. Monte Carlo simulations using the Sanford guide dose recommendations indicated an insufficient dose reduction in patients with a decreased kidney function, leading to potentially toxic levels. The Cockcroft-Gault formula was the best predictor for cefepime clearance in critically ill patients, although other creatinine- and cystatin C-based formulae and measured CLCR performed similarly

Illustration of the sudden awakening of gamma-hydroxybutyrate (GHB) associated intoxications

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Brachial plexus 3D reconstruction from MRI with dissection validation : a baseline study for clinical applications

Purpose The present study aimed to establish a baseline for detailed 3D brachial plexus reconstruction from magnetic resonance imaging (MRI). Concretely, the goal was to determine the individual brachial plexus anatomy with maximum detail and accuracy achievable, as yet irrespective of whether the methods used could be economically and practically applied in the clinical setting. Materials and methods Six embalmed cadavers were randomly taken for MRI imaging of the brachial plexus. Detailed two-dimensional (2D) segmentation for all brachial plexus parts was done. The 2D brachial plexus segmentations were 3D reconstructed using Mimics (R) software. Then, these 3D reconstructions were anatomically validated by dissection of the cadavers. After finalising the cadaver experiments, brachial plexus MRIs were obtained in three healthy male volunteers and the same reconstruction procedure as in vitro was followed. Results A procedure was developed for brachial plexus 3D reconstruction based on MRI without the use of any contrast agent. Anatomical validation of six cadaver brachial plexus reconstructions showed high correspondence with the dissected brachial plexuses. Anatomical variations of the main branches were equally present in the 3D reconstructions generated. However, there were also some differences that related to the difference between the surface anatomy of the nerve and the internal nerve structure. In vivo, it was possible to reconstruct the complete brachial plexus in such a manner that normal-appearing BPs were derived in a reproducible way. Conclusions This study showed that the described procedure results in accurate and reproducible brachial plexus 3D reconstructions