Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The extent to which therapeutic drug monitoring (TDM) in clinical practice can reduce insufficient ...antibiotic concentrations is an ongoing matter of investigation. We retrospectively evaluated routine meropenem and piperacillin measurements in critically ill patients who received antibiotics as short infusions in the first year after initiating a beta-lactam TDM program. Total trough concentrations above 8.0 mg/L for meropenem and above 22.5 mg/L for piperacillin were defined as the breakpoints for target attainment. We included 1832 meropenem samples and 636 piperacillin samples. We found that 39.3% of meropenem and 33.6% of piperacillin samples did not reach the target concentrations. We observed a clear correlation between renal function and antibiotic concentration (meropenem,
= 0.53; piperacillin,
= 0.63). Patients with renal replacement therapy or creatinine clearance (CrCl) of <70 mL/min had high rates of target attainment with the standard dosing regimens. There was a low number of patients with a CrCl >100 mL/min that achieved the target concentrations with the maximum recommended dosage. Patients with impaired renal function only required TDM if toxic side effects were noted. In contrast, patients with normal renal function required different dosage regimens and TDM-guided therapy to reach the breakpoints of target attainment.
Background
Rhabdomyolysis is a serious condition that can lead to acute kidney injury with the need of renal replacement therapy (RRT). The cytokine adsorber Cytosorb® (CS) can be used for ...extracorporeal myoglobin elimination in patients with rhabdomyolysis. However, data on adsorption capacity and saturation kinetics are still missing.
Methods
The prospective Cyto-SOLVE study (NCT04913298) included 20 intensive care unit patients with severe rhabdomyolysis (plasma myoglobin > 5000 ng/ml), RRT due to acute kidney injury and the use of CS for myoglobin elimination. Myoglobin and creatine kinase (CK) were measured in the patient´s blood and pre- and post-CS at defined time points (ten minutes, one, three, six, and twelve hours after initiation). We calculated Relative Change (RC, %) with:
. Myoglobin plasma clearances (ml/min) were calculated with:
Results
There was a significant decrease of the myoglobin plasma concentration six hours after installation of CS (median (IQR) 56,894 ng/ml (11,544; 102,737 ng/ml) vs. 40,125 ng/ml (7879; 75,638 ng/ml) (
p
< 0.001
). No significant change was observed after twelve hours. Significant extracorporeal adsorption of myoglobin can be seen at all time points (
p
< 0.05
) (ten minutes, one, three, six, and twelve hours after initiation). The median (IQR) RC of myoglobin at the above-mentioned time points was − 79.2% (-85.1; -47.1%), -34.7% (-42.7;-18.4%), -16.1% (-22.1; -9.4%), -8.3% (-7.5; -1.3%), and − 3.9% (-3.9; -1.3%), respectively. The median myoglobin plasma clearance ten minutes after starting CS treatment was 64.0 ml/min (58.6; 73.5 ml/min), decreasing rapidly to 29.1 ml/min (26.5; 36.1 ml/min), 16.1 ml/min (11.9; 22.5 ml/min), 7.9 ml/min (5.5; 12.5 ml/min), and 3.7 ml/min (2.4; 6.4 ml/min) after one, three, six, and twelve hours, respectively.
Conclusion
The Cytosorb® adsorber effectively eliminates myoglobin. However, the adsorption capacity decreased rapidly after about three hours, resulting in reduced effectiveness. Early change of the adsorber in patients with severe rhabdomyolysis might increase the efficacy. The clinical benefit should be investigated in further clinical trials.
Trial registration
ClinicalTrials.gov NCT04913298. Registered 07 May 2021, https//clinicaltrials.gov/study/NCT04913298.
Graphical Abstract
Background
The release of toxic bile acids (BAs) in the blood of critically ill patients with cholestatic liver dysfunction might lead to the damage of various organs. Their extracorporeal ...elimination using the cytokine adsorber Cytosorb
®
(CS) (adsorption of especially hydrophobic molecules < 60 kDa) might be promising, but data proving a potential adsorption are missing so far.
Methods
The prospective Cyto-SOVLE study (NCT04913298) included 20 intensive care patients with cholestatic liver dysfunction, continuous kidney replacement therapy, total bilirubin concentration > 10 mg/dl and the application of CS into the dialysis circuit. Bilirubin and different BAs were measured pre- and post-CS at defined timepoints (10 min, 1, 3, 6, and 12 h after initiation). Relative reduction (RR, %) was calculated with:
1
-
concentration
(
pre
-
post
)
concentration
(
pre
)
∗
100
.
Results
The median RR for total and conjugated bilirubin after initiation was − 31.8% and − 30.3%, respectively, and decreased to − 4.5% and − 4.8% after 6 h. A high initial RR was observed for the toxic BAs GCA (− 97.4%), TCA (− 94.9%), GCDCA (− 82.5%), and TCDCA (− 86.0%), decreasing after 6 h to − 32.9%, − 32.7%, − 12.8%, and − 14.3%, respectively. The protective hydrophilic BAs showed a comparable RR after initiation (UDCA: − 77.7%, GUDCA: − 83.0%, TUDCA: − 91.3%) dropping after 6 h to − 7.4%, − 8.5%, and − 12.5%, respectively.
Conclusions
Cytosorb
®
can adsorb bilirubin and toxic as well as protective BAs. However, a fast saturation of the adsorber resulting in a rapid decrease of the RR was observed. Furthermore, no relevant difference between hydrophobic toxic and hydrophilic protective BAs was detected regarding the adsorption amount. The clinical benefit or harm of the BA adsorption needs to be evaluated in the future.
Severe rhabdomyolysis frequently results in acute kidney injury (AKI) due to myoglobin accumulation with the need of kidney replacement therapy (KRT). The present study investigated whether the ...application of Cytosorb® (CS) led to an increased rate of kidney recovery in patients with KRT due to severe rhabdomyolysis. Adult patients with a myoglobin-concentration >10,000 ng/ml and KRT were included from 2014 to 2021. Exclusion criteria were chronic kidney disease and CS-treatment before study inclusion. Groups 1 and 2 were defined as KRT with and without CS, respectively. The primary outcome parameter was independence from KRT after 30 days. Propensity score (PS) matching was performed (predictors: myoglobin, SAPS-II, and age), and the chi2-test was used. 35 pairings could be matched (mean age: 57 vs. 56 years; mean myoglobin: 27,218 vs. 26,872 ng/ml; mean SAPS-II: 77 vs. 76). The probability of kidney recovery was significantly (p = .04) higher in group 1 (31.4 vs. 11.4%, mean difference: 20.0%, odds ratio (OR): 3.6). Considering patients who survived 30 days, kidney recovery was also significantly (p = .03) higher in patients treated with CS (61.1 vs. 23.5%, mean difference: 37.6%, OR: 5.1). In conclusion, the use of CS might positively affect renal recovery in patients with severe rhabdomyolysis. A prospective randomized controlled trial is needed to confirm this hypothesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Voriconazole (VRC) is used as first line antifungal agent against invasive aspergillosis. Model-based approaches might optimize VRC therapy. This study aimed to investigate the predictive performance ...of pharmacokinetic models of VRC without pharmacogenetic information for their suitability for model-informed precision dosing. Seven PopPK models were selected from a systematic literature review. A total of 66 measured VRC plasma concentrations from 33 critically ill patients was employed for analysis. The second measurement per patient was used to calculate relative Bias (rBias), mean error (ME), relative root mean squared error (rRMSE) and mean absolute error (MAE) (i) only based on patient characteristics and dosing history (a priori) and (ii) integrating the first measured concentration to predict the second concentration (Bayesian forecasting). The a priori rBias/ME and rRMSE/MAE varied substantially between the models, ranging from −15.4 to 124.6%/−0.70 to 8.01 mg/L and from 89.3 to 139.1%/1.45 to 8.11 mg/L, respectively. The integration of the first TDM sample improved the predictive performance of all models, with the model by Chen (85.0%) showing the best predictive performance (rRMSE: 85.0%; rBias: 4.0%). Our study revealed a certain degree of imprecision for all investigated models, so their sole use is not recommendable. Models with a higher performance would be necessary for clinical use.
Linezolid serum concentrations have been shown to be highly variable in critically ill patients with often sub-therapeutic drug levels regarding minimal inhibitory concentrations for relevant ...pathogens. Consequently, therapeutic drug monitoring of linezolid must be considered, requiring a reliable and convenient analytical method. We therefore developed and validated an LC-MS/MS method applying isotope dilution internal standardization and on-line solid phase extraction for serum linezolid quantification.
Sample preparation was based on protein precipitation and on-line solid phase extraction with two-dimensional liquid chromatography and column switching. Three-fold deuterated linezolid was used as the internal standard. The method was validated involving two separate LC-MS/MS systems covering the concentration range of 0.13–32 mg/L. The run time was 4 min.
Validation revealed good analytical performance, with inaccuracy <6% and imprecision of <7.3% (CV) for six quality control samples (0.38–16.0 mg/L). The method was found to be robust during the validation process and during a pharmacokinetic study so far involving 600 samples. Comparative measurements on two LC-MS/MS systems revealed close agreement.
This LC-MS/MS assay described herein is a convenient, robust and reliable method for linezolid quantification in serum which can be routinely applied using different LC-MS/MS systems. The method can be used for clinical studies and subsequent TDM of linezolid.
Background
Hemadsorption of cytokines is used in critically ill patients with sepsis or septic shock. Concerns have been raised that the cytokine adsorber CytoSorb
®
unintentionally adsorbs ...vancomycin. This study aimed to quantify vancomycin elimination by CytoSorb
®
.
Methods
Critically ill patients with sepsis or septic shock receiving continuous renal replacement therapy and CytoSorb
®
treatment during a prospective observational study were included in the analysis. Vancomycin pharmacokinetics was characterized using population pharmacokinetic modeling. Adsorption of vancomycin by the CytoSorb
®
was investigated as linear or saturable process. The final model was used to derive dosing recommendations based on stochastic simulations.
Results
20 CytoSorb
®
treatments in 7 patients (160 serum samples/24 during CytoSorb
®
-treatment, all continuous infusion) were included in the study. A classical one-compartment model, including effluent flow rate of the continuous hemodialysis as linear covariate on clearance, best described the measured concentrations (without CytoSorb
®
). Significant adsorption with a linear decrease during CytoSorb
®
treatment was identified (p < 0.0001) and revealed a maximum increase in vancomycin clearance of 291% (initially after CytoSorb
®
installation) and a maximum adsorption capacity of 572 mg. For a representative patient of our cohort a reduction of the area under the curve (AUC) by 93 mg/L*24 h during CytoSorb
®
treatment was observed. The additional administration of 500 mg vancomycin over 2 h during CytoSorb
®
attenuated the effect and revealed a negligible reduction of the AUC by 4 mg/L*24 h.
Conclusion
We recommend the infusion of 500 mg vancomycin over 2 h during CytoSorb
®
treatment to avoid subtherapeutic concentrations.
Trial registration
NCT03985605. Registered 14 June 2019,
https://clinicaltrials.gov/ct2/show/NCT03985605
IntroductionHerpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients and is associated with a worse outcome. The aim of this study is to ...determine whether antiviral therapy in HSV-positive patients improves outcome.Methods and analysisProspective, multicentre, open-label, randomised, controlled trial in parallel-group design. Adult, mechanically ventilated patients with pneumonia and HSV type 1 detected in bronchoalveolar lavage (≥105 copies/mL) are eligible for participation and will be randomly allocated (1:1) to receive acyclovir (10 mg/kg body weight every 8 hours) for 10 days (or until discharge from the intensive care unit if earlier) or no intervention (control group). The primary outcome is mortality measured at day 30 after randomisation (primary endpoint) and will be analysed with Cox mixed-effects model. Secondary endpoints include ventilator-free and vasopressor-free days up to day 30. A total of 710 patients will be included in the trial.Ethics and disseminationThe trial was approved by the responsible ethics committee and by Germany’s Federal Institute for Drugs and Medical Devices. The clinical trial application was submitted under the new Clinical Trials Regulation through CTIS (The Clinical Trials Information System). In this process, only one ethics committee, whose name is unknown to the applicant, and Germany’s Federal Institute for Drugs and Medical Devices are involved throughout the entire approval process. Results will be published in a journal indexed in MEDLINE and CTIS. With publication, de-identified, individual participant data will be made available to researchers.Trial registration number NCT06134492.
Early mobilization can help reduce severe side effects such as muscle atrophy that occur during hospitalization. However, due to time and staff shortages in intensive and critical care as well as ...safety risks for patients, it is often difficult to adhere to the recommended therapy time of twenty minutes twice a day. New robotic technologies might be one approach to achieve early mobilization effectively for patients and also relieve users from physical effort. Nevertheless, currently there is a lack of knowledge regarding the factors that are important for integrating of these technologies into complex treatment settings like intensive care units or rehabilitation units.
European experts from science, technical development and end-users of robotic systems (n = 13) were interviewed using a semi-structured interview guideline to identify barriers and facilitating factors for the integration of robotic systems into daily clinical practice. They were asked about structural, personnel and environmental factors that had an impact on integration and how they had solved challenges. A latent content analysis was performed regarding the COREQ criteria.
We found relevant factors regarding the development, introduction, and routine of the robotic system. In this context, costs, process adjustments, a lack of exemptions, and a lack of support from the manufacturers/developers were identified as challenges. Easy handling, joint decision making between the end-users and the decision makers in the hospital, an accurate process design and the joint development of the robotic system of end-users and technical experts were found to be facilitating factors.
The integration and preparation for the integration of robotic assistance systems into the inpatient setting is a complex intervention that involves many parties. This study provides evidence for hospitals or manufacturers to simplify the planning of integrations for permanent use.
DRKS-ID: DRKS00023848; registered 10/12/2020.
Background Early mobilization positively influences the outcome of critically ill patients, yet in clinical practice, the implementation is sometimes challenging. In this study, an adaptive robotic ...assistance system will be used for early mobilization in intensive care units. The study aims to evaluate the experience of the mobilizing professionals and the general feasibility of implementing robotic assistance for mobilization in intensive care as well as the effects on patient outcomes as a secondary outcome. Methods The study is single-centric, prospective, and interventional and follows a longitudinal study design. To evaluate the feasibility of robotic-assisted early mobilization, the number of patients included, the number of performed VEM (very early mobilization) sessions, and the number and type of adverse events will be collected. The behavior and experience of mobilizing professionals will be evaluated using standardized observations (n > 90) and episodic interviews (n > 36) before implementation, shortly after, and in routine. Patient outcomes such as duration of mechanical ventilation, loss of muscle mass, and physical activity will be measured and compared with a historical patient population. Approximately 30 patients will be included. Discussion The study will provide information about patient outcomes, feasibility, and the experience of mobilizing professionals. It will show whether robotic systems can increase the early mobilization frequency of critically ill patients. Within ICU structures, early mobilization as therapy could become more of a focus. Effects on the mobilizing professionals such as increased motivation, physical relief, or stress will be evaluated. In addition, this study will focus on whether current structures allow following the recommendation of mobilizing patients twice a day for at least 20 min. Trial registration ClinicalTrials.gov, NCT05071248. Date: 2021/10/21 Keywords: Robotics, Unit, Intensive care, Early mobilization, Feasibility study, Care, Nursing
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