Rapid and Effective Elimination of Myoglobin with CytoSorb® Hemoadsorber in Patients with Severe Rhabdomyolysis.

INTRODUCTION: Rhabdomyolysis is characterized by destruction of muscle fibers by various causes and is diagnosed by increased creatine kinase concentrations in the blood. Myoglobin released into the blood may cause acute kidney injury. In this randomized controlled study, we hypothesized that myoglobin elimination would be faster when a hemoadsorber was added to a continuous veno-venous hemodialysis (CVVHD). METHODS: Four patients in the control group received CVVHD with a high cut-off hemofilter using high blood and dialysate flows for 48 h. Four patients in the CytoSorb group received the same treatment, but in addition, the hemoadsorber CytoSorb® was inserted in front of the hemofilter and replaced once after 24 h. Blood samples were drawn simultaneously before (pre) and after (post) the hemofilter or else the hemoadsorber, after 5 and 30 min, as well as after 2, 4, 8, and 24 h. All measurements were repeated the next day after the hemoadsorber had been renewed in the CytoSorb group. Primary outcome was the area under the curve (AUC) of the relative myoglobin concentrations as percent of baseline. To evaluate the efficacy of myoglobin removal, relative reductions in myoglobin concentrations during one passage through each device at each time point were calculated. RESULTS: Patients in the CytoSorb group had a significantly lower AUC during the first 24 h (42 ± 10% vs. 63 ± 6%, p = 0.029) as well as during the observation period of 48 h (26 ± 7% vs. 51 ± 12%, p = 0.029). The relative reductions for myoglobin were considerably higher in the CytoSorb group compared to the control group during the first 8 h. CONCLUSION: Myoglobin concentrations declined considerably faster when CytoSorb was added to a CVVHD. When compared to a high-cut-off hemofilter, efficacy of CytoSorb in myoglobin elimination was much better. Because of saturation after 8-12 h an exchange may be necessary.

Increased Respiratory Drive after Prolonged Isoflurane Sedation: A Retrospective Cohort Study.

Low-dose isoflurane stimulates spontaneous breathing. We, therefore, tested the hypothesis that isoflurane compared to propofol sedation for at least 48 h is associated with increased respiratory drive in intensive care patients after sedation stop. All patients in our intensive care unit receiving at least 48 h of isoflurane or propofol sedation in 2019 were included. The primary outcome was increased respiratory drive over 72 h after sedation stop, defined as an arterial carbon dioxide pressure below 35 mmHg and a base excess more than -2 mmol/L. Secondary outcomes were acid-base balance and ventilatory parameters. We analyzed 64 patients, 23 patients sedated with isoflurane and 41 patients sedated with propofol. Patients sedated with isoflurane were about three times as likely to show increased respiratory drive after sedation stop than those sedated with propofol: adjusted risk ratio [95% confidence interval]: 2.9 [1.3, 6.5], p = 0.010. After sedation stop, tidal volumes were significantly greater and arterial carbon dioxide partial pressures were significantly lower, while respiratory rates did not differ in isoflurane versus propofol-sedated patients. In conclusion, prolonged isoflurane use in intensive care patients is associated with increased respiratory drive after sedation stop. Beneficial effects of isoflurane sedation on respiratory drive may, thus, extend beyond the actual period of sedation.

Combined antibiotic stewardship and infection control measures to contain the spread of linezolid-resistant Staphylococcus epidermidis in an intensive care unit.

BACKGROUND: The unrestricted use of linezolid has been linked to the emergence of linezolid-resistant Staphylococcus epidermidis (LRSE). We report the effects of combined antibiotic stewardship and infection control measures on the spread of LRSE in an intensive care unit (ICU). METHODS: Microbiological data were reviewed to identify all LRSE detected in clinical samples at an ICU in southwest Germany. Quantitative data on the use of antibiotics with Gram-positive coverage were obtained in defined daily doses (DDD) per 100 patient-days (PD). In addition to infection control measures, an antibiotic stewardship intervention was started in May 2019, focusing on linezolid restriction and promoting vancomycin, wherever needed. We compared data from the pre-intervention period (May 2018-April 2019) to the post-intervention period (May 2019-April 2020). Whole-genome sequencing (WGS) was performed to determine the genetic relatedness of LRSE isolates. RESULTS: In the pre-intervention period, LRSE were isolated from 31 patients (17 in blood cultures). The average consumption of linezolid and daptomycin decreased from 7.5 DDD/100 PD and 12.3 DDD/100 PD per month in the pre-intervention period to 2.5 DDD/100 PD and 5.7 DDD/100 PD per month in the post-intervention period (p = 0.0022 and 0.0205), respectively. Conversely, vancomycin consumption increased from 0.2 DDD/100 PD per month to 4.7 DDD/100 PD per month (p < 0.0001). In the post-intervention period, LRSE were detected in 6 patients (4 in blood cultures) (p = 0.0065). WGS revealed the predominance of one single clone. CONCLUSIONS: Complementing infection control measures by targeted antibiotic stewardship interventions was beneficial in containing the spread of LRSE in an ICU.

Changes in volatile organic compounds provoked by lipopolysaccharide- or alpha toxin-induced inflammation in ventilated rats.

Inflammation may alter volatile organic compounds (VOCs) in exhaled breath. We therefore used ion mobility spectrometry (IMS) to evaluate exhaled breath components in two non-infectious inflammatory models. Fifty male Sprague Dawley rats were anesthetized and ventilated for 24 h. Five treatments were randomly assigned: (1) lipopolysaccharide low dose [5 mg/kg]; (2) lipopolysaccharide high dose [10 mg/kg]; (3) alpha toxin low dose [40 µg/kg]; (4) alpha toxin high dose [80 µg/kg]; and, (5) NaCl 0.9% as control group. Gas was sampled from the expiratory line of the ventilator every 20 min and analyzed with IMS combined with a multi-capillary column. VOCs were identified by comparison with an established database. Survival analysis was performed by log-rank test, other analyses by one-way or paired ANOVA-tests and post-hoc analysis according to Holm-Sidak. Rats given NaCl and low-dose alpha toxin survived 24 h. The median survival time in alpha toxin high-dose group was 23 (95%-confidence interval (CI): 21, 24) h. In contrast, the median survival time in rats given high-dose lipopolysaccharide was 12 (95% CI: 9, 14) and only 13 (95% CI: 10, 16) h in those given high-dose lipopolysaccharide. 73 different VOCs were detected, of which 35 were observed only in the rats, 38 could be found both in the blank measurements of ventilator air and in the exhaled air of the rats. Forty-nine of the VOCs were identifiable from a registry of compounds. Exhaled volatile compounds were comparable in each group before injection of lipopolysaccharide and alpha toxin. In the LPS groups, 1-pentanol increased and 2-propanol decreased. After alpha toxin treatment, 1-butanol and 1-pentanol increased whereas butanal and isopropylamine decreased. Induction of a non-infectious systemic inflammation (niSI) by lipopolysaccharide and alpha toxin changes VOCs in exhaled breath. Exhalome analysis may help identify niSI.

Exhaled Volatile Organic Compounds during Inflammation Induced by TNF-α in Ventilated Rats.

Systemic inflammation alters the composition of exhaled breath, possibly helping clinicians diagnose conditions such as sepsis. We therefore evaluated changes in exhaled breath of rats given tumor necrosis factor-alpha (TNF-α). Thirty male Sprague-Dawley rats were randomly assigned to three groups (n = 10 each) with intravenous injections of normal saline (control), 200 µg·kg-1 bodyweight TNF-α (TNF-α-200), or 600 µg·kg-1 bodyweight TNF-α (TNF-α-600), and were observed for 24 h or until death. Animals were ventilated with highly-purified synthetic air to analyze exhaled air by multicapillary column-ion mobility spectrometry. Volatile organic compounds (VOCs) were identified from a database. We recorded blood pressure and cardiac output, along with cytokine plasma concentrations. Control rats survived the 24 h observation period, whereas mean survival time decreased to 22 h for TNF-α-200 and 23 h for TNF-α-600 rats. Mean arterial pressure decreased in TNF-α groups, whereas IL-6 increased, consistent with mild to moderate inflammation. Hundreds of VOCs were detected in exhalome. P-cymol increased by a factor-of-two 4 h after injection of TNF-α-600 compared to the control and TNF-α-200. We found that 1-butanol and 1-pentanol increased in both TNF-α groups after 20 h compared to the control. As breath analysis distinguishes between two doses of TNF-α and none, we conclude that it might help clinicians identify systemic inflammation.

Metabolism of 3-pentanone under inflammatory conditions.

Breath analysis of rats using multi-capillary column ion-mobility spectrometry (MCC-IMS) revealed alterations in acetone and other ketones, including 3-pentanone, during inflammation. The alterations seem likely to result from oxidative branched-chain keto acid (BCKA) catabolism. We therefore tested the hypothesis that 3-pentanone arises during inflammation from increased BCKA oxidation in the liver with consequent accumulation of propionyl-CoA and its condensation products. Male Sprague-Dawley rats were anaesthetised and ventilated for 24 h or until death. Exhaled breath was analysed by MCC-IMS while rats were injected with low and high doses of lipopolysaccharide (LPS), tumour necrosis factor α (TNFα), or vehicle. The exhaled 3-pentanone peak was identified by pure substance measurements. Blood was collected 12 h after treatment for the determination of cytokine concentrations; transcription enzymes for BCKA catabolism and the activity of the BCKA dehydrogenase were analysed in liver tissue by quantitative real-time PCR and western blotting. Exhaled 3-pentanone decreased in all groups, but minimum concentrations with high-dose LPS (0.24 ± 0.31 volts; mean ± SD), low-dose TNFα (0.17 ± 0.10 volts) and high-dose TNFα (0.13 ± 0.04 volts) were lower than in vehicle animals (0.27 ± 0.12 volts). At 60% and 85% survival times (svt) concentrations of exhaled 3-pentanone increased significantly in all animals treated with low-dose LPS, (svt60% 0.38 ± 0.18 volts, svt85% 0.62 ± 0.15 volts) and high-dose LPS (0.26 ± 0.28 volts, 0.40 ± 0.22 volts), as well as low-dose TNFα, (0.20 ± 0.09 volts, 0.39 ± 0.17 volts) and high-dose TNFα (0.18 ± 0.06 volts, 0.34 ± 0.08 volts), but not in vehicle rats (0.27 ± 0.12 volts, 0.30 ± 0.09 volts). BCKA catabolism was seen in the liver, with increased expression and activity of the branched-chain alpha-keto acid dehydrogenase (BCKD), lower expression of the propionyl-CoA carboxylase (PCC) subunits, and altered expression levels of BCKD regulating enzymes. Exhaled 3-pentanone may arise from altered BCKA catabolism. Our results suggest that excessive propionyl-CoA is possibly generated from BCKAs via increased activity of BCKD, but may undergo unusual condensation reactions rather than being physiologically processed to methylmalonyl-CoA by PCC. The pattern of 3-pentanone during early and prolonged inflammation suggests that reuse of BCKAs for the synthesis of new proteins might be initially favoured. As inflammatory conditions persist, substrates for cellular energy supply are required which activate irreversible degradation of excessive BCKA to propionyl-CoA yielding increased levels of exhaled 3-pentanone.

A change of colloid from hydroxyethyl starch to gelatin does not reduce rate of renal failure or mortality in surgical critical care patients: Results of a retrospective cohort study.

PURPOSE: Hydroxyethyl starch (HES) may compromise renal function in critically ill patients. As an alternative, gelatin (GEL) was suggested. This study investigated whether GEL (4%) may have advantages over HES (6%, 130/0.4) with respect to acute renal failure (ARF), length of intensive care unit /hospital stay, and 30-day mortality and evaluated dose-dependent effects. MATERIAL AND METHODS: We performed a retrospective cohort analysis of 1522 surgical intensive care patients in a single university hospital where HES was changed to GEL in June 2006. The year before, 515 patients received HES; the year after, 540 patients received GEL. Within both years, 497 patients received crystalloids (CRY) only. Fluid therapy was performed upon clinical judgment and did not follow a study protocol. RESULTS: There was no difference in ARF between HES and GEL (P=.292), but ARF was more frequent in both colloid cohorts compared with CRY (HES/GEL vs CRY, P<.05). Mortality and maximum daily dose of both HES (r=0.93) and GEL (r=0.93) were significantly correlated, but mortality and total amount of CRY or total fluid intake were not significantly correlated. Cumulative amounts of fluids given were significantly higher in both colloid groups compared with CRY only, and GEL was given in higher doses than HES. In both colloid cohorts, the need for renal replacement therapy and 30-day mortality were significantly higher, and intensive care unit and hospital stay was longer, compared with CRY. CONCLUSIONS: A change of colloid from HES to GEL did not reduce the rate of ARF or mortality in surgical critical care patients. Both colloids appear to have dose-dependent effects on renal function.

On the origin and nature of the grating interferometric dark-field contrast obtained with low-brilliance x-ray sources.

The x-ray dark-field contrast accessible via grating interferometry is sensitive to features at length scales well below what is resolvable by a detector system. It is commonly explained as arising from small-angle x-ray scattering (SAXS), and can be implemented both at synchrotron beamlines and with low-brilliance sources such as x-ray tubes. Here, we demonstrate that for tube based setups the underlying process of image formation can be fundamentally different. For focal spots or detector pixels that comprise multiple grating periods, we show that dark-field images contain a strong artificial and system-specific component not arising from SAXS. Based on experiments carried out with a nanofocus x-ray tube and the example of an excised rat lung, we demonstrate that the dark-field contrast observed for porous media transforms into a differential phase contrast for large geometric magnifications. Using a photon counting detector with an adjustable point spread function, we confirm that a dark-field image can indeed be formed by an intra-pixel differential phase contrast that cannot be resolved as such due to a dephasing between the periodicities of the absorption grating and the Talbot carpet. Our findings are further corroborated by a link between the strength of this pseudo-dark-field contrast and our x-ray tube's focal spot size in a three-grating setup. These results must not be ignored when measurements are intended to be reproducible across systems.

Exhalation of volatile organic compounds during hemorrhagic shock and reperfusion in rats: an exploratory trial.

Ischemia and reperfusion alter metabolism. Multi-capillary column ion-mobility spectrometry (MCC-IMS) can identify volatile organic compounds (VOCs) in exhaled gas. We therefore used MCC-IMS to evaluate exhaled gas in a rat model of hemorrhagic shock with reperfusion. Adult male Sprague-Dawley rats (n = 10 in control group, n = 15 in intervention group) were anaesthetized and ventilated via tracheostomy for 14 h or until death. Hemorrhagic shock was maintained for 90 min by removing blood from the femoral artery to a target of MAP 35 ± 5 mmHg, and then retransfusing the blood over 60 min in 15 rats; 10 control rats were evaluated without shock and reperfusion. Exhaled gas was analyzed with MCC-IMS, VOCs were identified using the BS-MCC/IMS analytes database (Version 1209). VOC intensities were analyzed at the end of shock, end of reperfusion, and after 9 h. All normotensive animals survived the observation period, whereas mean survival time was 11.2 h in shock and reperfusion animals. 16 VOCs differed significantly for at least one of the three analysis periods. Peak intensities of butanone, 2-ethyl-1-hexanol, nonanal, and an unknown compound were higher in shocked than normotensive rats, and another unknown compound increased over the time. 1-butanol increased only during reperfusion. Acetone, butanal, 1.2-butandiol, isoprene, 3-methylbutanal, 3-pentanone, 2-propanol, and two unknown compounds were lower and decreased during shock and reperfusion. 1-pentanol and 1-propanol were significant greater in the hypotensive animals during shock, were comparable during reperfusion, and then decreased after resuscitation. VOCs differ during hemorrhagic shock, reperfusion, and after reperfusion. MCC-IMS of exhaled breath deserves additional study as a non-invasive approach for monitoring changes in metabolism during ischemia and reperfusion.

Imaging properties of high aspect ratio absorption gratings for use in preclinical x-ray grating interferometry.

X-ray grating interferometry is one among various methods that allow extracting the so-called phase and visibility contrasts in addition to the well-known transmission images. Crucial to achieving a high image quality are the absorption gratings employed. Here, we present an in-depth analysis of how the grating type and lamella heights influence the final images. Benchmarking gratings of two different designs, we show that a frequently used proxy for image quality, a grating's so-called visibility, is insufficient to predict contrast-to-noise ratios (CNRs). Presenting scans from an excised rat lung, we demonstrate that the CNRs obtained for transmission and visibility images anti-correlate. This is explained by the stronger attenuation implied by gratings that are engineered to provide high visibilities by means of an increased lamella height. We show that even the visibility contrast can suffer from this effect when the associated reduced photon flux on the detector is not outweighed by a corresponding gain in visibility. Resulting in an inevitable trade-off between the quality of the two contrasts, the question of how an optimal grating should be designed can hence only be answered in terms of Pareto optimality.

Exhalation pattern changes during fasting and low dose glucose treatment in rats.

The analysis of exhaled metabolites has become a promising field of research in recent decades. Several volatile organic compounds reflecting metabolic disturbance and nutrition status have even been reported. These are particularly important for long-term measurements, as needed in medical research for detection of disease progression and therapeutic efficacy. In this context, it has become urgent to investigate the effect of fasting and glucose treatment for breath analysis. In the present study, we used a model of ventilated rats that fasted for 12 h prior to the experiment. Ten rats per group were randomly assigned for continuous intravenous infusion without glucose or an infusion including 25 mg glucose per 100 g per hour during an observation period of 12 h. Exhaled gas was analysed using multicapillary column ion-mobility spectrometry. Analytes were identified by the BS-MCC/IMS database (version 1209; B & S Analytik, Dortmund, Germany). Glucose infusion led to a significant increase in blood glucose levels (p < 0.05 at 4 h and thereafter) and cardiac output (p < 0.05 at 4 h and thereafter). During the observation period, 39 peaks were found collectively. There were significant differences between groups in the concentration of ten volatile organic compounds: p < 0.001 at 4 h and thereafter for isoprene, cyclohexanone, acetone, p-cymol, 2-hexanone, phenylacetylene, and one unknown compound, and p < 0.001 at 8 h and thereafter for 1-pentanol, 1-propanol, and 2-heptanol. Our results indicate that for long-term measurement, fasting and the withholding of glucose could contribute to changes of volatile metabolites in exhaled air.

Volatile organic compounds during inflammation and sepsis in rats: a potential breath test using ion-mobility spectrometry.

BACKGROUND: Multicapillary column ion-mobility spectrometry (MCC-IMS) may identify volatile components in exhaled gas. The authors therefore used MCC-IMS to evaluate exhaled gas in a rat model of sepsis, inflammation, and hemorrhagic shock. METHODS: Male Sprague-Dawley rats were anesthetized and ventilated via tracheostomy for 10 h or until death. Sepsis was induced by cecal ligation and incision in 10 rats; a sham operation was performed in 10 others. In 10 other rats, endotoxemia was induced by intravenous administration of 10 mg/kg lipopolysaccharide. In a final 10 rats, hemorrhagic shock was induced to a mean arterial pressure of 35 ± 5 mmHg. Exhaled gas was analyzed with MCC-IMS, and volatile compounds were identified using the BS-MCC/IMS-analytes database (Version 1209; B&S Analytik, Dortmund, Germany). RESULTS: All sham animals survived the observation period, whereas mean survival time was 7.9 h in the septic animals, 9.1 h in endotoxemic animals, and 2.5 h in hemorrhagic shock. Volatile compounds showed statistically significant differences in septic and endotoxemic rats compared with sham rats for 3-pentanone and acetone. Endotoxic rats differed significantly from sham for 1-propanol, butanal, acetophenone, 1,2-butandiol, and 2-hexanone. Statistically significant differences were observed between septic and endotoxemic rats for butanal, 3-pentanone, and 2-hexanone. 2-Hexanone differed from all other groups in the rats with shock. CONCLUSIONS: Breath analysis of expired organic compounds differed significantly in septic, inflammation, and sham rats. MCC-IMS of exhaled breath deserves additional study as a noninvasive approach for distinguishing sepsis from inflammation.

Effect of three-dimensional computed tomography reconstructions on reliability.

BACKGROUND: This study evaluated the impact of three-dimensional (3D) volume-rendering computed tomography (CT) reconstructions on the inter- and intraobserver reliability of six commonly used classification systems in the assessment of calcaneal fractures. METHODS: Four independent observers with different levels of clinical training evaluated 64 fractures according to the classifications of the Orthopaedic Trauma Association (OTA), Essex-Lopresti, Sanders, Crosby, Zwipp, and Regazzoni, using two-dimensional (2D) CT scans with multiplanar reconstructions and 3D volume-rendering reconstructions. RESULTS: Interobserver reliability was moderate for the OTA, Essex-Lopresti, Sanders, Crosby, and Regazzoni classifications with 2D CT scans and 3D CT reconstructions. The Zwipp classification was poor with 2D CT scans and improved to moderate with 3D reconstructions. Intraobserver reliability with 2D CT scans was good for the Essex-Lopresti classification and moderate for the OTA, Sanders, Crosby, Zwipp, and Regazzoni classifications. After the addition of 3D reconstructions, all classifications showed moderate intraobserver reliability. CONCLUSION: According to the findings of this study, the additional use of 3D reconstructions is of minor value when used in conjunction with the classifications of the OTA, Sanders, Crosby, Regazzoni, and Essex-Lopresti. If calcaneal fractures are assessed with the Zwipp classification, 3D reconstructions could be used to achieve comparable reproducibility compared to other classifications. CLINICAL RELEVANCE: 3D reconstructions may have other benefits not evaluated in the presented study and may give useful information not captured by current classification systems.