Population pharmacokinetic modeling of multiple-dose intravenous fosfomycin in critically ill patients during continuous venovenous hemodialysis.

The aim of this study was to investigate the pharmacokinetics of multiple-dose intravenous (i.v.) fosfomycin in critically ill patients during continuous venovenous hemodialysis (CVVHD). Non-compartmental analysis and population pharmacokinetic modeling were used to simulate different dosing regimens. We evaluated 15 critically ill patients with renal insufficiency and CVVHD undergoing anti-infective treatment with fosfomycin in our ICU. Five grams of fosfomycin were administered for 120 min every 6 h. Plasma concentrations were determined with and without CVVHD. Pharmacokinetic analysis and simulations were performed using non-linear mixed effects modelling (NONMEM). A two-compartment model with renal and dialysis clearance was most accurate in describing the pharmacokinetics of i.v. fosfomycin during CVVHD. Population parameter estimates were 18.20 L and 20.80 L for the central and peripheral compartment volumes, and 0.26 L/h and 5.08 L/h for renal and intercompartmental clearance, respectively. Urinary creatinine clearance (CLCR) represented a considerable component of renal clearance. Central compartment volume increased over time after the first dose. For patients with CLCR > 50 (90) mL/min and CVVHD, dosage should be increased to ≥ 15 (16) grams of i.v. fosfomycin across three (four) daily doses. Individual CLCR must be considered when dosing i.v. fosfomycin in critically ill patients during CVVHD.

Sex Differences in Clinical Course and Intensive Care Unit Admission in a National Cohort of Hospitalized Patients with COVID-19.

Males have a higher risk for an adverse outcome of COVID-19. The aim of the study was to analyze sex differences in the clinical course with focus on patients who received intensive care. Research was conducted as an observational retrospective cohort study. A group of 23,235 patients from 83 hospitals with PCR-confirmed infection with SARS-CoV-2 between 4 February 2020 and 22 March 2021 were included. Data on symptoms were retrieved from a separate registry, which served as a routine infection control system. Males accounted for 51.4% of all included patients. Males received more intensive care (ratio OR = 1.61, 95% CI = 1.51-1.71) and mechanical ventilation (invasive or noninvasive, OR = 1.87, 95% CI = 1.73-2.01). A model for the prediction of mortality showed that until the age 60 y, mortality increased with age with no substantial difference between sexes. After 60 y, the risk of death increased more in males than in females. At 90 y, females had a predicted mortality risk of 31%, corresponding to males of 84 y. In the intensive care unit (ICU) cohort, females of 90 y had a mortality risk of 46%, equivalent to males of 72 y. Seventy-five percent of males over 90 died, but only 46% of females of the same age. In conclusion, the sex gap was most evident among the oldest in the ICU. Understanding sex-determined differences in COVID-19 can be useful to facilitate individualized treatments.

High Central Venous Pressure after Cardiac Surgery Might Depict Hemodynamic Deterioration Associated with Increased Morbidity and Mortality.

BACKGROUND: Cardiac surgery patients represent a high-risk cohort in intensive care units (ICUs). Central venous pressure (CVP) measurement seems to remain an integral part in hemodynamic monitoring, especially in cardio-surgical ICUs. However, its value as a prognostic marker for organ failure is still unclear. Therefore, we analyzed postoperative CVP values after adult cardiac surgery in a large cohort with regard to its prognostic value for morbidity and mortality. METHODS: All adult patients admitted to our ICUs between 2006 and 2019 after cardiac surgery were eligible for inclusion in the study (n = 11,198). We calculated the median initial CVP (miCVP) after admission to the ICU, which returned valid values for 9802 patients. An ROC curve analysis for optimal cut-off miCVP to predict ICU mortality was conducted with consecutive patient allocation into a (a) low miCVP (LCVP) group (≤11 mmHg) and (b) high miCVP (HCVP) group (>11 mmHg). We analyzed the impact of high miCVP on morbidity and mortality by propensity score matching (PSM) and logistic regression. RESULTS: ICU mortality was increased in HCVP patients. In addition, patients in the HCVP group required longer mechanical ventilation, had a higher incidence of acute kidney injury, were more frequently treated with renal replacement therapy, and showed a higher risk for postoperative liver dysfunction, parametrized by a postoperative rise of ≥ 10 in MELD Score. Multiple regression analysis confirmed HCVP has an effect on postoperative ICU-mortality and intrahospital mortality, which seems to be independent. CONCLUSIONS: A high initial CVP in the early postoperative ICU course after cardiac surgery is associated with worse patient outcome. Whether or not CVP, as a readily and constantly available hemodynamic parameter, should promote clinical efforts regarding diagnostics and/or treatment, warrants further investigations.

Real-Time Evaluation of Optic Nerve Sheath Diameter (ONSD) in Awake, Spontaneously Breathing Patients.

(1) Background: Reliable ultrasonographic measurements of optic nerve sheath diameter (ONSD) to detect increased intracerebral pressure (ICP) has not been established in awake patients with continuous invasive ICP monitoring. Therefore, in this study, we included fully awake patients with and without raised ICP and correlated ONSD with continuously measured ICP values. (2) Methods: In a prospective study, intracranial pressure (ICP) was continuously measured in 25 patients with an intraparenchymatic P-tel probe. Ultrasonic measurements were carried out three times for each optic nerve in vertical and horizontal directions. ONSD measurements and ICP were correlated. Patients with ICP of 2.0-10.0 mmHg were compared with patients suffering from an ICP of 10.1-24.2 mmHg. (3) Results: In all patients, the ONSD vertical and horizontal measurement for both eyes correlated well with the ICP (Pearson R = 0.68-0.80). Both measurements yielded similar results (Bland-Altman: vertical bias: -0.09 mm, accuracy: ±0.66 mm; horizontal bias: -0.06 mm, accuracy: ±0.48 mm). For patients with an ICP of 2.0-10.0 mmHg compared to an ICP of 10.1-24.2, ROC (receiver operating characteristic) analyses showed that ONSD measurement accurately predicts elevated ICP (optimal cut-off value 5.05 mm, AUC of 0.91, sensitivity 92% and specificity 90%, p < 0.001). (4) Conclusions: Ultrasonographic measurement of ONSD in awake, spontaneously breathing patients provides a valuable method to evaluate patients with suspected increased ICP. Additionally, it provides a potential tool for rapid assessment of ICP at the bedside and to identify patients at risk for a poor neurological outcome.

Washout and Awakening Times after Inhaled Sedation of Critically Ill Patients: Desflurane Versus Isoflurane.

In recent years, inhaled sedation has been increasingly used in the intensive care unit (ICU). The aim of this prospective, controlled trial was to compare washout and awakening times after long term sedation with desflurane and isoflurane both administered with the Mirus™ system (TIM GmbH, Koblenz, Germany). Twenty-one consecutive critically ill patients were alternately allocated to the two study groups, obtaining inhaled sedation with either desflurane or isoflurane. After 24 h study sedation, anesthetic washout curves were recorded, and a standardized wake-up test was performed. The primary outcome measure was the time required to decrease the endtidal concentration to 50% (T50%). Secondary outcome measures were T80% and awakening times (all extremities moved, RASS -2). Decrement times (min) (desflurane versus isoflurane, median (1st quartile-3rd quartile)) (T50%: 0.3 (0.3-0.4) vs. 1.3 (0.4-2.3), log-rank test P = 0.002; P80%: 2.5 (2-5.9) vs. 12.1 (5.1-20.2), P = 0.022) and awakening times (to RASS -2: 7.5 (5.5-8.8) vs. 41.0 (24.5-43.0), P = 0.007; all extremities moved: 5.0 (4.0-8.5) vs. 13.0 (8.0-41.25), P = 0.037) were significantly shorter after desflurane compared to isoflurane. The use of desflurane with the Mirus™ system significantly shortens the washout times and leads to faster awakening after sedation of critically ill patients.

Quantitative Determination of Fosfomycin in 10 µL of Plasma and Dialysate by Hydrophilic Interaction Liquid Chromatography Electrospray Ionization Mass Spectrometry.

Fosfomycin is an antibiotic with a broad spectrum of activity against many multidrug-resistant bacterial strains. It is mainly excreted unchanged by the kidneys, and its half-life therefore depends on kidney function which varies considerably among individuals, and within individuals over time. Proper fosfomycin dosing thus depends on assaying blood concentration of the drug. We developed and validated a simple, sensitive and specific chromatography assay, which was coupled to electrospray ionization mass spectrometry for determination of fosfomycin. Separation of fosfomycin was based on the method of the hydrophilic interaction liquid chromatography; specifically, plasma and dialysate samples were acidified and the protein precipitated with acetonitrile. The calibration curves showed excellent coefficients of determination (R2 > 0.999) over the relevant concentration range of 25-700 µg/mL. Intraday precision was 1.1-1.2% and accuracy was -5.9% to 0.9% for quality control samples. Interday precision was 2.9-3.4% and accuracy was -3.7% to 5.5%. Extraction recovery was ≥87% and matrix effects ranged from 2.2% to 4.3%. After laboratory validation, the method was successfully applied to clinical samples.

Evaluating the Use of Circulating MicroRNA Profiles for Lung Cancer Detection in Symptomatic Patients.

Importance: The overall low survival rate of patients with lung cancer calls for improved detection tools to enable better treatment options and improved patient outcomes. Multivariable molecular signatures, such as blood-borne microRNA (miRNA) signatures, may have high rates of sensitivity and specificity but require additional studies with large cohorts and standardized measurements to confirm the generalizability of miRNA signatures. Objective: To investigate the use of blood-borne miRNAs as potential circulating markers for detecting lung cancer in an extended cohort of symptomatic patients and control participants. Design, Setting, and Participants: This multicenter, cohort study included patients from case-control and cohort studies (TREND and COSYCONET) with 3102 patients being enrolled by convenience sampling between March 3, 2009, and March 19, 2018. For the cohort study TREND, population sampling was performed. Clinical diagnoses were obtained for 3046 patients (606 patients with non-small cell and small cell lung cancer, 593 patients with nontumor lung diseases, 883 patients with diseases not affecting the lung, and 964 unaffected control participants). No samples were removed because of experimental issues. The collected data were analyzed between April 2018 and November 2019. Main Outcomes and Measures: Sensitivity and specificity of liquid biopsy using miRNA signatures for detection of lung cancer. Results: A total of 3102 patients with a mean (SD) age of 61.1 (16.2) years were enrolled. Data on the sex of the participants were available for 2856 participants; 1727 (60.5%) were men. Genome-wide miRNA profiles of blood samples from 3046 individuals were evaluated by machine-learning methods. Three classification scenarios were investigated by splitting the samples equally into training and validation sets. First, a 15-miRNA signature from the training set was used to distinguish patients diagnosed with lung cancer from all other individuals in the validation set with an accuracy of 91.4% (95% CI, 91.0%-91.9%), a sensitivity of 82.8% (95% CI, 81.5%-84.1%), and a specificity of 93.5% (95% CI, 93.2%-93.8%). Second, a 14-miRNA signature from the training set was used to distinguish patients with lung cancer from patients with nontumor lung diseases in the validation set with an accuracy of 92.5% (95% CI, 92.1%-92.9%), sensitivity of 96.4% (95% CI, 95.9%-96.9%), and specificity of 88.6% (95% CI, 88.1%-89.2%). Third, a 14-miRNA signature from the training set was used to distinguish patients with early-stage lung cancer from all individuals without lung cancer in the validation set with an accuracy of 95.9% (95% CI, 95.7%-96.2%), sensitivity of 76.3% (95% CI, 74.5%-78.0%), and specificity of 97.5% (95% CI, 97.2%-97.7%). Conclusions and Relevance: The findings of the study suggest that the identified patterns of miRNAs may be used as a component of a minimally invasive lung cancer test, complementing imaging, sputum cytology, and biopsy tests.

Halving the Volume of AnaConDa: Evaluation of a New Small-Volume Anesthetic Reflector in a Test Lung Model.

BACKGROUND: Volatile anesthetics are increasingly used for sedation in intensive care units. The most common administration system is AnaConDa-100 mL (ACD-100; Sedana Medical, Uppsala, Sweden), which reflects volatile anesthetics in open ventilation circuits. AnaConDa-50 mL (ACD-50) is a new device with half the volumetric dead space. Carbon dioxide (CO2) can be retained with both devices. We therefore compared the CO2 elimination and isoflurane reflection efficiency of both devices. METHODS: A test lung constantly insufflated with CO2 was ventilated with a tidal volume of 500 mL at 10 breaths/min. End-tidal CO2 (EtCO2) partial pressure was measured using 3 different devices: a heat-and-moisture exchanger (HME, 35 mL), ACD-100, and ACD-50 under 4 different experimental conditions: ambient temperature pressure (ATP), body temperature pressure saturated (BTPS) conditions, BTPS with 0.4 Vol% isoflurane (ISO-0.4), and BTPS with 1.2 Vol% isoflurane. Fifty breaths were recorded at 3 time points (n = 150) for each device and each condition. To determine device dead space, we adjusted the tidal volume to maintain normocapnia (n = 3), for each device. Thereafter, we determined reflection efficiency by measuring isoflurane concentrations at infusion rates varying from 0.5 to 20 mL/h (n = 3), for each device. RESULTS: EtCO2 was consistently greater with ACD-100 than with ACD-50 and HME (ISO-0.4, mean ± standard deviations: ACD-100, 52.4 ± 0.8; ACD-50, 44.4 ± 0.8; HME, 40.1 ± 0.4 mm Hg; differences of means of EtCO2 [respective 95% confidence intervals]: ACD-100 - ACD-50, 8.0 [7.9-8.1] mm Hg, P < .001; ACD-100 - HME, 12.3 [12.2-12.4] mm Hg, P < .001; ACD-50 - HME, 4.3 [4.2-4.3] mm Hg, P < .001). It was greatest under ATP, less under BTPS, and least with ISO-0.4 and BTPS with 1.2 Vol% isoflurane. In addition to the 100 or 50 mL "volumetric dead space" of each AnaConDa, "reflective dead space" was 40 mL with ACD-100 and 25 mL with ACD-50 when using isoflurane. Isoflurane reflection was highest under ATP. Under BTPS with CO2 insufflation and isoflurane concentrations around 0.4 Vol%, reflection efficiency was 93% with ACD-100 and 80% with ACD-50. CONCLUSIONS: Isoflurane reflection remained sufficient with the ACD-50 at clinical anesthetic concentrations, while CO2 elimination was improved. The ACD-50 should be practical for tidal volumes as low as 200 mL, allowing lung-protective ventilation even in small patients.

Establishment of Predictive Models for Nonocclusive Mesenteric Ischemia Comparing 8,296 Control with 452 Study Patients.

OBJECTIVE: The aim of this study was to develop clinical preoperative, intraoperative, and postoperative scores for early identification of patients who are at risk of nonocclusive mesenteric ischemia (NOMI). DESIGN: A retrospective analysis. SETTING: Single center. PARTICIPANTS: From January 2008 to December 2014, all patients from the Department of Thoracic and Cardiovascular Surgery were included on the basis of the hospital database. INTERVENTIONS: All mesenteric angiographically identified NOMI patients were compared with non-NOMI patients. MEASUREMENTS AND MAIN RESULTS: The study population of 8,748 patients was randomized into a cohort for developing the scores (non-NOMI 4,214 and NOMI 235) and a cohort for control (non-NOMI 4,082 and NOMI 217). Risk factors were identified using forward and backward Wald test and were included in the predictive scores for the occurrence of NOMI. C statistic showed that the scores had a high discrimination for the prediction of NOMI preoperatively (C statistic 0.79; p < 0.001), intraoperatively (C statistic 0.68; p < 0.001), and postoperatively (C statistic 0.85; p < 0.001). A combination of the preoperative, intraoperative, and postoperative risk scores demonstrated the highest discrimination (C statistic 0.87; p < 0.001). The combined score included the following risk factors: renal insufficiency (preoperative); use of cardiopulmonary bypass and intra-aortic balloon pump support (intraoperative); and reexploration for bleeding, renal replacement therapy, and packed red blood cells ≥ 4 units (postoperative). The results were similar in the control group. CONCLUSIONS: These scores could be useful to identify patients at risk for NOMI and promote a rapid diagnosis and therapy.

Utilization of echocardiography in Intensive Care Units: results of an online survey in Germany.

BACKGROUND: In patients with hemodynamic instability echocardiography has been recommended as the preferred modality to evaluate the underlying pathophysiology. However, due to the fact that recent scientific data on the utilization of echocardiography in German Intensive Care Units (ICU) are scarce, we sought to investigate current practice. METHODS: A structured, web-based, anonymized survey was performed from May until July 2015 among members of the German Interdisciplinary Association of Critical Care and Emergency Medicine (DIVI) consisting of 14 questions. Descriptive data analysis was performed. RESULTS: One hundred four intensivists participated in the survey. Two-thirds of participants (66%) used echocardiography regularly for hemodynamic monitoring and stated that it changed the therapy in 26-50% of the cases irrespective of the time performed after ordering the examination. Transthoracic (TTE) were more frequently used than transesophageal (TEE) examinations. Twenty-six percent of the participants held an echocardiography certificate with a formal examination, 27% completed a structured training without an examination and almost half of the questioned ICU personnel (47%) did not complete a comprehensive training. CONCLUSIONS: The results of this survey demonstrate a widespread utilization of echocardiography as part of routine diagnostic on frequent number of operative ICUs. However, there might be a lack of structured echocardiographic training especially for anesthesiologists.

Flavonifractor (Eubacterium) plautii bloodstream infection following acute cholecystitis.

Flavonifractor plautii (formerly Eubacterium plautii) is an anaerobic gram positive rod shaped bacterium belonging to the family of Clostridiales, and a common member of the human gut microbiome. However, it is very rarely isolated from clinical human specimens, so data about its clinical significance are scarce. Here we report of a bloodstream infection due to F. plautii following gangrenous cholecystitis in a 69 year old man. After cholecystectomy and empirical antimicrobial treatment with ceftriaxone and metronidazole the patient recovered. F. plautii was the only bacterium detected in blood culture, suggesting that it might have been causative for cholecystitis. Antimicrobial resistance testing identified decreased susceptibilities against linezolid and penicillin indicating that a targeted therapy might be necessary. F. plautii can be considered a potential pathogen for cholecystitis.

Halving the volume of AnaConDa: initial clinical experience with a new small-volume anaesthetic reflector in critically ill patients-a quality improvement project.

AnaConDa-100 ml (ACD-100, Sedana Medical, Uppsala, Sweden) is well established for inhalation sedation in the intensive care unit. But because of its large dead space, the system can retain carbon dioxide (CO2) and increase ventilatory demands. We therefore evaluated whether AnaConDa-50 ml (ACD-50), a device with half the internal volume, reduces CO2 retention and ventilatory demands during sedation of invasively ventilated, critically ill patients. Ten patients participated in this cross-over protocol. After sedation with isoflurane via ACD-100 for 24 h, the 5-h observation period started. During the first hour, ACD-100 was used; for the next 2 h, ACD-50; and for the last 2 h, ACD-100 was used again. Sedation was titrated to Richmond Agitation and Sedation Scale (RASS) score - 3 to - 4 and a processed electroencephalogram (Narcotrend Index, Narcotrend-Gruppe, Hannover, Germany) was recorded. Minute ventilation, CO2 elimination, and isoflurane consumption were compared. All patients were deeply sedated (Narcotrend Index, mean ± SD: 38 ± 10; RASS scores - 3 to - 5) and breathed spontaneously with pressure support throughout the observation period. Infusion rates of isoflurane and opioid, either remifentanil or sufentanil, as well as ventilator settings were unchanged. Minute ventilation and end-tidal CO2 were significantly reduced with the ACD-50, respiratory rate remained unchanged, and tidal volume decreased by 66 ± 43 ml. End-tidal isoflurane concentrations were also slightly reduced while haemodynamic measures remained constant. The ACD-50 reduces the tidal volume needed to eliminate carbon dioxide without augmenting isoflurane consumption.

Efficient application of volatile anaesthetics: total rebreathing or specific reflection?

The circle system has been in use for more than a 100 years, whereas the first clinical application of an anaesthetic reflector was reported just 15 years ago. Its functional basis relies on molecular sieves such as zeolite crystals or activated carbon. In a circle system, the breathing gas is rebreathed after carbon dioxide absorption; a reflector on the other hand specifically retains the anaesthetic during expiration and resupplies it during the next inspiration. Reflection systems can be used in conjunction with intensive care ventilators and do not need the permanent presence of trained qualified staff. Because of easy handling and better ventilatory capabilities of intensive care ventilators, reflection systems facilitate the routine use of volatile anaesthetics in intensive care units. Until now, there are three reflection systems commercially available: the established AnaConDa™ (Sedana Medical, Uppsala, Sweden), the new smaller AnaConDa-S™, and the Mirus™ (Pall Medical, Dreieich, Germany). The AnaConDa consists only of a reflector which is connected to a syringe pump for infusion of liquid sevoflurane or isoflurane. The Mirus represents a technical advancement; its control unit includes a gas and ventilation monitor as well as a gas dispensing unit. The functionality, specific features, advantages and disadvantages of both systems are discussed in the text.

Volumetric and reflective device dead space of anaesthetic reflectors under different conditions.

Inhalation sedation is increasingly performed in intensive care units. For this purpose, two anaesthetic reflectors, AnaConDa™ and Mirus™ are commercially available. However, their internal volume (100 ml) and possible carbon dioxide reflection raised concerns. Therefore, we compared carbon dioxide elimination of both with a heat moisture exchanger (HME, 35 ml) in a test lung model. A constant flow of carbon dioxide was insufflated into the test lung, ventilated with 500 ml, 10 breaths per minute. HME, MIRUS and AnaConDa were connected successively. Inspired (insp-CO2) and end-tidal carbon dioxide concentrations (et-CO2) were measured under four conditions: ambient temperature pressure (ATP), body temperature pressure saturated (BTPS), BTPS with 0.4 Vol% (ISO-0.4), and 1.2 Vol% isoflurane (ISO-1.2). Tidal volume increase to maintain normocapnia was also determined. Insp-CO2 was higher with AnaConDa compared to MIRUS and higher under ATP compared to BTPS. Isoflurane further decreased insp-CO2 and abolished the difference between AnaConDa and MIRUS. Et-CO2 showed similar effects. In addition to volumetric dead space, reflective dead space was determined as 198 ± 6/58 ± 6/35 ± 0/25 ± 0 ml under ATP/BTPS/ISO-0.4/ISO-1.2 conditions for AnaConDa, and 92 ± 6/25 ± 0/25 ± 0/25 ± 0 ml under the same conditions for MIRUS, respectively. Under BTPS conditions and with the use of moderate inhaled agent concentrations, reflective dead space is small and similar between the two devices.

Evaluating the efficiency of desflurane reflection in two commercially available reflectors.

With the AnaConDa™ and the MIRUS™ system, volatile anesthetics can be administered for inhalation sedation in intensive care units. Instead of a circle system, both devices use anesthetic reflectors to save on the anesthetic agent. We studied the efficiency of desflurane reflection with both devices using different tidal volumes (VT), respiratory rates (RR), and 'patient' concentrations (CPat) in a bench study. A test lung was ventilated with four settings (volume control, RR × VT: 10 × 300 mL, 10 × 500 mL, 20 × 500 mL, 10 × 1000 mL). Two different methods for determination of reflection efficiency were established: First (steady state), a bypass flow carried desflurane into the test lung (flowin), the input concentration (Cin) was varied (1-17 vol%), and the same flow (flowex, Cex) was suctioned from the test lung. After equilibration, CPat was stored online and averaged; efficiency [%] was calculated [Formula: see text]. Second (washout), flowin and flowex were stopped, the decline of CPat was measured; efficiency was calculated from the decay constant of the exponential regression equation. Both measurement methods yielded similar results (Bland-Altman: bias: -0.9 %, accuracy: ±5.55 %). Efficiencies higher than 80 % (>80 % of molecules exhaled are reflected) could be demonstrated in the clinical range of CPat and VT. Efficiency inversely correlates with the product of CPat and VT which can be imagined as the volume of anesthetic vapor exhaled by the patient in one breath, but not with the respiratory frequency. Efficiency of the AnaConDa™ was higher for each setting compared with the MIRUS™. Desflurane is reflected by both reflectors with efficiencies high enough for clinical use.

Inhalation Sedation in Subjects With ARDS Undergoing Continuous Lateral Rotational Therapy.

INTRODUCTION: Isoflurane has shown better sedation control and potential benefits in patients with ARDS compared to propofol or midazolam, but the practical use during continuous lateral rotational therapy remains unknown. We therefore compared isoflurane with propofol and midazolam regarding sedation depth (per the Richmond Agitation-Sedation Scale), opioid consumption, lung function, and hemodynamics in patients treated with continuous lateral rotational therapy. METHODS: 38 consecutive critically ill surgical subjects were retrospectively studied using a hospital database. All subjects suffered from ARDS and were treated with continuous lateral rotational therapy between May 2010 and September 2013. Nineteen subjects were sedated with propofol or midazolam and compared with 19 subjects sedated with isoflurane using the AnaConDa-system. RESULTS: Isoflurane sedation resulted in significantly lower Richmond Agitation-Sedation Scale scores compared with propofol or midazolam. Despite deep isoflurane sedation, opioid consumption could be significantly reduced. Spontaneous breathing was possible in 90% of the subjects on isoflurane sedation compared with 16% of the subjects sedated with propofol or midazolam. The difference between peak inspiratory pressure and PEEP was significantly decreased after 24 h of isoflurane sedation. Oxygenation (PaO2 /FIO2 ) improved in both groups. Hemodynamics and need for vasopressor therapy were comparable between groups. CONCLUSIONS: This study supports the feasibility of isoflurane sedation using continuous lateral rotational therapy.

Long-term continuous renal replacement therapy and anticoagulation with citrate in critically ill patients with severe liver dysfunction.

BACKGROUND: As of 2009, anticoagulation with citrate was standard practice in continuous renal replacement therapy (CRRT) for critically ill patients at the University Medical Centre of Saarland, Germany. Partial hepatic metabolism of citrate means accumulation may occur during CRRT in critically ill patients with impaired liver function. The aim of this study was to evaluate the actual influence of hepatic function on citrate-associated complications during long-term CRRT. METHODS: In a retrospective study conducted between January 2009 and November 2012, all cases of dialysis therapy performed in the interdisciplinary surgical intensive care unit were analysed. Inclusion criteria were CRRT and regional anticoagulation with citrate, pronounced liver dysfunction, and pathologically reduced indocyanine green plasma disappearance rate (ICG-PDR). RESULTS: A total of 1339 CRRTs were performed in 69 critically ill patients with liver failure. At admission, the mean Model for End-stage Liver Disease score was 19.2, and the mean ICG-PDR was 9.8%. Eight patients were treated with liver replacement therapy, and 30 underwent transplants. The mortality rate was 40%. The mean duration of dialysis was 19.4 days, and the circuit patency was 62.2 h. Accumulation of citrate was detected indirectly by total serum calcium/ionised serum calcium (tCa/iCa) ratio > 2.4. This was noted in 16 patients (23.2%). Dialysis had not to be discontinued for metabolic disorder or accumulation of citrate in any case. In 26% of cases, metabolic alkalosis occurred with pH > 7.5. Interestingly, no correlation between citrate accumulation and liver function parameters was detected. Moreover, most standard laboratory liver function parameters showed poor predictive capabilities for accumulation of citrate. CONCLUSIONS: Our findings indicate that extra-hepatic metabolism of citrate seems to exist, avoiding in most cases citrate accumulation in critically ill patients despite impaired liver function. Because the citric acid cycle is oxygen-dependent, disturbed microcirculation would result in inadequate citrate metabolism. Raising the tCa/iCa ratio would therefore be an indicator of severity of illness and mortality rather than of liver failure. However, further studies are warranted for confirmation.

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.

BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. FINDINGS: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies. INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.