Development and simultaneous application of multiple care protocols in critical care: a multicenter feasibility study

OBJECTIVE: To test the feasibility of and interactions among three software-driven critical care protocols. DESIGN: Prospective cohort study. SETTING: Intensive care units in six European and American university hospitals. PATIENTS: 174 cardiac surgery and 41 septic patients. INTERVENTIONS: Application of software-driven protocols for cardiovascular management, sedation, and weaning during the first 7 days of intensive care. MEASUREMENTS AND RESULTS: All protocols were used simultaneously in 85% of the cardiac surgery and 44% of the septic patients, and any one of the protocols was used for 73 and 44% of study duration, respectively. Protocol use was discontinued in 12% of patients by the treating clinician and in 6% for technical/administrative reasons. The number of protocol steps per unit of time was similar in the two diagnostic groups (n.s. for all protocols). Initial hemodynamic stability (a protocol target) was achieved in 26+/-18 min (mean+/-SD) in cardiac surgery and in 24+/-18 min in septic patients. Sedation targets were reached in 2.4+/-0.2h in cardiac surgery and in 3.6 +/-0.2h in septic patients. Weaning protocol was started in 164 (94%; 154 extubated) cardiac surgery and in 25 (60%; 9 extubated) septic patients. The median (interquartile range) time from starting weaning to extubation (a protocol target) was 89 min (range 44-154 min) for the cardiac surgery patients and 96 min (range 56-205 min) for the septic patients. CONCLUSIONS: Multiple software-driven treatment protocols can be simultaneously applied with high acceptance and rapid achievement of primary treatment goals. Time to reach these primary goals may provide a performance indicator.

Nighttime vagal cardiac control and plasma fibrinogen levels in a population of working men and women

BACKGROUND: Elevated plasma fibrinogen levels have prospectively been associated with an increased risk of coronary artery disease in different populations. Plasma fibrinogen is a measure of systemic inflammation crucially involved in atherosclerosis. The vagus nerve curtails inflammation via a cholinergic antiinflammatory pathway. We hypothesized that lower vagal control of the heart relates to higher plasma fibrinogen levels. METHODS: Study participants were 559 employees (age 17-63 years; 89% men) of an airplane manufacturing plant in southern Germany. All subjects underwent medical examination, blood sampling, and 24-hour ambulatory heart rate recording while kept on their work routine. The root mean square of successive differences in RR intervals during the night period (nighttime RMSSD) was computed as the heart rate variability index of vagal function. RESULTS: After controlling for demographic, lifestyle, and medical factors, nighttime RMSSD explained 1.7% (P = 0.001), 0.8% (P = 0.033), and 7.8% (P = 0.007), respectively, of the variance in fibrinogen levels in all subjects, men, and women. Nighttime RMSSD and fibrinogen levels were stronger correlated in women than in men. In all workers, men, and women, respectively, there was a mean +/- SEM increase of 0.41 +/- 0.13 mg/dL, 0.28 +/- 0.13 mg/dL, and 1.16 +/- 0.41 mg/dL fibrinogen for each millisecond decrease in nighttime RMSSD. CONCLUSIONS: Reduced vagal outflow to the heart correlated with elevated plasma fibrinogen levels independent of the established cardiovascular risk factors. This relationship seemed comparably stronger in women than men. Such an autonomic mechanism might contribute to the atherosclerotic process and its thrombotic complications.

A validated assay by liquid chromatography-tandem mass spectrometry for the simultaneous quantification of elvitegravir and rilpivirine in HIV positive patients

Because of the large variability in the pharmacokinetics of anti-HIV drugs, therapeutic drug monitoring in patients may contribute to optimize the overall efficacy and safety of antiretroviral therapy. An LC–MS/MS method for the simultaneous assay in plasma of the novel antiretroviral agents rilpivirine (RPV) and elvitegravir (EVG) has been developed to that endeavor. Plasma samples (100 μL) extraction is performed by protein precipitation with acetonitrile, and the supernatant is subsequently diluted 1:1 with 20-mM ammonium acetate/MeOH 50:50. After reverse-phase chromatography, quantification of RPV and EVG, using matrix-matched calibration samples, is performed by electrospray ionization–triple quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. The stable isotopic-labeled compounds RPV-13C6 and EVG-D6 were used as internal standards. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effects variability (<6.4%), as well as EVG and RPV short and long-term stability in plasma. Calibration curves were validated over the clinically relevant concentrations ranging from 5 to 2500 ng/ml for RPV and from 50 to 5000 ng/ml for EVG. The method is precise (inter-day CV%: 3–6.3%) and accurate (3.8–7.2%). Plasma samples were found to be stable (<15%) in all considered conditions (RT/48 h, +4°C/48 h, −20°C/3 months and 60°C/1 h). Selected metabolite profiles analysis in patients' samples revealed the presence of EVG glucuronide, that was well separated from parent EVG, allowing to exclude potential interferences through the in-source dissociation of glucuronide to parent drug. This new, rapid and robust LCMS/MS assay for the simultaneous quantification of plasma concentrations of these two major new anti-HIV drugs EVG and RPV offers an efficient analytical tool for clinical pharmacokinetics studies and routine therapeutic drug monitoring service.

Simultaneous registration of ECG and cardiac motion by a single esophageal probe

Long-term surface ECG is routinely used to diagnose paroxysmal arrhythmias. However, this method only provides information about the heart's electrical activity. To this end, we investigated a novel esophageal catheter that features synchronous esophageal ECG and acceleration measurements, the latter being a record of the heart's mechanical activity. The acceleration data were quantified in a small study and successfully linked to the activity sequences of the heart in all subjects. The acceleration signals were additionally transformed into motion. The extracted cardiac motion was proved to be a valid reference input for an adaptive filter capable of removing relevant baseline wandering in the recorded esophageal ECGs. Taking both capabilities into account, the proposed recorder might be a promising tool for future long-term heart monitoring.

The basel cocktail for simultaneous phenotyping of human cytochrome P450 isoforms in plasma, saliva and dried blood spots.

BACKGROUND AND OBJECTIVE Phenotyping cocktails use a combination of cytochrome P450 (CYP)-specific probe drugs to simultaneously assess the activity of different CYP isoforms. To improve the clinical applicability of CYP phenotyping, the main objectives of this study were to develop a new cocktail based on probe drugs that are widely used in clinical practice and to test whether alternative sampling methods such as collection of dried blood spots (DBS) or saliva could be used to simplify the sampling process. METHODS In a randomized crossover study, a new combination of commercially available probe drugs (the Basel cocktail) was tested for simultaneous phenotyping of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Sixteen subjects received low doses of caffeine, efavirenz, losartan, omeprazole, metoprolol and midazolam in different combinations. All subjects were genotyped, and full pharmacokinetic profiles of the probe drugs and their main metabolites were determined in plasma, dried blood spots and saliva samples. RESULTS The Basel cocktail was well tolerated, and bioequivalence tests showed no evidence of mutual interactions between the probe drugs. In plasma, single timepoint metabolic ratios at 2 h (for CYP2C19 and CYP3A4) or at 8 h (for the other isoforms) after dosing showed high correlations with corresponding area under the concentration-time curve (AUC) ratios (AUC0-24h parent/AUC0-24h metabolite) and are proposed as simple phenotyping metrics. Metabolic ratios in dried blood spots (for CYP1A2 and CYP2C19) or in saliva samples (for CYP1A2) were comparable to plasma ratios and offer the option of minimally invasive or non-invasive phenotyping of these isoforms. CONCLUSIONS This new combination of phenotyping probe drugs can be used without mutual interactions. The proposed sampling timepoints have the potential to facilitate clinical application of phenotyping but require further validation in conditions of altered CYP activity. The use of DBS or saliva samples seems feasible for phenotyping of the selected CYP isoforms.

An initiative for participatory monitoring of large scale acquisitions: Opportunities and results thus far

Increasing commercial pressures on land are provoking fundamental and far-reaching changes in the relationships between people and land. Much knowledge on land-oriented investments projects currently comes from the media. Although this provides a good starting point, lack of transparency and rapidly changing contexts mean that this is often unreliable. The International Land Coalition, in partnership with Oxfam Novib, Centre de coopération internationale en recherche agronomique pour le développement (CIRAD), University of Pretoria, Centre for Development and Environment of the University of Bern (CDE), and GIZ, started to compile an inventory of land-related investments. This project aims to better understand the extent, trends and impacts of land-related investments by supporting an ongoing and systematic stocktaking exercise of the various investment projects currently taking place worldwide. It involves a large number of organizations and individuals working in areas where land transactions are being made, and able to provide details of such investments. The project monitors land transactions in rural areas that imply a transformation of land use rights from communities and smallholders to commercial use, and are made both by domestic and foreign investors (private actors, governments, government-back private investors). The focus is on investments for food or agrofuel production, timber extraction, carbon trading, mineral extraction, conservation and tourism. A novel way of using ITC to document land acquisitions in a spatially explicit way and by using an approach called “crowdsourcing” is being developed. This approach will allow actors to share information and knowledge directly and at any time on a public platform, where it will be scrutinized in terms of reliability and cross checked with other sources. Up to now, over 1200 deals have been recorded across 96 countries. Details of such transactions have been classified in a matrix and distributed to over 350 contacts worldwide for verification. The verified information has been geo-referenced and represented in two global maps. This is an open database enabling a continued monitoring exercise and the improvement of data accuracy. More information will be released over time. The opportunities arise from overcoming constraints by incomplete information by proposing a new way of collecting, enhancing and sharing information and knowledge in a more democratic and transparent manner. The intention is to develop interactive knowledge platform where any interested person can share and access information on land deals, their link to involved stakeholders, and their embedding into a geographical context. By making use of new ICT technologies that are more and more in the reach of local stakeholders, as well as open access and web-based spatial information systems, it will become possible to create a dynamic database containing spatial explicit data. Feeding in data by a large number of stakeholders, increasingly also by means of new mobile ITC technologies, will open up new opportunities to analyse, monitor and assess highly dynamic trends of land acquisition and rural transformation.

A plasma global metabolic profiling approach applied to an exercise study monitoring the effects of glucose, galactose and fructose drinks during post-exercise recovery

A global metabolic profiling methodology based on gas chromatography coupled to time-of-flight mass spectrometry (GC-TOFMS) for human plasma was applied to a human exercise study focused on the effects of beverages containing glucose, galactose, or fructose taken after exercise and throughout a recovery period of 6 h and 45 min. One group of 10 well trained male cyclists performed 3 experimental sessions on separate days (randomized, single center). After performing a standardized depletion protocol on a bicycle, subjects consumed one of three different beverages: maltodextrin (MD)+glucose (2:1 ratio), MD+galactose (2:1), and MD+fructose (2:1), consumed at an average of 1.25 g of carbohydrate (CHO) ingested per minute. Blood was taken straight after exercise and every 45 min within the recovery phase. With the resulting blood plasma, insulin, free fatty acid (FFA) profile, glucose, and GC-TOFMS global metabolic profiling measurements were performed. The resulting profiling data was able to match the results obtained from the other clinical measurements with the addition of being able to follow many different metabolites throughout the recovery period. The data quality was assessed, with all the labelled internal standards yielding values of <15% CV for all samples (n=335), apart from the labelled sucrose which gave a value of 15.19%. Differences between recovery treatments including the appearance of galactonic acid from the galactose based beverage were also highlighted.

Application of a new laser Doppler imaging system in planning and monitoring of surgical flaps

There is a demand for technologies able to assess the perfusion of surgical flaps quantitatively and reliably to avoid ischemic complications. The aim of this study is to test a new high-speed high-definition laser Doppler imaging (LDI) system (FluxEXPLORER, Microvascular Imaging, Lausanne, Switzerland) in terms of preoperative mapping of the vascular supply (perforator vessels) and postoperative flow monitoring. The FluxEXPLORER performs perfusion mapping of an area 9 x 9 cm with a resolution of 256 x 256 pixels within 6 s in high-definition imaging mode. The sensitivity and predictability to localize perforators is expressed by the coincidence of preoperatively assessed LDI high flow spots with intraoperatively verified perforators in nine patients. 18 free flaps are monitored before, during, and after total ischemia. 63% of all verified perforators correspond to a high flow spot, and 38% of all high flow spots correspond to a verified perforator (positive predictive value). All perfused flaps reveal a value of above 221 perfusion units (PUs), and all values obtained in the ischemic flaps are beneath 187 PU. In summary, we conclude that the present LDI system can serve as a reliable, fast, and easy-to-handle tool to detect ischemia in free flaps, whereas perforator vessels cannot be detected appropriately.

Addressing schemes of self-monitoring of blood glucose in type 2 diabetes: a European perspective and expert recommendation

Self-monitoring of blood glucose (SMBG) in type 2 diabetes has increasingly been shown to display beneficial effects on glycemic control. SMBG is not only associated with a reduction of hemoglobin A1c but has also been demonstrated to increase patients' awareness of the disease. SMBG has also the potential to visualize and predict hypoglycemic episodes. International guidelines by the International Diabetes Federation, the European Society of Cardiology, and the European Association for the Study of Diabetes and also the International Society for Pediatric and Adolescent Diabetes emphasize that SMBG is an integral part of self-management. More recently, two European consensus documents have been published to give recommendations for frequency and timing of SMBG also for various clinical scenarios. Recently, a European expert panel was held to further facilitate and enhance standardized approaches to SMBG. The aim was to present simple, clinically meaningful, and standardized SMBG strategies for type 2 diabetes. The panel recommended a less intensive and an intensive scheme for SMBG across the type 2 diabetes continuum. The length and frequency of SMBG performance depend on the clinical circumstances and the quality of glycemic control. The expert panel also recommended further evaluation of various schemes for SMBG in type 2 diabetes in clinical studies.

Development and validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of nine corticosteroid residues in bovine liver samples

A liquid chromatography tandem mass spectrometry (LC-MS/MS) confirmatory method for the simultaneous determination of nine corticosteroids in liver, including the four MRL compounds listed in Council Regulation 37/2010, was developed. After an enzymatic deconjugation and a solvent extraction of the liver tissue, the resulting solution was cleaned up through an SPE Oasis HLB cartridge. The analytes were then detected by liquid chromatography-negative-ion electrospray tandem mass spectrometry, using deuterium-labelled internal standards. The procedure was validated as a quantitative confirmatory method according to the Commission Decision 2002/657/EC criteria. The results showed that the method was suitable for statutory residue testing regarding the following performance characteristics: instrumental linearity, specificity, precision (repeatability and intra-laboratory reproducibility), recovery, decision limit (CCα), detection capability (CCβ) and ruggedness. All the corticosteroids can be detected at a concentration around 1 μg kg(-1); the recoveries were above 62% for all the analytes. Repeatability and reproducibility (within-laboratory reproducibility) for all the analytes were below 7.65% and 15.5%, respectively.

Viral load monitoring of antiretroviral therapy, cohort viral load and HIV transmission in Southern Africa: A mathematical modelling analysis

In low-income settings, treatment failure is often identified using CD4 cell count monitoring. Consequently, patients remain on a failing regimen, resulting in a higher risk of transmission. We investigated the benefit of routine viral load monitoring for reducing HIV transmission.

Measurements of Humidity in the Atmosphere and Validation Experiments MOHAVE-2009; overview of campaign operations and results

The Measurements of Humidity in the Atmosphere and Validation Experiment (MOHAVE) 2009 campaign took place on 11–27 October 2009 at the JPL Table Mountain Facility in California (TMF). The main objectives of the campaign were to (1) validate the water vapor measurements of several instruments, including, three Raman lidars, two microwave radiometers, two Fourier-Transform spectrometers, and two GPS receivers (column water), (2) cover water vapor measurements from the ground to the mesopause without gaps, and (3) study upper tropospheric humidity variability at timescales varying from a few minutes to several days. A total of 58 radiosondes and 20 Frost-Point hygrometer sondes were launched. Two types of radiosondes were used during the campaign. Non negligible differences in the readings between the two radiosonde types used (Vaisala RS92 and InterMet iMet-1) made a small, but measurable impact on the derivation of water vapor mixing ratio by the Frost-Point hygrometers. As observed in previous campaigns, the RS92 humidity measurements remained within 5% of the Frost-point in the lower and mid-troposphere, but were too dry in the upper troposphere. Over 270 h of water vapor measurements from three Raman lidars (JPL and GSFC) were compared to RS92, CFH, and NOAA-FPH. The JPL lidar profiles reached 20 km when integrated all night, and 15 km when integrated for 1 h. Excellent agreement between this lidar and the frost-point hygrometers was found throughout the measurement range, with only a 3% (0.3 ppmv) mean wet bias for the lidar in the upper troposphere and lower stratosphere (UTLS). The other two lidars provided satisfactory results in the lower and mid-troposphere (2–5% wet bias over the range 3–10 km), but suffered from contamination by fluorescence (wet bias ranging from 5 to 50% between 10 km and 15 km), preventing their use as an independent measurement in the UTLS. The comparison between all available stratospheric sounders allowed to identify only the largest biases, in particular a 10% dry bias of the Water Vapor Millimeter-wave Spectrometer compared to the Aura-Microwave Limb Sounder. No other large, or at least statistically significant, biases could be observed. Total Precipitable Water (TPW) measurements from six different co-located instruments were available. Several retrieval groups provided their own TPW retrievals, resulting in the comparison of 10 different datasets. Agreement within 7% (0.7 mm) was found between all datasets. Such good agreement illustrates the maturity of these measurements and raises confidence levels for their use as an alternate or complementary source of calibration for the Raman lidars. Tropospheric and stratospheric ozone and temperature measurements were also available during the campaign. The water vapor and ozone lidar measurements, together with the advected potential vorticity results from the high-resolution transport model MIMOSA, allowed the identification and study of a deep stratospheric intrusion over TMF. These observations demonstrated the lidar strong potential for future long-term monitoring of water vapor in the UTLS.