Bioelectrical impedance spectroscopy to estimate fluid balance in critically ill patients

Fluid management is a crucial issue in intensive-care medicine. This study evaluated the feasibility and reproducibility of bioimpedance spectroscopy to measure body-water composition in critically ill patients, and compared fluid balance and daily changes in total body water (TBW) measured by bioimpedance. This observational study included 25 patients under mechanical ventilation. Fluid balance and bioimpedance measurements were recorded on 3 consecutive days. Whole-body bioimpedance spectroscopy was performed with exact or ideal body weights entered into the device, and with or without ICU monitoring. Reproducibility of bioimpedance spectroscopy was very good in all conditions despite ICU monitoring and mechanical ventilation. Bioimpedance measurements using an ideal body weight varied significantly, making the weighing procedure necessary. Comparison of fluid balance and daily changes in body weight provided the best correlation (ρ = 0.74; P < 0.0001). Daily changes in TBW were correlated with fluid balance (Spearman coefficient ρ = 0.31; P = 0.003) and this correlation was improved after exclusion of patients with a SOFA score >10 (ρ = 0.36; P = 0.05) and with extracorporeal circulation (ρ = 0.50; P = 0.005). Regardless of the technique used to estimate volume status, important limits of agreement were observed. Non-invasive determination of body-water composition using bioimpedance spectroscopy is feasible in critically ill patients but requires knowledge of the patient’s weight. The best method to assess volume status after fluid resuscitation and the value gained from information about body composition provided by bioimpedance techniques needs further evaluation.     

A model to identify direct costs of nursing education: the Colorado experience

During spring 2003, national, state, and local economic factors converged in a manner that propelled us to better identify the costs of the educational programs offered within the University of Colorado Health Sciences Center School of Nursing (SON). Two factors prompted analysis of direct costs of the nursing education programs: a shrinking state appropriation and a 36.7% rescission of state funds during that academic year. The SON supports 618 students in four programs (baccalaureate, master of science, doctor of nursing, and doctor of philosophy). During summer 2003, the SON leadership team met numerous times in an iterative process to clarify assumptions and make recommendations in an attempt to cost out academic programs. Data were obtained from a variety of sources. The SON Office of Budget and Finance provided revenue and expense data. The Office of Academic Affairs provided course schedules, the course offering plan, and projected student enrollment in courses. The Division Chairs provided data concerning faculty workload and faculty areas of expertise. The data were compiled in Access tables and arrayed in a series of Excel spreadsheets that captured course data and faculty data. A "what-if" analysis was completed to determine cost of a pilot accelerated baccalaureate program. This method provides a dynamic analytic system shown to be prospectively and retrospectively effective. As a result of this analysis, the following metrics are available: direct cost per student per course/program; revenue per student per course/program; faculty teaching FTE; and faculty-to-student ratio.     

Protease-activated receptors: new concepts in regulation of G protein-coupled receptor signaling and trafficking

Most G protein-coupled receptors (GPCRs) are reversibly activated upon ligand binding. However, activation of protease-activated G protein-coupled receptors (PARs) occurs through an irreversible proteolytic event that results in the generation of a tethered ligand that cannot diffuse away. This unusual mode of PAR activation raises important questions regarding the mechanisms responsible for termination of receptor signaling. There are currently four members of the PAR family. Thrombin activates PAR1, PAR3, and PAR4, whereas multiple trypsin-like serine proteases activate PAR2. The regulation of signaling by PAR1 has been extensively studied, whereas considerably less is known about the other PARs. It has been demonstrated that rapid termination of PAR1 signaling is critical in determining the magnitude and kinetics of the cellular protease response. Therefore, elucidating the molecular mechanisms involved in the regulation of PAR signaling is essential to fully understand protease-mediated responses. Recent findings indicate that novel mechanisms contribute to PAR1 desensitization, internalization, and down-regulation. This review focuses on the intracellular mechanisms that regulate PAR signaling and the recent progress in developing inhibitors of PAR signaling.     

Advancing performance measures for use of medications in substance abuse treatment

Performance measures have the potential to drive high-quality health care. However, technical and policy challenges exist in developing and implementing measures to assess substance use disorder (SUD) pharmacotherapy. Of critical importance in advancing performance measures for use of SUD pharmacotherapy is the recognition that different measurement approaches may be needed in the public and private sectors and will be determined by the availability of different data collection and monitoring systems. In 2009, the Washington Circle convened a panel of nationally recognized insurers, purchasers, providers, policy makers, and researchers to address this topic. The charge of the panel was to identify opportunities and challenges in advancing use of SUD pharmacotherapy performance measures across a range of systems. This article summarizes those findings by identifying a number of critical themes related to advancing SUD pharmacotherapy performance measures, highlighting examples from the field, and recommending actions for policy makers.     

Alternate strategies to obtain mass balance without the use of radiolabeled compounds: application of quantitative fluorine (19F) nuclear magnetic resonance (NMR) spectroscopy in metabolism studies

Nuclear magnetic resonance (NMR) spectroscopy is playing an increasingly important role in the quantitation of small and large molecules. Recently, we demonstrated that (1)H NMR could be used to quantitate drug metabolites isolated in submilligram quantities from biological sources. It was shown that these metabolites, once quantitated by NMR, were suitable to be used as reference standards in quantitative LC/MS-based assays, hence circumventing the need for radiolabeled material or synthetic standards to obtain plasma exposure estimates in humans and preclinical species. The quantitative capabilities of high-field NMR is further demonstrated in the current study by obtaining the mass balance of fluorinated compounds using (19)F-NMR. Two fluorinated compounds which were radio-labeled with carbon-14 on metabolically stable positions were dosed in rats and urine and feces collected. The mass balance of the compounds was obtained initially by counting the radioactivity present in each sample. Subsequently, the same sets of samples were analyzed by (19)F-NMR, and the concentrations determined by this method were compared with data obtained using radioactivity counting. It was shown that the two methods produced comparable values. To demonstrate the value of this analytical technique in drug discovery, a fluorinated compound was dosed intravenously in dogs and feces and urine collected. Initial profiling of samples showed that this compound was excreted mainly unchanged in feces, and hence, an estimate of mass balance was obtained using (19)F-NMR. The data obtained by this method was confirmed by additional quantitative studies using mass spectrometry. Hence cross-validations of the quantitative (19)F-NMR method by radioactivity counting and mass spectrometric analysis were demonstrated in this study. A strategy outlining the use of fluorinated compounds in conjunction with (19)F-NMR to understand their routes of excretion or mass balance in animals is proposed. These studies demonstrate that quantitative (19)F-NMR could be used as an alternate technique to obtain an estimate of the mass balance of fluorinated compounds, especially in early drug development where attrition of the compounds is high, and cost savings could be realized through the use of such a technique rather than employing radioactive compounds. The potential application of qNMR in conducting early human ADME studies with fluorinated compounds is also discussed.     

Immediate financial impact of computerized clinical decision support for long-term care residents with renal insufficiency: a case study

In a randomized trial of a clinical decision support system for drug prescribing for residents with renal insufficiency in a large long-term care facility, analyses were conducted to estimate the system's immediate, direct financial impact. We determined the costs that would have been incurred if drug orders that triggered the alert system had actually been completed compared to the costs of the final submitted orders and then compared intervention units to control units. The costs incurred by additional laboratory testing that resulted from alerts were also estimated. Drug orders were conservatively assigned a duration of 30 days of use for a chronic drug and 10 days for antibiotics. It was determined that there were modest reductions in drug costs, partially offset by an increase in laboratory-related costs. Overall, there was a reduction in direct costs (US$1391.43, net 7.6% reduction). However, sensitivity analyses based on alternative estimates of duration of drug use suggested a reduction as high as US$7998.33 if orders for non-antibiotic drugs were assumed to be continued for 180 days. The authors conclude that the immediate and direct financial impact of a clinical decision support system for medication ordering for residents with renal insufficiency is modest and that the primary motivation for such efforts must be to improve the quality and safety of medication ordering.     

The design and performance of the exubera pulmonary insulin delivery system

The Exubera system (Pfizer, New York, NY/Nektar Therapeutics, San Carlos, CA) is an integration of five major new technologies: protein formulation, powder processing, powder filling, drug packaging, and delivery device. The product provides a simple interface, where the patient interacts only with the delivery device and powder packaging. These components were designed together to assure repeatable dosing when used by a wide range of patients under real-world life-style and handling conditions. The device design is purely mechanical, using patient-generated compressed air as the energy source. Upon actuation, a sonic discharge of air through the novel release unit reproducibly extracts, de-agglomerates, and disperses the inhalation powder into a respirable aerosol. A clear holding chamber allows for patient feedback via dose visualization and separates aerosol cloud generation from the inspiratory effort. The Exubera product was tested under a wide range of typical use conditions and potential misuse scenarios and following long-term usage in clinical trials. These comprehensive characterization programs demonstrated robust aerosol and mechanical performance, confirming the design intent of the inhaler. These studies provide assurance of consistent and reliable dose delivery in a real-world use of the product.     

Frequent detection of acute HIV infection in pregnant women

BACKGROUND: Universal prenatal HIV antibody testing, which does not detect acute HIV, is standard for pregnant women in the United States. Unrecognized HIV acquisition during pregnancy may result in higher rates of perinatal transmission. OBJECTIVE: To determine the prevalence of acute (antibody-negative) HIV infection in pregnant women and to assess the potential for prompt initiation of antiretroviral therapy to prevent perinatal transmission. METHODS: From 1 November 2002 to 30 April 2005, all publicly funded HIV testing sites participated in North Carolina's Screening and Tracing Active Transmission (STAT) Program, which retested all specimens that were HIV antibody negative for HIV RNA using specimen pooling. All patients with acute HIV infection were immediately traced for evaluation, confirmatory testing, counseling, and referral services. For this study, all pregnant women with acute HIV were immediately initiated onto antiretroviral therapy and followed prospectively for pregnancy outcomes. RESULTS: During the study period, 443 women were HIV positive by antibody testing; 15 were HIV antibody negative but positive by RNA assay and of these five were pregnant at the time of testing. The pregnant women received antiretroviral drugs and delivered HIV-uninfected infants. Maternal testing records of all six HIV-infected infants born in North Carolina showed three mothers with chronic HIV infection and three HIV antibody negative at private prenatal testing facilities. CONCLUSIONS: In resource-rich settings, a substantial proportion of residual perinatal transmission may be from HIV acquisition during pregnancy. Standard antibody tests miss acute HIV infection and so algorithms that include pooled HIV RNA testing may improve its detection and represent a further opportunity to prevent perinatal transmission.