Recording of a left ventricle assist device electrical current with a neurally adjusted ventilation assist (NAVA) catheter: a small case series.

BACKGROUND: Neurally Adjusted Ventilatory Assist (NAVA) is an adaptive ventilation mode that recognizes electromyographic diaphragmatic activation as a sensory input to control the ventilator. NAVA may be of interest in prolonged mechanical ventilation and weaning, as it provides effort-adapted support, improves patient-ventilator synchronization, and allows additional monitoring of neuromuscular function and drive. Ventricular assist devices (VAD), especially for the left ventricle (LVAD), are increasingly entering clinical practice, and intensivists are faced with distinct challenges such as the interaction between the system and other measures of organ support. CASE PRESENTATION: We present two cases in which a NAVA mode was intended to support ventilator weaning in patients with recent LVAD implantation (HeartMate III®). However, in these patients, the electrical activity of the diaphragm (Edi) could not be used to control the ventilator, because the LVAD current detected by the catheter superposed the Edi current, making usage of this mode impossible. DISCUSSION/CONCLUSIONS: An implanted LVAD can render the NAVA signal unusable for ventilatory support because the LVAD signal can interfere with the recording of electromyographic activation of the diaphragm. Therefore, patients with implanted LVAD may need other modes of ventilation than NAVA for advanced weaning strategies.

Noninvasive Neurally Adjusted Ventilator Assist Ventilation in the Postoperative Period Produces Better Patient-Ventilator Synchrony but Not Comfort.

BACKGROUND: Noninvasive neurally adjusted ventilatory assist (NAVA) has been shown to improve patient-ventilator interaction in many settings. There is still scarce data with regard to postoperative patients indicated for noninvasive ventilation (NIV) which this study elates. The purpose of this trial was to evaluate postoperative patients for synchrony and comfort in noninvasive pressure support ventilation (NIV-PSV) vs. NIV-NAVA. METHODS: Twenty-two subjects received either NIV-NAVA or NIV-PSV in an object-blind, prospective, randomized, crossover fashion (observational trial). We evaluated blood gases and ventilator tracings throughout as well as comfort of ventilation at the end of each ventilation phase. RESULTS: There was an effective reduction in ventilator delays (p < 0.001) and negative pressure duration in NIV-NAVA as compared to NIV-PSV (p < 0.001). Although we used optimized settings in NIV-PSV, explaining the overall low incidence of asynchrony, NIV-NAVA led to reductions in the NeuroSync-index (p < 0.001) and all types of asynchrony except for double triggering that was significantly more frequent in NIV-NAVA vs. NIV-PSV (p = 0.02); ineffective efforts were reduced to zero by use of NIV-NAVA. In our population of previously lung-healthy subjects, we did not find differences in blood gases and patient comfort between the two modes. CONCLUSION: In the postoperative setting, NIV-NAVA is well suitable for use and effective in reducing asynchronies as well as a surrogate for work of breathing. Although increased synchrony was not transferred into an increased comfort, there was an advantage with regard to patient-ventilator interaction. The trial was registered at the German clinical Trials Register (DRKS no.: DRKS00005408).

Preemptive veno-venous ECMO support in a patient with anticipated difficult airway: A case report.

This report presents a case of endotracheal metastasis in which elective veno-venous extracorporeal membrane oxygenation (VV ECMO) was used to undergo tracheal laser-surgery prior to establishment of a definitive airway. Specifically, we describe the respiratory and airway management in an adult patient from the preclinical phase throughout elective preoperative ECMO implantation to postoperative ECMO weaning and decannulation in the Intensive Care Unit. This case report lends further supports to the idea that the extracorporeal membrane oxygenation could be electively used to provide safe environment for surgery in situations where the standard maneuvers of sustaining adequate gas exchange are anticipated to fail.

Sequential use of extracorporeal devices to avoid mechanical ventilation in a patient with complicated pulmonary fibrosis.

Extracorporeal lung assist devices are widely used these days for a growing number of indications. We report the case of a patient managed with three different flow-range devices sequentially, enabling us to avoid mechanical ventilation. Handling and ethics of this approach are discussed.

Thoughtflow: Standards and Tools for Provenance Capture and Workflow Definition to Support Model-Informed Drug Discovery and Development.

Pharmacometric analyses are complex and multifactorial. It is essential to check, track, and document the vast amounts of data and metadata that are generated during these analyses (and the relationships between them) in order to comply with regulations, support quality control, auditing, and reporting. It is, however, challenging, tedious, error-prone, and time-consuming, and diverts pharmacometricians from the more useful business of doing science. Automating this process would save time, reduce transcriptional errors, support the retention and transfer of knowledge, encourage good practice, and help ensure that pharmacometric analyses appropriately impact decisions. The ability to document, communicate, and reconstruct a complete pharmacometric analysis using an open standard would have considerable benefits. In this article, the Innovative Medicines Initiative (IMI) Drug Disease Model Resources (DDMoRe) consortium proposes a set of standards to facilitate the capture, storage, and reporting of knowledge (including assumptions and decisions) in the context of model-informed drug discovery and development (MID3), as well as to support reproducibility: "Thoughtflow." A prototype software implementation is provided.

Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa.

This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.

Bifidobacterium breve reduces apoptotic epithelial cell shedding in an exopolysaccharide and MyD88-dependent manner.

Certain members of the microbiota genus Bifidobacterium are known to positively influence host well-being. Importantly, reduced bifidobacterial levels are associated with inflammatory bowel disease (IBD) patients, who also have impaired epithelial barrier function, including elevated rates of apoptotic extrusion of small intestinal epithelial cells (IECs) from villi-a process termed 'cell shedding'. Using a mouse model of pathological cell shedding, we show that mice receiving Bifidobacterium breve UCC2003 exhibit significantly reduced rates of small IEC shedding. Bifidobacterial-induced protection appears to be mediated by a specific bifidobacterial surface exopolysaccharide and interactions with host MyD88 resulting in downregulation of intrinsic and extrinsic apoptotic responses to protect epithelial cells under highly inflammatory conditions. Our results reveal an important and previously undescribed role for B. breve, in positively modulating epithelial cell shedding outcomes via bacterial- and host-dependent factors, supporting the notion that manipulation of the microbiota affects intestinal disease outcomes.

Making Every Subject Count: A Case Study of Drug Development Path for Medication in a Pediatric Rare Disease.

Approximately 50% of rare diseases are evident in children. Fatal disease prognosis and lack of treatments causes 30% of affected children to not live past their fifth birthday. This clear sense of urgency demands innovation and acceleration in drug development. A case study is discussed highlighting the need for data-rich phase I study design, extensive use of modeling and simulation, use of diverse data sources, and input from collaborators to respond to this urgent call.

Good Practices in Model-Informed Drug Discovery and Development: Practice, Application, and Documentation.

This document was developed to enable greater consistency in the practice, application, and documentation of Model-Informed Drug Discovery and Development (MID3) across the pharmaceutical industry. A collection of "good practice" recommendations are assembled here in order to minimize the heterogeneity in both the quality and content of MID3 implementation and documentation. The three major objectives of this white paper are to: i) inform company decision makers how the strategic integration of MID3 can benefit R&D efficiency; ii) provide MID3 analysts with sufficient material to enhance the planning, rigor, and consistency of the application of MID3; and iii) provide regulatory authorities with substrate to develop MID3 related and/or MID3 enabled guidelines.

Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development.

The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps.

Drug and disease model resources: a consortium to create standards and tools to enhance model-based drug development.

Model-based drug development (MBDD) is accepted as a vital approach in understanding patients' drug-related benefit and risk by integrating quantitative information integration from diverse sources collected throughout drug development.(1) This perspective introduces the activities of the Drug and Disease Model Resources (DDMoRe) consortium, founded in 2011 through the Innovative Medicines Initiative Joint Undertaking (IMI-JU)(2) as a European public-private partnership to address a lack of common tools, languages, and standards for modeling and simulation (M&S) to improve model-based knowledge integration.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e34; doi:10.1038/psp.2013.10; advance online publication 20 March 2013.

Modeling and simulation as a tool to bridge efficacy and safety data in special populations.

The registration and approval of novel medicines have traditionally been based on evidence arising from large prospective trials. Such an approach is often not possible or unsuitable to evaluate the benefit-risk balance in special populations (e.g., children, ethnic groups, rare diseases). Inferences by modeling and simulation can play a major role in evidence synthesis. A framework is proposed that promotes its acceptability and the basis for decision making during development, registration, and therapeutic use of drugs.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e28; doi:10.1038/psp.2013.6; advance online publication 27 February 2013.

NONMEM analysis in determining the tri-exponential disposition of cefotaxime: a method of evaluating serum and urinary phase I data.

The time above the minimum inhibitory concentration (MIC) is an important surrogate parameter for the efficacy of cephalosporines. In clinical practice cefotaxime (CTX) is usually administered every 8 h or 12 h. Unfortunately the limit of quantification (LOQ) of the available assay is not low enough to detect CTX concentrations in serum later than 6 h after a 2 g i.v. dose. Consequently the time above MIC has to be estimated by extrapolation of the available serum data. Due to the concentrating properties of the kidney, concentrations in urine following a 2 g dose however remain above the LOQ for up to 16 h. It is therefore possible to follow the pharmacokinetics of CTX in urine within a 12 h dosing interval. Due to the linear pharmacokinetics of CTX, serum concentrations, and accordingly the time above MIC, can be estimated by using the measured urinary excretion and the calculated renal clearance. The pharmacokinetics of cefotaxime were studied in 12 healthy subjects who received a single 2 g i.v. dose administered as a short infusion. Blood and fractional urine were collected up to 24 h after dosing. For the characterization of the true terminal half-life only sparse and unbalanced serum and urinary data was available. In such situations, the population approach is the method of choice for estimating the kinetic parameters. The combined analysis of serum and urinary data using NONMEM shows the superiority of a tri-exponential compared to a bi-exponential pharmacokinetics model. As a result, the predicted serum trough levels of cefotaxime following twice daily dosing are about 30-fold higher than those extrapolated from the bi-exponential model. Consequently, the concentrations of CTX- and its metabolite desacetyl-CTX--are above the MIC of many therapeutically relevant pathogens for a longer period of time than previously assumed. In conclusion, a twice daily dosing regimen for cefotaxime is adequate for a number of clinically relevant pathogens. This is supported by the positive outcome in previous clinical trials following this dosing regimen.

Population kinetics of gentamicin in neonates.

A population kinetic analysis was carried out on sparse plasma gentamicin (GE) concentration data from 469 neonates obtained as part of a routine therapeutic drug monitoring (TDM) programme in the hospital neonatology unit. The best predictors of the kinetic parameters of the monoexponential model, volume of distribution (Vd) and clearance (CL), were the weight (WT) and gestational age (GA). Vd of the neonates was only related to WT, whereas the half-life was only related to the GA. The clinical implications of the findings are that the initial dose per WT administered to premature infants should be larger than that for term infants, because of a larger Vd per unit WT, and the intervals between maintenance doses should extended due to the prolonged half-life. Apart from these general guidelines, specific dose recommendations are also given.

Method for individualizing patient care for chronic obstructive pulmonary disease patients.

Chronic obstructive pulmonary disease is a progressively debilitating disease that affects not only the patient's physical capabilities, but the patient's entire psychosocial network, including family and friends. A patient education program has been developed to assist each patient individually in dealing more effectively with all aspects of care.