BackgroundFluid therapy is a common intervention in critically ill patients. It is increasingly recognised that deresuscitation is an essential part of fluid therapy and delayed deresuscitation is associated with longer invasive ventilation and length of intensive care unit (ICU) stay. However, optimal timing and rate of deresuscitation remain unclear. Lung ultrasound (LUS) may be used to identify fluid overload. We hypothesise that daily LUS-guided deresuscitation is superior to deresuscitation without LUS in critically ill patients expected to undergo invasive ventilation for more than 24 h in terms of ventilator free-days and being alive at day 28.MethodsThe “effect of lung ultrasound-guided fluid deresuscitation on duration of ventilation in intensive care unit patients” (CONFIDENCE) is a national, multicentre, open-label, randomised controlled trial (RCT) in adult critically ill patients that are expected to be invasively ventilated for at least 24 h. Patients with conditions that preclude a negative fluid balance or LUS examination are excluded. CONFIDENCE will operate in 10 ICUs in the Netherlands and enrol 1000 patients. After hemodynamic stabilisation, patients assigned to the intervention will receive daily LUS with fluid balance recommendations. Subjects in the control arm are deresuscitated at the physician’s discretion without the use of LUS. The primary endpoint is the number of ventilator-free days and being alive at day 28. Secondary endpoints include the duration of invasive ventilation; 28-day mortality; 90-day mortality; ICU, in hospital and total length of stay; cumulative fluid balance on days 1–7 after randomisation and on days 1–7 after start of LUS examination; mean serum lactate on days 1–7; the incidence of reintubations, chest drain placement, atrial fibrillation, kidney injury (KDIGO stadium ≥ 2) and hypernatremia; the use of invasive hemodynamic monitoring, and chest-X-ray; and quality of life at day 28.DiscussionThe CONFIDENCE trial is the first RCT comparing the effect of LUS-guided deresuscitation to routine care in invasively ventilated ICU patients. If proven effective, LUS-guided deresuscitation could improve outcomes in some of the most vulnerable and resource-intensive patients in a manner that is non-invasive, easy to perform, and well-implementable.Trial registrationClinicalTrials.gov NCT05188092. Registered since January 12, 2022
MULTIFILE
BACKGROUND: Increasing evidence indicates the potential benefits of restricted fluid management in critically ill patients. Evidence lacks on the optimal fluid management strategy for invasively ventilated COVID-19 patients. We hypothesized that the cumulative fluid balance would affect the successful liberation of invasive ventilation in COVID-19 patients with acute respiratory distress syndrome (ARDS).METHODS: We analyzed data from the multicenter observational 'PRactice of VENTilation in COVID-19 patients' study. Patients with confirmed COVID-19 and ARDS who required invasive ventilation during the first 3 months of the international outbreak (March 1, 2020, to June 2020) across 22 hospitals in the Netherlands were included. The primary outcome was successful liberation of invasive ventilation, modeled as a function of day 3 cumulative fluid balance using Cox proportional hazards models, using the crude and the adjusted association. Sensitivity analyses without missing data and modeling ARDS severity were performed.RESULTS: Among 650 patients, three groups were identified. Patients in the higher, intermediate, and lower groups had a median cumulative fluid balance of 1.98 L (1.27-7.72 L), 0.78 L (0.26-1.27 L), and - 0.35 L (- 6.52-0.26 L), respectively. Higher day 3 cumulative fluid balance was significantly associated with a lower probability of successful ventilation liberation (adjusted hazard ratio 0.86, 95% CI 0.77-0.95, P = 0.0047). Sensitivity analyses showed similar results.CONCLUSIONS: In a cohort of invasively ventilated patients with COVID-19 and ARDS, a higher cumulative fluid balance was associated with a longer ventilation duration, indicating that restricted fluid management in these patients may be beneficial. Trial registration Clinicaltrials.gov ( NCT04346342 ); Date of registration: April 15, 2020.
Many affective experiences and learning processes including attachment patterns from early developmental phases manifest during psychotherapy. The first 15 min in art therapy can potentially reveal clients’ preferred ways of processing information or Expressive Therapies Continuum components, attachment patterns in the material handling process, and emotion regulation strategies during art making. This article discusses how, through clients’ choice of materials and manner of interaction with those materials, information about attachment patterns and preferred emotion regulation is available in art therapy. Paying close attention to the first image and material interaction provides crucial information that will guide the goals and course of art therapy. Two case vignettes demonstrate that within the first 15 min of art therapy information is readily gathered about attachment styles, Expressive Therapies Continuum components, emotion regulation, and the course of art therapy.
Biotherapeutic medicines such as peptides, recombinant proteins, and monoclonal antibodies have successfully entered the market for treating or providing protection against chronic and life-threatening diseases. The number of relevant commercial products is rapidly increasing. Due to degradation in the gastro-intestinal tract, protein-based drugs cannot be taken orally but need to be administered via alternative routes. The parenteral injection is still the most widely applied administration route but therapy compliance of injection-based pharmacotherapies is a concern. Long-acting injectable (LAI) sustained release dosage forms such as microparticles allow less frequent injection to maintain plasma levels within their therapeutic window. Spider Silk Protein and Poly Lactic-co-Glycolic Acid (PLGA) have been attractive candidates to fabricate devices for drug delivery applications. However, conventional microencapsulation processes to manufacture microparticles encounter drawbacks such as protein activity loss, unacceptable residual organic solvents, complex processing, and difficult scale-up. Supercritical fluids (SCF), such as supercritical carbon dioxide (scCO2), have been used to produce protein-loaded microparticles and is advantageous over conventional methods regarding adjustable fluid properties, mild operating conditions, interfacial tensionless, cheap, non-toxicity, easy downstream processing and environment-friendly. Supercritical microfluidics (SCMF) depict the idea to combine strengths of process scale reduction with unique properties of SCF. Concerning the development of long-acting microparticles for biological therapeutics, SCMF processing offers several benefits over conventionally larger-scale systems such as enhanced control on fluid flow and other critical processing parameters such as pressure and temperature, easy modulation of product properties (such as particle size, morphology, and composition), cheaper equipment build-up, and convenient parallelization for high-throughput production. The objective of this project is to develop a mild microfluidic scCO2 based process for the production of long-acting injectable protein-loaded microparticles with, for example, Spider Silk Protein or PLGA as the encapsulating materials, and to evaluate the techno-economic potential of such SCMF technology for practical & industrial production.
Biotherapeutic medicines such as peptides, recombinant proteins, and monoclonal antibodies have successfully entered the market for treating or providing protection against chronic and life-threatening diseases. The number of relevant commercial products is rapidly increasing. Due to degradation in the gastro-intestinal tract, protein-based drugs cannot be taken orally but need to be administered via alternative routes. The parenteral injection is still the most widely applied administration route but therapy compliance of injection-based pharmacotherapies is a concern. Long-acting injectable (LAI) sustained release dosage forms such as microparticles allow less frequent injection to maintain plasma levels within their therapeutic window. Spider Silk Protein and Poly Lactic-co-Glycolic Acid (PLGA) have been attractive candidates to fabricate devices for drug delivery applications. However, conventional microencapsulation processes to manufacture microparticles encounter drawbacks such as protein activity loss, unacceptable residual organic solvents, complex processing, and difficult scale-up. Supercritical fluids (SCF), such as supercritical carbon dioxide (scCO2), have been used to produce protein-loaded microparticles and is advantageous over conventional methods regarding adjustable fluid properties, mild operating conditions, interfacial tensionless, cheap, non-toxicity, easy downstream processing and environment-friendly. Supercritical microfluidics (SCMF) depict the idea to combine strengths of process scale reduction with unique properties of SCF. Concerning the development of long-acting microparticles for biological therapeutics, SCMF processing offers several benefits over conventionally larger-scale systems such as enhanced control on fluid flow and other critical processing parameters such as pressure and temperature, easy modulation of product properties (such as particle size, morphology, and composition), cheaper equipment build-up, and convenient parallelization for high-throughput production. The objective of this project is to develop a mild microfluidic scCO2 based process for the production of long-acting injectable protein-loaded microparticles with, for example, Spider Silk Protein or PLGA as the encapsulating materials, and to evaluate the techno-economic potential of such SCMF technology for practical & industrial production.
