A randomized, clinical trial investigating the use of a digital intervention to reduce delirium-associated agitation.

We aimed to determine if a novel digital therapeutic intervention could reduce agitation and unscheduled medication use in an adult delirious acute care population. Delirious participants were randomly allocated (1:1) to receive standard of care plus a single 4-hour exposure to the digital intervention "MindfulGarden", which uses a screen-based delivery to display a nature landscape with dynamic adjustment of screen content in response to movement and sound or standard of care only. Between March 2021 and January 2022, 73 participants were enrolled with 70 completing the trial protocol and included in the final analysis with a mean age of 61 years and 68% being male (35 intervention, 35 control). Mean RASS was significantly lower across the 4-hour study period in the intervention arm 0.3 (0.85) vs 0.9 (0.93), p = 0.01. Exposure to a nature-based dynamic digital intervention showed benefits in agitation reduction.

Locking solutions for prevention of central venous access device complications in the adult critical care population: A systematic review.

BACKGROUND: The objective of this systematic review is to determine the extent and quality of evidence for use of different types of locking fluids to prevent central venous access device complications in adult critical care patients. Specifically, rates of catheter-related bloodstream infection, colonization, and occlusion were considered. All types of devices were included in the review: central venous catheters, peripherally- inserted central catheters and hemodialysis catheters. METHODS: Eligibility criteria. Papers had to include adult (>18 years old) critical care patients, be experimental trials, conducted in North America and Europe, and published in peer-reviewed journals from 2010 onwards. Information sources. A search of Medline and EMBASE databases was performed. The search is current as of November 28th, 2022. Risk of bias. The Cochrane Risk of Bias 2 and the Risk of Bias In Non-Randomized Studies of Intervention tools were used to assess the risk of bias in included studies. RESULTS: Included studies. A total of 240 paper titles and abstracts underwent review, of these seven studies met the final criteria for quality appraisal. A total of three studies earned a low risk of bias quality appraisal. DISCUSSION: Limitations of evidence. Due to heterogeneity of types of locking fluids investigated and small number of studies identified, meta-analysis of results was not possible. Interpretation. Out of all fluids investigated, only citrate 46.7% was found to statistically reduce central venous access device complication rates. This systematic review has also identified a gap in the literature regarding studies of locking fluids that are adequately powered in this patient population. FUTURE DIRECTIONS: Future research should include investigations and use of novel locking fluids with more effective properties against complications. It is imperative that future studies are adequately powered, randomized controlled trials in this patient population to facilitate optimal evidence-based care.

Transvenous stimulation yields exposure-dependent protection from ventilator-induced diaphragm atrophy.

Mechanical ventilation (MV)-induced diaphragmatic atrophy can contribute to weaning difficulties. A temporary transvenous diaphragm neurostimulation (TTDN) device that elicits diaphragm contractions has previously been shown to mitigate atrophy during MV in a preclinical model; however, its effects on different myofiber types remain unknown. It is important to examine these effects, as each myofiber type plays a role in the range of diaphragmatic movements to ensure successful liberation from MV. Eighteen pigs were assigned to one of three ventilation conditions for 50 hours: MV-Only and TTDN contracting the diaphragm every other breath or every breath synchronously with MV (TTDN50% + MV and TTDN100% + MV, respectively). Six pigs were assigned to a never-ventilated, never-paced (NV-NP) group. Diaphragm biopsies were fiber-typed, and myofiber cross-sectional areas were measured and normalized to subject weight. There were effect differences based on TTDN exposure. The TTDN100% + MV group showed less atrophy in Type 2A and 2X myofibers than the TTDN50% + MV group, relative to the NV-NP group. The TTDN50% + MV animals showed less MV-induced atrophy in type 1 myofibers than TTDN100% + MV animals. Additionally, there were no significant differences in proportions of myofiber types between each condition. TTDN applied synchronously with MV for 50 hours mitigates MV-induced atrophy in all myofiber types, with no evidence of stimulation-induced myofiber-type shift. At this stimulation profile, enhanced protection for type 1 myofibers and type 2 myofibers was seen when diaphragm contractions occurred every other breath and every breath, respectively.NEW & NOTEWORTHY This research adds to our current understanding of applying temporary transvenous diaphragmatic neurostimulation (TTDN) synchronously with mechanical ventilation by examining its diaphragm-myofiber effects. We observed that using this therapy for 50 hours with mechanical ventilation not only mitigated ventilator-induced atrophy on all myofiber types with dose effects, it also did not invoke alterations in diaphragm myofiber type proportions. These findings suggest that applying TTDN with mechanical ventilation at different doses represents its broad spectrum use and viability as a diaphragm protective strategy.

Phrenic nerve stimulation mitigates hippocampal and brainstem inflammation in an ARDS model.

Rationale: In porcine healthy-lung and moderate acute respiratory distress syndrome (ARDS) models, groups that received phrenic nerve stimulation (PNS) with mechanical ventilation (MV) showed lower hippocampal apoptosis, and microglia and astrocyte percentages than MV alone. Objectives: Explore whether PNS in combination with MV for 12 h leads to differences in hippocampal and brainstem tissue concentrations of inflammatory and synaptic markers compared to MV-only animals. Methods: Compare tissue concentrations of inflammatory markers (IL-1α, IL-1ß, IL-6, IL-8, IL-10, IFN-γ, TNFα and GM-CSF), pre-synaptic markers (synapsin and synaptophysin) and post-synaptic markers (disc-large-homolog 4, N-methyl-D-aspartate receptors 2A and 2B) in the hippocampus and brainstem in three groups of mechanically ventilated pigs with injured lungs: MV only (MV), MV plus PNS every other breath (MV + PNS50%), and MV plus PNS every breath (MV + PNS100%). MV settings in volume control were tidal volume 8 ml/kg, and positive end-expiratory pressure 5 cmH2O. Moderate ARDS was achieved by infusing oleic acid into the pulmonary artery. Measurements and Main Results: Hippocampal concentrations of GM-CSF, N-methyl-D-aspartate receptor 2B, and synaptophysin were greater in the MV + PNS100% group compared to the MV group, p = 0.0199, p = 0.0175, and p = 0.0479, respectively. The MV + PNS100% group had lower brainstem concentrations of IL-1ß, and IL-8 than the MV group, p = 0.0194, and p = 0.0319, respectively; and greater brainstem concentrations of IFN-γ and N-methyl-D-aspartate receptor 2A than the MV group, p = 0.0329, and p = 0.0125, respectively. Conclusion: In a moderate-ARDS porcine model, MV is associated with hippocampal and brainstem inflammation, and phrenic nerve stimulation on every breath mitigates that inflammation.

Risk factors for ventilator-induced-lung injury develop three to five times faster after a single episode of lung injury.

Introduction: Mechanical ventilator breaths provided to deeply sedated patients have an abnormal volume distribution, encouraging alveolar collapse in dependent regions and promoting alveolar overdistention in non-dependent regions. Collapse and overdistention both start with the first breath and worsen over time, driving ventilator-induced lung injury (VILI). This is exacerbated when the lung is already injured or has increased heterogeneity. Our study investigated the impact of a single episode of lung injury on lung mechanics and the risk factors for ventilator-induced injury, compared with non-injured lungs. Methods: Two groups of pigs were sedated and ventilated using lung-protective volume-controlled mode at 8 mL/kg, positive end-expiratory pressure (PEEP) 5 cmH2O, with respiratory rate and FiO2 set to maintain normal blood gas values. Animals in one group were ventilated for 50 h (50-Hour MV group, n=10). Animals in the second group had lung injury induced using oleic acid and were ventilated for 12 h post-injury (LI MV group, n=6). Both groups were compared with a never-ventilated control group (NV, n=6). Lung mechanics and injury were measured using electrical impedance tomography, esophageal pressure monitoring and tissue histology. Results: End-expiratory lung-volume loss was greater in the 50-Hour MV group (P<0.05). Plateau pressure, driving pressure and lung injury score were higher in the LI MV group, (P<0.05). Conclusion: Risk factors for VILI developed three- to five-times faster in the group with injured lungs, demonstrating that a single lung-injury episode substantially increased the risk of VILI, compared with normal lungs, despite using a lung-protective mechanical ventilation protocol.

The use of ketamine as a neuroprotective agent following cardiac arrest: A scoping review of current literature.

AIMS: The objective of this article is to summarize the state of the literature surrounding the use of ketamine as a neuroprotective agent following cardiac arrest. METHODS: Five electronic databases were used to search for studies related to the use of ketamine for neuroprotection following cardiac arrest. This search was performed once in May 2020, and an updated search was conducted in May 2021 and March 2022. RESULTS: All searches combined retrieved 181 results; no clinical trials were identified. As such, the authors were limited to writing a scoping review of the literature rather than a systematic review. CONCLUSIONS: The current state of the literature describes the mechanism of action of ketamine as a neuroprotective agent through its action as an NMDA antagonist. There is evidence of its efficacy as a neuroprotective agent in preclinical models of cardiac arrest. Current published clinical work supports the use of ketamine ameliorating neurologic outcomes in other conditions such as epilepsy, traumatic brain injury, and depression. The current state of the literature is reflective of the notion that the use of ketamine following cardiac arrest may result in improved neurologic outcomes. Future research directions should focus on the use of ketamine as a possible clinical intervention following cardiac arrest.

Negative-pressure-assisted ventilation lowers driving pressure and mechanical power in an ARDS model.

Increased lung heterogeneity from regional alveolar collapse drives ventilator-induced lung injury in patients with acute respiratory distress syndrome (ARDS). New methods of preventing this injury require study. Our study objective was to determine whether the combination of temporary transvenous diaphragm neurostimulation (TTDN) with standard-of-care volume-control mode ventilation changes lung mechanics, reducing ventilator-induced lung injury risk in a preclinical ARDS model. Moderate ARDS was induced using oleic acid administered into the pulmonary artery in pigs, which were ventilated for 12 h postinjury using volume-control mode at 8 mL/kg, positive end-expiratory pressure (PEEP) 5 cmH2O, with respiratory rate and [Formula: see text] set to achieve normal arterial blood gases. Two groups received TTDN, either every second breath [mechanical ventilation (MV) + TTDN50%, n = 6] or every breath (MV + TTDN100%, n = 6). A third group received volume-control ventilation only (MV, n = 6). At study-end, [Formula: see text]/[Formula: see text] was highest and alveolar-arterial oxygen (A-a) gradient was lowest for MV + TTDN100% (P < 0.05). MV + TTDN100% had the smallest end-expiratory lung volume loss and lowest extravascular lung water at study-end (P < 0.05). Static lung compliance was highest and transpulmonary driving pressure was lowest at baseline, postinjury, and study-end in MV + TTDN100% (P < 0.05). The total exposure to transpulmonary driving pressure, mechanical power, and mechanical work was the lowest in MV + TTDN100% (P < 0.05). Lung injury score and total inflammatory cytokine concentration in lung tissue were the lowest in MV + TTDN100% (P < 0.05). Volume-control ventilation plus transvenous diaphragm neurostimulation on every breath improved [Formula: see text]/[Formula: see text], A-a gradient, and alveolar homogeneity, as well as reduced driving pressure, mechanical power, and mechanical work, and resulted in lower lung injury scores and tissue cytokine concentrations in a preclinical ARDS model.NEW & NOTEWORTHY Combining temporary transvenous diaphragm neurostimulation with volume-control ventilation on every breath, called negative-pressure-assisted ventilation, improved gas exchange and alveolar homogeneity in a preclinical model of moderate ARDS. Transpulmonary driving pressure, mechanical power, and mechanical work reductions were observed and resulted in lower lung injury scores and tissue cytokine concentrations in the every-breath-neurostimulation group compared with volume-control ventilation only. Negative-pressure-assisted ventilation is an exciting new potential tool to reduce ventilator-induced lung injury in patients with ARDS.

Central venous access device locking practices in the adult critical care setting: a single-centre, observational study establishing duration of locking per catheter lumen.

PURPOSE: Central line complications remain a problem in critical care patient populations. Various interventions to prevent or treat complications, such as central line-associated bloodstream infection and occlusion, have been the focus of recent research. Although alternative catheter locking solutions have been shown to be effective in other patient populations, their applicability to the critical care setting remains unclear. Due to the high acuity of critical care patients, it is uncertain whether their central lines remain locked for a duration long enough for alternative locking solutions to provide any effect. METHODS: This single-centre, prospective, observational study aimed to gather information about the length of time central line lumens remain in a locked state in the average critical care patient. Baseline rates of various central line complications were also tracked. RESULTS: Results of this study indicate that the majority of central lines will have at least one lumen locked for an average of 36.6% of their time in situ. CONCLUSIONS: It is anticipated that this length of time provides enough exposure for alternative locking solutions to potentially make a difference in central line complications in this patient population. Results of this study can be used for planning future multi-centre, randomized controlled trials investigating the efficacy of novel central line locking solutions to prevent central line complications in critically ill patients.

Control of Line Complications with KiteLock (CLiCK) in the critical care unit: study protocol for a multi-center, cluster-randomized, double-blinded, crossover trial investigating the effect of a novel locking fluid on central line complications in the critical care population.

BACKGROUND: Insertion of a central venous access device (CVAD) allows clinicians to easily access the circulation of a patient to administer life-saving interventions. Due to their invasive nature, CVADs are prone to complications such as bacterial biofilm production and colonization, catheter-related bloodstream infection, occlusion, and catheter-related venous thrombosis. A CVAD is among the most common interventions for patients in the intensive care unit (ICU), exposing this vulnerable population to the risk of nosocomial infection and catheter occlusion. The current standard of care involves the use of normal saline as a catheter locking solution for central venous catheters (CVCs) and peripherally inserted central catheter (PICC) lines, and a citrate lock for hemodialysis catheters. Saline offers little prophylactic measures against catheter complications. Four percent of tetrasodium ethylenediaminetetraacetic acid (EDTA) fluid (marketed as KiteLock Sterile Locking Solution™) is non-antibiotic, possesses antimicrobial, anti-biofilm, and anti-coagulant properties, and is approved by Health Canada as a catheter locking solution. As such, it may be a superior CVAD locking solution than the present standard of care lock in the ICU patient population. METHODS: Our team proposes to fill this knowledge gap by performing a multi-center, cluster-randomized, crossover trial evaluating the impact of 4% tetrasodium EDTA on a primary composite outcome of the incidence rate of central line-associated bloodstream infection (CLABSI), catheter occlusion leading to removal, and use of alteplase to resolve catheter occlusion compared to the standard of care. The study will be performed at five critical care units. DISCUSSION: If successful, the results of this study can serve as evidence for a shift of standard of care practices to include EDTA locking fluid in routine CVAD locking procedures. Completion of this study has the potential to improve CVAD standard of care to become safer for patients, as well as provides an opportunity to decrease strain on healthcare budgets related to treating preventable CVAD complications. Success and subsequent implementation of this intervention in the ICU may also be extrapolated to other patient populations with heavy CVAD use including hemodialysis, oncology, parenteral nutrition, and pediatric patient populations. On a global scale, eradicating biofilm produced by antibiotic-resistant bacteria may serve to lessen the threat of "superbugs" and contribute to international initiatives supporting the termination of antibiotic overuse. TRIAL REGISTRATION: ClinicalTrials.gov NCT04548713, registered on September 9th, 2020.

Transvenous Diaphragm Neurostimulation Mitigates Ventilation-associated Brain Injury.

Rationale: Mechanical ventilation (MV) is associated with hippocampal apoptosis and inflammation, and it is important to study strategies to mitigate them. Objectives: To explore whether temporary transvenous diaphragm neurostimulation (TTDN) in association with MV mitigates hippocampal apoptosis and inflammation after 50 hours of MV. Methods: Normal-lung porcine study comparing apoptotic index, inflammatory markers, and neurological-damage serum markers between never-ventilated subjects, subjects undergoing 50 hours of MV plus either TTDN every other breath or every breath, and subjects undergoing 50 hours of MV (MV group). MV settings in volume control were Vt of 8 ml/kg, and positive end-expiratory pressure of 5 cm H2O. Measurements and Main Results: Apoptotic indices, microglia percentages, and reactive astrocyte percentages were greater in the MV group in comparison with the other groups (P < 0.05). Transpulmonary pressure at baseline and at study end were both lower in the group receiving TTDN every breath, but lung injury scores and systemic inflammatory markers were not different between the groups. Serum concentrations of four neurological-damage markers were lower in the group receiving TTDN every breath than in the MV group (P < 0.05). Heart rate variability declined significantly in the MV group and increased significantly in both TTDN groups over the course of the experiments. Conclusions: Our study found that mechanical ventilation is associated with hippocampal apoptosis and inflammation, independent of lung injury and systemic inflammation. Also, in a porcine model, TTDN results in neuroprotection after 50 hours, and the degree of neuroprotection increases with greater exposure to TTDN.

Diaphragm neurostimulation during mechanical ventilation reduces atelectasis and transpulmonary plateau pressure, preserving lung homogeneity and [Formula: see text]/[Formula: see text].

Tidal volume delivered by mechanical ventilation to a sedated patient is distributed in a nonphysiological pattern, causing atelectasis (underinflation) and overdistension (overinflation). Activation of the diaphragm during controlled mechanical ventilation in these sedated patients may provide a method to reduce atelectasis and alveolar inhomogeneity, protecting the lungs from ventilator-induced lung injury while also protecting the diaphragm by preventing ventilator-induced diaphragm dysfunction. We studied the hypothesis that diaphragm contractions elicited by transvenous phrenic nerve stimulation, delivered in synchrony with volume-control ventilation, would reduce atelectasis and lung inhomogeneity in a healthy, normal lung pig model. Twenty-five large pigs were ventilated for 50 h with lung-protective volume-control ventilation combined with synchronous transvenous phrenic-nerve neurostimulation on every breath, or every second breath. This was compared to lung-protective ventilation alone. Lung mechanics and ventilation pressures were measured using esophageal pressure manometry and electrical impedance tomography. Alveolar homogeneity was measured using alveolar chord length of preserved lung tissue. Lung injury was measured using inflammatory cytokine concentration in bronchoalveolar lavage fluid and serum. We found that diaphragm neurostimulation on every breath preserved [Formula: see text]/[Formula: see text] and significantly reduced the loss of end-expiratory lung volume after 50 h of mechanical ventilation. Neurostimulation on every breath reduced plateau and driving pressures, improved both static and dynamic compliance and resulted in less alveolar inhomogeneity. These findings support that temporary transvenous diaphragm neurostimulation during volume-controlled, lung-protective ventilation may offer a potential method to provide both lung- and diaphragm-protective ventilation.NEW & NOTEWORTHY Temporary transvenous diaphragm neurostimulation has been shown to mitigate diaphragm atrophy in a preclinical model. This study contributes to this work by demonstrating that diaphragm neurostimulation can also offer lung protection from ventilator injury, providing a potential solution to the dilemma of lung- versus diaphragm-protective ventilation. Our findings show that neurostimulation on every breath preserved [Formula: see text]/[Formula: see text], end-expiratory lung volume, alveolar homogeneity, and required lower pressures than lung-protective ventilation over 50 h in healthy pigs.

Brain injury after 50 h of lung-protective mechanical ventilation in a preclinical model.

Mechanical ventilation is the cornerstone of the Intensive Care Unit. However, it has been associated with many negative consequences. Recently, ventilator-induced brain injury has been reported in rodents under injurious ventilation settings. Our group wanted to explore the extent of brain injury after 50 h of mechanical ventilation, sedation and physical immobility, quantifying hippocampal apoptosis and inflammation, in a normal-lung porcine study. After 50 h of lung-protective mechanical ventilation, sedation and immobility, greater levels of hippocampal apoptosis and neuroinflammation were clearly observed in the mechanically ventilated group, in comparison to a never-ventilated group. Markers in the serum for astrocyte damage and neuronal damage were also higher in the mechanically ventilated group. Therefore, our study demonstrated that considerable hippocampal insult can be observed after 50 h of lung-protective mechanical ventilation, sedation and physical immobility.