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.

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.

Diaphragm Neurostimulation Mitigates Ventilation-Associated Brain Injury in a Preclinical Acute Respiratory Distress Syndrome Model.

In a porcine healthy lung model, temporary transvenous diaphragm neurostimulation (TTDN) for 50 hours mitigated hippocampal apoptosis and inflammation associated with mechanical ventilation (MV). HYPOTHESIS: Explore whether TTDN in combination with MV for 12 hours mitigates hippocampal apoptosis and inflammation in an acute respiratory distress syndrome (ARDS) preclinical model. METHODS AND MODELS: Compare hippocampal apoptosis, inflammatory markers, and serum markers of neurologic injury between never ventilated subjects and three groups of mechanically ventilated subjects with injured lungs: MV only (LI-MV), MV plus TTDN every other breath, and MV plus TTDN every breath. MV settings in volume control were tidal volume 8 mL/kg and positive end-expiratory pressure 5 cm H2O. Lung injury, equivalent to moderate ARDS, was achieved by infusing oleic acid into the pulmonary artery. RESULTS: Hippocampal apoptosis, microglia, and reactive-astrocyte percentages were similar between the TTDN-every-breath and never ventilated groups. The LI-MV group had a higher percentage of these measures than all other groups (p < 0.05). Transpulmonary driving pressure at study end was lower in the TTDN-every-breath group than in the LI-MV group; systemic inflammation and lung injury scores were not significantly different. The TTDN-every-breath group had considerably lower serum concentration of homovanillic acid (cerebral dopamine production surrogate) at study end than the LI-MV group (p < 0.05). Heart rate variability declined in the LI-MV group and increased in both TTDN groups (p < 0.05). INTERPRETATIONS AND CONCLUSIONS: In a moderate-ARDS porcine model, MV is associated with hippocampal apoptosis and inflammation, and TTDN mitigates that hippocampal apoptosis and inflammation.

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.

Systematic review of cognitive impairment and brain insult after mechanical ventilation.

We conducted a systematic review following the PRISMA protocol primarily to identify publications that assessed any links between mechanical ventilation (MV) and either cognitive impairment or brain insult, independent of underlying medical conditions. Secondary objectives were to identify possible gaps in the literature that can be used to inform future studies and move toward a better understanding of this complex problem. The preclinical literature suggests that MV is associated with neuroinflammation, cognitive impairment, and brain insult, reporting higher neuroinflammatory markers, greater evidence of brain injury markers, and lower cognitive scores in subjects that were ventilated longer, compared to those ventilated less, and to never-ventilated subjects. The clinical literature suggests an association between MV and delirium, and that delirium in mechanically ventilated patients may be associated with greater likelihood of long-term cognitive impairment; our systematic review found no clinical study that demonstrated a causal link between MV, cognitive dysfunction, and brain insult. More studies should be designed to investigate ventilation-induced brain injury pathways as well as any causative linkage between MV, cognitive impairment, and brain insult.

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.