TGB and DE were responsible for hypothesis generation. TGB, SCR and ECR were responsible for the conception of this study. TGB, SCR, ECR and MG contributed to study design and data interpretation. TGB, ECR, SCR and MG were responsible for writing the article. TGB, ECR, KCF, MO, SCR and MN performed data acquisition. TGB, ECR, MO, SCR and MN conducted data analysis. All authors have agreed with the final version of the manuscript before submission.

Tidal volume delivered by mechanical ventilation to a sedated patient is distributed in a non-physiological pattern, causing atelectasis (underinflation) and overdistension (overinflation). Activation of the diaphragm during mechanical ventilation provides a way 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 hours 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 PaO2/FiO2 and significantly reduced the loss of end-expiratory lung volume after 50 hours 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.

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.

Increased lung heterogeneity from regional alveolar collapse drives ventilator-induced lung injury in ARDS patients. New methods of preventing this injury require study. Our study objective was to determine whether the combination of temporary transvenous diaphragm neurostimulation 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 hours post-injury using volume-control mode at 8 ml/kg, PEEP 5 cmH2O, with respiratory rate and FiO2 set to achieve normal arterial blood gases. Two groups received TTDN, either every second breath (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, PaO2/FiO2 was highest and alveolar-arterial oxygen 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, post-injury, 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 PaO2/FiO2, 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.

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