The dorsal cochlear nucleus (DCN) is a first relay of the central auditory system as well as a site for integration of multimodal information. Vesicular glutamate transporters VGLUT-1 and VGLUT-2 selectively package glutamate into synaptic vesicles and are found to have different patterns of organization in the DCN. Whereas auditory nerve fibers predominantly co-label with VGLUT-1, somatosensory inputs predominantly co-label with VGLUT-2. Here, we used retrograde and anterograde transport of fluorescent conjugated dextran amine (DA) to demonstrate that the lateral vestibular nucleus (LVN) exhibits ipsilateral projections to both fusiform and deep layers of the rat DCN. Stimulating the LVN induced glutamatergic synaptic currents in fusiform cells and granule cell interneurones. We combined the dextran amine neuronal tracing method with immunohistochemistry and showed that labeled projections from the LVN are co-labeled with VGLUT-2 by contrast to VGLUT-1. Wistar rats were exposed to a loud single tone (15 kHz, 110 dB SPL) for 6 hours. Five days after acoustic overexposure, the level of expression of VGLUT-1 in the DCN was decreased whereas the level of expression of VGLUT-2 in the DCN was increased including terminals originating from the LVN. VGLUT-2 mediated projections from the LVN to the DCN are likely to play a role in the head position in response to sound. Amplification of VGLUT-2 expression after acoustic overexposure could be a compensatory mechanism from vestibular inputs in response to hearing loss and to a decrease of VGLUT-1 expression from auditory nerve fibers.

Due to the coronavirus disease 2019 pandemic, the number of coronavirus disease 2019-associated acute respiratory distress syndrome is rapidly increasing. The heterogeneity of coronavirus disease 2019-associated acute respiratory distress syndrome contributes to the complexity of managing patients. Here we described two patients with coronavirus disease 2019-associated acute respiratory distress syndrome showing that the bedside physiological approach including careful evaluation of respiratory system mechanics and visualization of ventilation with electrical impedance tomography was useful to individualize ventilatory management.

Objectives: Patient-ventilator asynchrony is often observed during mechanical ventilation and is associated with higher mortality. We hypothesized that patient-ventilator asynchrony causes lung and diaphragm injury and dysfunction. Design: Prospective randomized animal study. Setting: University research laboratory. Subjects: Eighteen New Zealand White rabbits. Interventions: Acute respiratory distress syndrome (ARDS) model was established by depleting surfactants. Each group (assist control, breath stacking, and reverse triggering) was simulated by phrenic nerve stimulation. The effects of each group on lung function, lung injury (wet-to-dry lung weight ratio, total protein, and interleukin-6 in bronchoalveolar lavage), diaphragm function (diaphragm force generation curve), and diaphragm injury (cross-sectional area of diaphragm muscle fibers, histology) were measured. Diaphragm RNA sequencing was performed using breath stacking and assist control (n = 2 each). Measurements and Main Results: Inspiratory effort generated by phrenic nerve stimulation was small and similar among groups (esophageal pressure swing ≈ –2.5 cm H2O). Breath stacking resulted in the largest tidal volume (>10 mL/kg) and highest inspiratory transpulmonary pressure, leading to worse oxygenation, worse lung compliance, and lung injury. Reverse triggering did not cause lung injury. No asynchrony events were observed in assist control, whereas eccentric contractions occurred in breath stacking and reverse triggering, but more frequently in breath stacking. Breath stacking and reverse triggering significantly reduced diaphragm force generation. Diaphragmatic histology revealed that the area fraction of abnormal muscle was ×2.5 higher in breath stacking (vs assist control) and ×2.1 higher in reverse triggering (vs assist control). Diaphragm RNA sequencing analysis revealed that genes associated with muscle differentiation and contraction were suppressed, whereas cytokine- and chemokine-mediated proinflammatory responses were activated in breath stacking versus assist control. Conclusions: Breath stacking caused lung and diaphragm injury, whereas reverse triggering caused diaphragm injury. Thus, careful monitoring and management of patient-ventilator asynchrony may be important to minimize lung and diaphragm injury from spontaneous breathing in ARDS.

Background Heterogeneity is an inherent nature of ARDS. Recruitment-to-inflation ratio has been developed to identify the patients who has lung recruitablity. This technique might be useful to identify the patients that match specific interventions, such as higher positive end-expiratory pressure (PEEP) or prone position or both. We aimed to evaluate the physiological effects of PEEP and body position on lung mechanics and regional lung inflation in COVID-19-associated ARDS and to propose the optimal ventilatory strategy based on recruitment-to-inflation ratio. Methods Patients with COVID-19-associated ARDS were consecutively enrolled. Lung recruitablity (recruitment-to-inflation ratio) and regional lung inflation (electrical impedance tomography [EIT]) were measured with a combination of body position (supine or prone) and PEEP (low 5 cmH2O or high 15 cmH2O). The utility of recruitment-to-inflation ratio to predict responses to PEEP were examined with EIT. Results Forty-three patients were included. Recruitment-to-inflation ratio was 0.68 (IQR 0.52–0.84), separating high recruiter versus low recruiter. Oxygenation was the same between two groups. In high recruiter, a combination of high PEEP with prone position achieved the highest oxygenation and less dependent silent spaces in EIT (vs. low PEEP in both positions) without increasing non-dependent silent spaces in EIT. In low recruiter, low PEEP in prone position resulted in better oxygenation (vs. both PEEPs in supine position), less dependent silent spaces (vs. low PEEP in supine position) and less non-dependent silent spaces (vs. high PEEP in both positions). Recruitment-to-inflation ratio was positively correlated with the improvement in oxygenation and respiratory system compliance, the decrease in dependent silent spaces, and was inversely correlated with the increase in non-dependent silent spaces, when applying high PEEP. Conclusions Recruitment-to-inflation ratio may be useful to personalize PEEP in COVID-19-associated ARDS. Higher PEEP in prone position and lower PEEP in prone position decreased the amount of dependent silent spaces (suggesting lung collapse) without increasing the amount of non-dependent silent spaces (suggesting overinflation) in high recruiter and in low recruiter, respectively.

Background Spontaneous breathing potentially injures lungs and diaphragm when spontaneous effort is vigorous in acute respiratory distress syndrome (ARDS) while immobility also has risks of Intensive Care Unit (ICU) acquired weakness and diaphragm atrophy. Thus, ventilatory strategy to mitigate strong spontaneous effort should be promptly established without a systemic use of neuromuscular blocking agent. Here, we investigated the impacts of positive end-expiratory pressure (PEEP) and body position on the capacity of force generation from diaphragm following bilateral phrenic nerve stimulations in a rabbit ARDS model. Methods Using lung-injured rabbits, we measured 1) transdiaphragmatic pressure by bilateral phrenic nerve stimulation and 2) end-expiratory lung volume using computed tomography, under two different levels of PEEP (high, low) and body positions (supine, prone). Results Overall, transdiaphragmatic pressure was the highest at low PEEP in supine position and the lowest at high PEEP in prone position. Compared to values in low PEEP + supine, transdiaphragmatic pressure was significantly reduced by either prone alone (the same PEEP) or increasing PEEP alone (the same position) or both combinations. End-expiratory lung volume was significantly increased with increasing PEEP in both positions, but it was not altered by body position. Interpretation The capacity of force generation from diaphragm was modulated by PEEP and body position during mechanical ventilation in ARDS. Higher PEEP or prone position per se or both was effective to decrease the force generation from diaphragm.

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