Feasibility of neurally adjusted positive end-expiratory pressure in rabbits with early experimental lung injury

Background During conventional Neurally Adjusted Ventilatory Assist (NAVA), the electrical activity of the diaphragm (EAdi) is used for triggering and cycling-off inspiratory assist, with a fixed PEEP (so called “Triggered Neurally Adjusted Ventilatory Assist” or “tNAVA”). However, significant post-inspiratory activity of the diaphragm can occur, believed to play a role in maintaining end-expiratory lung volume. Adjusting pressure continuously, in proportion to both inspiratory and expiratory EAdi (Continuous NAVA, or cNAVA), would not only offer inspiratory assist for tidal breathing, but also may aid in delivering a “neurally adjusted PEEP”, and more specific breath-by-breath unloading. Methods Nine adult New Zealand white rabbits were ventilated during independent conditions of: resistive loading (RES1 or RES2), CO2 load (CO2) and acute lung injury (ALI), either via tracheotomy (INV) or non-invasively (NIV). There were a total of six conditions, applied in a non-randomized fashion: INV-RES1, INV-CO2, NIV-CO2, NIV-RES2, NIV-ALI, INV-ALI. For each condition, tNAVA was applied first (3 min), followed by 3 min of cNAVA. This comparison was repeated 3 times (repeated cross-over design). The NAVA level was always the same for both modes, but was newly titrated for each condition. PEEP was manually set to zero during tNAVA. During cNAVA, the assist during expiration was proportional to the EAdi. During all runs and conditions, ventilator-delivered pressure (Pvent), esophageal pressure (Pes), and diaphragm electrical activity (EAdi) were measured continuously. The tracings were analyzed breath-by-breath to obtain peak inspiratory and mean expiratory values. Results For the same peak Pvent, the distribution of inspiratory and expiratory pressure differed between tNAVA and cNAVA. For each condition, the mean expiratory Pvent was always higher (for all conditions 4.0 ± 1.1 vs. 1.1 ± 0.5 cmH2O, P < 0.01) in cNAVA than in tNAVA. Relative to tNAVA, mean inspiratory EAdi was reduced on average (for all conditions) by 19 % (range 14 %–25 %), p < 0.05. Mean expiratory EAdi was also lower during cNAVA (during INV-RES1, INV-CO2, INV-ALI, NIV-CO2 and NIV-ALI respectively, P < 0.05). The inspiratory Pes was reduced during cNAVA all 6 conditions (p < 0.05). Unlike tNAVA, during cNAVA the expiratory pressure was comparable with that predicted mathematically (mean difference of 0.2 ± 0.8 cmH2O). Conclusion Continuous NAVA was able to apply neurally adjusted PEEP, which led to a reduction in inspiratory effort compared to triggered NAVA.

Feasibility of neurally adjusted positive end-expiratory pressure in rabbits with early experimental lung injury

Background During conventional Neurally Adjusted Ventilatory Assist (NAVA), the electrical activity of the diaphragm (EAdi) is used for triggering and cycling-off inspiratory assist, with a fixed PEEP (so called “Triggered Neurally Adjusted Ventilatory Assist” or “tNAVA”). However, significant post-inspiratory activity of the diaphragm can occur, believed to play a role in maintaining end-expiratory lung volume. Adjusting pressure continuously, in proportion to both inspiratory and expiratory EAdi (Continuous NAVA, or cNAVA), would not only offer inspiratory assist for tidal breathing, but also may aid in delivering a “neurally adjusted PEEP”, and more specific breath-by-breath unloading. Methods Nine adult New Zealand white rabbits were ventilated during independent conditions of: resistive loading (RES1 or RES2), CO2 load (CO2) and acute lung injury (ALI), either via tracheotomy (INV) or non-invasively (NIV). There were a total of six conditions, applied in a non-randomized fashion: INV-RES1, INV-CO2, NIV-CO2, NIV-RES2, NIV-ALI, INV-ALI. For each condition, tNAVA was applied first (3 min), followed by 3 min of cNAVA. This comparison was repeated 3 times (repeated cross-over design). The NAVA level was always the same for both modes, but was newly titrated for each condition. PEEP was manually set to zero during tNAVA. During cNAVA, the assist during expiration was proportional to the EAdi. During all runs and conditions, ventilator-delivered pressure (Pvent), esophageal pressure (Pes), and diaphragm electrical activity (EAdi) were measured continuously. The tracings were analyzed breath-by-breath to obtain peak inspiratory and mean expiratory values. Results For the same peak Pvent, the distribution of inspiratory and expiratory pressure differed between tNAVA and cNAVA. For each condition, the mean expiratory Pvent was always higher (for all conditions 4.0 ± 1.1 vs. 1.1 ± 0.5 cmH2O, P < 0.01) in cNAVA than in tNAVA. Relative to tNAVA, mean inspiratory EAdi was reduced on average (for all conditions) by 19 % (range 14 %–25 %), p < 0.05. Mean expiratory EAdi was also lower during cNAVA (during INV-RES1, INV-CO2, INV-ALI, NIV-CO2 and NIV-ALI respectively, P < 0.05). The inspiratory Pes was reduced during cNAVA all 6 conditions (p < 0.05). Unlike tNAVA, during cNAVA the expiratory pressure was comparable with that predicted mathematically (mean difference of 0.2 ± 0.8 cmH2O). Conclusion Continuous NAVA was able to apply neurally adjusted PEEP, which led to a reduction in inspiratory effort compared to triggered NAVA.

Rapid activation of esophageal mechanoreceptors alters the pharyngeal phase of swallow: Evidence for inspiratory activity during swallow

Swallow is a complex behavior that consists of three coordinated phases: oral, pharyngeal, and esophageal. Esophageal distension (EDist) has been shown to elicit pharyngeal swallow, but the physiologic characteristics of EDist-induced pharyngeal swallow have not been specifically described. We examined the effect of rapid EDist on oropharyngeal swallow, with and without an oral water stimulus, in spontaneously breathing, sodium pentobarbital anesthetized cats (n = 5). Electromyograms (EMGs) of activity of 8 muscles were used to evaluate swallow: mylohyoid (MyHy), geniohyoid (GeHy), thyrohyoid (ThHy), thyropharyngeus (ThPh), thyroarytenoid (ThAr), cricopharyngeus (upper esophageal sphincter: UES), parasternal (PS), and costal diaphragm (Dia). Swallow was defined as quiescence of the UES with overlapping upper airway activity, and it was analyzed across three stimulus conditions: 1) oropharyngeal water infusion only, 2) rapid esophageal distension (EDist) only, and 3) combined stimuli. Results show a significant effect of stimulus condition on swallow EMG amplitude of the mylohyoid, geniohyoid, thyroarytenoid, diaphragm, and UES muscles. Collectively, we found that, compared to rapid cervical esophageal distension alone, the stimulus condition of rapid distension combined with water infusion is correlated with increased laryngeal adductor and diaphragm swallow-related EMG activity (schluckatmung), and post-swallow UES recruitment. We hypothesize that these effects of upper esophageal distension activate the brainstem swallow network, and function to protect the airway through initiation and/or modulation of a pharyngeal swallow response.

Deficiency of Biogenic Amines Modulates the Activity of Hypoglossal Nerve in the Reserpine Model of Parkinson’s Disease

The underlying cause of respiratory impairments appearing in Parkinson’s disease (PD) is still far from being elucidated. To better understand the pathogenesis of respiratory disorders appearing in PD, we studied hypoglossal (HG) and phrenic (PHR) motoneuron dysfunction in a rat model evoked with reserpine administration. After reserpine, a decrease in the baseline amplitude and minute HG activity was noted, and no depressive phase of the hypoxic ventilatory response was observed. The pre-inspiratory time of HG activity along with the ratio of pre-inspiratory time to total respiratory cycle time and the ratio of pre-inspiratory to inspiratory amplitude were significantly reduced during normoxia, hypoxia, and recovery compared to sham rats. We suggest that the massive depletion of not only dopamine, but above all noradrenaline and serotonin in the brainstem observed in our study, has an impact on the pre-inspiratory activity of the HG. The shortening of the pre-inspiratory activity of the HG in the reserpine model may indicate a serious problem with maintaining the correct diameter of the upper airways in the preparation phase for inspiratory effort and explain the development of obstructive sleep apnea in some PD patients. Therapies involving the supplementation of amine depletion other than dopamine should be considered.

Essential Role of the cVRG in the Generation of Both the Expiratory and Inspiratory Components of the Cough Reflex

As stated by Korpáš and Tomori (1979), cough is the most important airway protective reflex which provides airway defensive responses to nociceptive stimuli. They recognized that active expiratory efforts, due to the activation of caudal ventral respiratory group (cVRG) expiratory premotoneurons, are the prominent component of coughs. Here, we discuss data suggesting that neurons located in the cVRG have an essential role in the generation of both the inspiratory and expiratory components of the cough reflex. Some lines of evidence indicate that cVRG expiratory neurons, when strongly activated, may subserve the alternation of inspiratory and expiratory cough bursts, possibly owing to the presence of axon collaterals. Of note, experimental findings such as blockade or impairment of glutamatergic transmission to the cVRG neurons lead to the view that neurons located in the cVRG are crucial for the production of the complete cough motor pattern. The involvement of bulbospinal expiratory neurons seems unlikely since their activation affects differentially expiratory and inspiratory muscles, while their blockade does not affect baseline inspiratory activity. Thus, other types of cVRG neurons with their medullary projections should have a role and possibly contribute to the fine tuning of the intensity of inspiratory and expiratory efforts.

Phrenic-specific transcriptional programs shape respiratory motor output

The precise pattern of motor neuron (MN) activation is essential for the execution of motor actions; however, the molecular mechanisms that give rise to specific patterns of MN activity are largely unknown. Phrenic MNs integrate multiple inputs to mediate inspiratory activity during breathing and are constrained to fire in a pattern that drives efficient diaphragm contraction. We show that Hox5 transcription factors shape phrenic MN output by connecting phrenic MNs to inhibitory premotor neurons. Hox5 genes establish phrenic MN organization and dendritic topography through the regulation of phrenic-specific cell adhesion programs. In the absence of Hox5 genes, phrenic MN firing becomes asynchronous and erratic due to loss of phrenic MN inhibition. Strikingly, mice lacking Hox5 genes in MNs exhibit abnormal respiratory behavior throughout their lifetime. Our findings support a model where MN-intrinsic transcriptional programs shape the pattern of motor output by orchestrating distinct aspects of MN connectivity.