Positive end-expiratory pressure limits inspiratory effort through modulation of the effort-to-drive ratio: an experimental crossover study

Abstract Background How assisted spontaneous breathing should be used during acute respiratory distress syndrome is questioned. Recent evidence suggests that high positive end-expiratory pressure (PEEP) may limit the risk of patient self-inflicted lung injury (P-SILI). The aim of this study was to assess the effects of PEEP on esophageal pressure swings, inspiratory drive, and the neuromuscular efficiency of ventilation. We hypothesized that high PEEP would reduce esophageal pressure swings, regardless of inspiratory drive changes, by modulating the effort-to-drive ratio (EDR). This was tested retrospectively in an experimental animal crossover study. Anesthetized pigs (n = 15) were subjected to mild to moderate lung injury and different PEEP levels were applied, changing PEEP from 0 to 15 cmH2O and back to 0 cmH2O in steps of 3 cmH2O. Airway pressure, esophageal pressure (Pes), and electric activity of the diaphragm (Edi) were collected. The EDR was calculated as the tidal change in Pes divided by the tidal change in Edi. Statistical differences were tested using the Wilcoxon signed-rank test. Results Inspiratory esophageal pressure swings decreased from − 4.2 ± 3.1 cmH2O to − 1.9 ± 1.5 cmH2O (p < 0.01), and the mean EDR fell from − 1.12 ± 1.05 cmH2O/µV to − 0.24 ± 0.20 (p < 0.01) as PEEP was increased from 0 to 15 cmH2O. The EDR was significantly correlated to the PEEP level (rs = 0.35, p < 0.01). Conclusions Higher PEEP limits inspiratory effort by modulating the EDR of the respiratory system. These findings indicate that PEEP may be used in titration of the spontaneous impact on ventilation and in P-SILI risk reduction, potentially facilitating safe assisted spontaneous breathing. Similarly, ventilation may be shifted from highly spontaneous to predominantly controlled ventilation using PEEP. These findings need to be confirmed in clinical settings

Homogenizing effect of PEEP on tidal volume distribution during neurally adjusted ventilatory assist : study of an animal model of acute respiratory distress syndrome

Background The physiological response and the potentially beneficial effects of positive end-expiratory pressure (PEEP) for lung protection and optimization of ventilation during spontaneous breathing in patients with acute respiratory distress syndrome (ARDS) are not fully understood. The aim of the study was to compare the effect of different PEEP levels on tidal volume distribution and on the ventilation of dependent lung region during neurally adjusted ventilatory assist (NAVA). Methods ARDS-like lung injury was induced by using saline lavage in 10 anesthetized and spontaneously breathing farm-bred pigs. The animals were ventilated in NAVA modality and tidal volume distribution as well as dependent lung ventilation were assessed using electric impedance tomography during the application of PEEP levels from 0 to 15 cmH20, in steps of 3 cmH20. Tidal volume distribution and dependent fraction of ventilation were analysed using Wilcoxon signed rank test. Furthermore, airway, esophageal and transpulmonary pressure, as well as airway flow and delivered volume, were continuously measured during the assisted spontaneous breathing. Results Increasing PEEP improved oxygenation and re-distributed tidal volume. Specifically, ventilation distribution changed from a predominant non-dependent to a more even distribution between non-dependent and dependent areas of the lung. Dependent fraction of ventilation reached 47 ± 9% at PEEP 9 cmH20. Further increasing PEEP led to a predominant dependent ventilation. Conclusion During assisted spontaneous breathing in this model of induced ARDS, PEEP modifies the distribution of ventilation and can achieve a homogenizing effect on its spatial arrangement. The study indicates that PEEP is an important factor during assisted spontaneous breathing and that EIT can be of valuable interest when titrating PEEP level during spontaneous breathing, by indicating the most homogeneous distribution of gas volumes throughout the PEEP spectrum

The use of positive end expiratory pressure in patients affected by COVID-19 : Time to reconsider the relation between morphology and physiology

Coronavirus disease 2019 (COVID-19) is a new disease with different phases that can be catastrophic for subpopulations of patients with cardiovascular and pulmonary disease states at baseline. Appreciation for these different phases and treatment modalities, including manipulation of ventilatory settings and therapeutics, has made it a less lethal disease than when it emerged earlier this year. Different aspects of the disease are still largely unknown. However, laboratory investigation and clinical course of the COVID-19 show that this new disease is not a typical acute respiratory distress syndrome process, especially during the first phase. For this reason, the best strategy to be applied is to treat differently the single phases and to support the single functions of the failing organs as they appear

Awake prone position reduces work of breathing in patients with COVID-19 ARDS supported by CPAP

Background The use of awake prone position concomitant to non-invasive mechanical ventilation in acute respiratory distress syndrome (ARDS) secondary to COVID-19 has shown to improve gas exchange, whereas its effect on the work of breathing remain unclear. The objective of this study was to evaluate the effects of awake prone position during helmet continuous positive airway pressure (CPAP) ventilation on inspiratory effort, gas exchange and comfort of breathing. Methods Forty consecutive patients presenting with ARDS due to COVID-19 were prospectively enrolled. Gas exchange, esophageal pressure swing (ΔPes), dynamic transpulmonary pressure (dTPP), modified pressure time product (mPTP), work of breathing (WOB) and comfort of breathing, were recorded on supine position and after 3 h on prone position. Results The median applied PEEP with helmet CPAP was 10 [8–10] cmH2O. The PaO2/FiO2 was higher in prone compared to supine position (Supine: 166 [136–224] mmHg, Prone: 314 [232–398] mmHg, p < 0.001). Respiratory rate and minute ventilation decreased from supine to prone position from 20 [17–24] to 17 [15–19] b/min (p < 0.001) and from 8.6 [7.3–10.6] to 7.7 [6.6–8.6] L/min (p < 0.001), respectively. Prone position did not reduce ΔPes (Supine: − 7 [− 9 to − 5] cmH2O, Prone: − 6 [− 9 to − 5] cmH2O, p = 0.31) and dTPP (Supine: 17 [14–19] cmH2O, Prone: 16 [14–18] cmH2O, p = 0.34). Conversely, mPTP and WOB decreased from 152 [104–197] to 118 [90–150] cmH2O/min (p < 0.001) and from 146 [120–185] to 114 [95–151] cmH2O L/min (p < 0.001), respectively. Twenty-six (65%) patients experienced a reduction in WOB of more than 10%. The overall sensation of dyspnea was lower in prone position (p = 0.005). Conclusions Awake prone position with helmet CPAP enables a reduction in the work of breathing and an improvement in oxygenation in COVID-19-associated ARDS

PET-CT imaging of pulmonary inflammation using [Ga-68]Ga-DOTA-TATE

Purpose In the characterization of severe lung diseases, early detection of specific inflammatory cells could help to monitor patients' response to therapy and increase chances of survival. Macrophages contribute to regulating the resolution and termination of inflammation and have increasingly been of interest for targeted therapies. [Ga-68]Ga-DOTA-TATE is an established clinical radiopharmaceutical targeting somatostatin receptor subtype 2 (SSTR 2). Since activated macrophages (M1) overexpress SSTR 2, the aim of this study was to investigate the applicability of [Ga-68]Ga-DOTA-TATE for positron emission tomography (PET) imaging of M1 macrophages in pulmonary inflammation. Methods Inflammation in the pig lungs was induced by warm saline lavage followed by injurious ventilation in farm pigs (n = 7). Healthy pigs (n = 3) were used as control. A 60-min dynamic PET scan over the lungs was performed after [Ga-68]Ga-DOTA-TATE injection and [F-18]FDG scan was executed afterward for comparison. The uptake of both tracers was assessed as mean standardized uptake values (SUVmean) 30-60-min post-injection. The PET scans were followed by computed tomography (CT) scans, and the Hounsfield units (HU) were quantified of the coronal segments. Basal and apical segments of the lungs were harvested for histology staining. A rat lung inflammation model was also studied for tracer specificity using lipopolysaccharides (LPS) by oropharyngeal aspiration. Organ biodistribution, ex vivo autoradiography (ARG) and histology samples were conducted on LPS treated, octreotide induced blocking and control healthy rats. Results The accumulation of [Ga-68]Ga-DOTA-TATE on pig lavage model was prominent in the more severely injured dorsal segments of the lungs (SUVmean = 0.91 +/- 0.56), compared with control animals (SUVmean = 0.27 +/- 0.16, p &lt; 0.05). The tracer uptake corresponded to the damaged areas assessed by CT and histology and were in line with HU quantification. The [Ga-68]Ga-DOTA-TATE uptake in LPS treated rat lungs could be blocked and was significantly higher compared with control group. Conclusion The feasibility of the noninvasive assessment of tissue macrophages using [Ga-68]Ga-DOTA-TATE/PET was demonstrated in both porcine and rat lung inflammation models. [Ga-68]Ga-DOTA-TATE has a great potential to be used to study the role and presence of macrophages in humans in fight against severe lung diseases

PET imaging of neutrophil elastase with 11C-GW457427 in Acute Respiratory Distress Syndrome in pigs

Today, there is a lack of clinically available imaging techniques to detect and quantify specific immune cell populations. Neutrophils are one of the first immune cells at the site of inflammation and they secrete the serine protease neutrophil elastase (NE), which is crucial in the fight against pathogens. However, the prolonged lifespan of neutrophils increases the risk for patients to develop severe complications, such as Acute Respiratory Distress Syndrome (ARDS). Here, we evaluated novel radiolabeled NE inhibitor 11C-GW457427 in a pig model of ARDS, for detection and quantification of neutrophil activity in the lungs. Methods: ARDS was induced by intravenous administration of oleic acid on 5 farm pigs and 4 were considered as healthy controls. The severity of ARDS was monitored by clinical parameters of lung function and plasma biomarkers. Each pig was studied with 11C-GW457427 and PET-CT, before and after pretreatment with the NE inhibitor GW311616 to determine in vivo binding specificity. PET image data was analyzed as Standard Uptake Values (SUV) and correlated to immunohistochemical staining for NE in biopsies. Results: The binding of 11C-GW457427 was increased in pig lungs with induced ARDS (median SUVmean = 1.91, inter-quartile range (IQR) = 1.67-2.55) compared with healthy controls pigs (P &lt;0.05, P = 0.03, median SUVmean = 1.04, IQR= 0.66-1.47). The binding was especially strong in lung regions with high levels of neutrophil elastase and ongoing inflammation, as verified by immunohistochemistry. The binding was successfully blocked by pretreatment of a NE inhibitor drug, which demonstrated the in vivo specificity of 11C-GW457427 (P &lt;0.05, P = 0.04, median SUVmean = 0.60, IQR= 0.58-0.77). The binding in neutrophil rich tissues such as bone marrow (P &lt;0.05, P = 0.04, baseline median SUVmean = 5.01, IQR= 4.48-5.49, block median SUVmean = 1.57, IQR= 0.95-1.85) and spleen (median SUVmean = 2.14, IQR= 1.19-2.36) was also high in all pigs. Conclusion: 11C-GW457427 binds to NE in a porcine model of oleic acid induced lung inflammation in vivo with specific increase in regional lung, bone marrow, and spleen SUV. 11C-GW457427 is a promising tool for localizing, tracking and quantifying neutrophil facilitated inflammation in clinical diagnostics and drug development