Clinical relevance of lung transplantation for COVID-19 ARDS: a nationwide study.

BACKGROUND: Although the number of lung transplantations (LTx) performed worldwide for COVID-19 induced acute respiratory distress syndrome (ARDS) is still low, there is general agreement that this treatment can save a subgroup of most severly ill patients with irreversible lung damage. However, the true proportion of patients eligible for LTx, the overall outcome and the impact of LTx to the pandemic are unknown. METHODS: A retrospective analysis was performed using a nationwide registry of hospitalised patients with confirmed severe acute respiratory syndrome coronavirus type 2 (SARS-Cov-2) infection admitted between January 1, 2020 and May 30, 2021 in Austria. Patients referred to one of the two Austrian LTx centers were analyzed and grouped into patients accepted and rejected for LTx. Detailed outcome analysis was performed for all patients who received a LTx for post-COVID-19 ARDS and compared to patients who underwent LTx for other indications. RESULTS: Between January 1, 2020 and May 30, 2021, 39.485 patients were hospitalised for COVID-19 in Austria. 2323 required mechanical ventilation, 183 received extra-corporeal membrane oxygenation (ECMO) support. 106 patients with severe COVID-19 ARDS were referred for LTx. Of these, 19 (18%) underwent LTx. 30-day mortality after LTx was 0% for COVID-19 ARDS transplant recipients. With a median follow-up of 134 (47-450) days, 14/19 patients are alive. CONCLUSIONS: Early referral of ECMO patients to a LTx center is pivotal in order to select patients eligible for LTx. Transplantation offers excellent midterm outcomes and should be incorporated in the treatment algorithm of post-COVID-19 ARDS.

Ropivacaine Activates Multiple Proapoptotic and Inflammatory Signaling Pathways That Might Subsume to Trigger Epidural-Related Maternal Fever.

BACKGROUND: Epidural-related maternal fever (ERMF) is an adverse effect of epidural analgesia during labor and is associated with perinatal and neonatal morbidity. Local anesthetics have been proposed to trigger ERMF via sterile inflammation. Ropivacaine is currently the most frequently used epidural anesthetic and considered least toxic. This study investigates molecular effects of ropivacaine on human umbilical vein endothelial cells (HUVECs) as model system for endothelial cells and human placental trophoblasts (TBs), compares the effects to the putative anti-inflammatory lidocaine and investigates the partially alleviating impact of the anti-inflammatory corticosteroid dexamethasone. METHODS: HUVECs and TBs were exposed to ropivacaine (35 µM-7 mM) or lidocaine (21 mM) with or without dexamethasone (1 µM). AnnexinV/propidium iodide staining and lactate dehydrogenase release were used to analyze apoptosis and cytotoxicity. Proinflammatory interleukins-6 (IL-6) and IL-8 as well as prostaglandin E2 (PGE2) were measured by enzyme-linked immunosorbent assay (ELISA), while activation of signaling pathways was detected by Western blotting. Oxidative stress was visualized by live cell imaging and quantification of antioxidant proteins, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, platelet endothelial cell adhesion molecule 1, cyclooxygenase 2, and mitochondrial deoxyribonucleic acid by real-time polymerase chain reaction. Dissipation of the mitochondrial membrane potential was assessed with cytofluorimetric analysis using the J-Aggregate (JC-1 staining [cytofluorimetric analysis using the J-Aggregate]). RESULTS: Ropivacaine exposure dose-dependently induced apoptosis and an increased release of IL-6, IL-8, and PGE2 from HUVECs and TBs. Furthermore, caspase-3, nuclear factor-κB, and p38 mitogen-activated protein kinase pathways were activated, while extracellular signal-regulated kinase 1/2 and protein kinase B (Akt) were dephosphorylated. Downregulation of antioxidative proteins induced oxidative stress and upregulation of ICAM1, VCAM1, and PECAM1 possibly facilitate leukocyte transmigration. Mitochondrial effects included increased release of the proinflammatory mitochondrial DNA damage-associated molecular patterns, but no significant dissipation of the mitochondrial membrane potential. Conversely, lidocaine exhibited repression of IL-6 and IL-8 release over all time points, and early downregulation of COX2 and cell adhesion molecules, which was followed by a late overshooting reaction. Dexamethasone reduced especially inflammatory effects, but as an inducer of mitophagy, had negative long-term effects on mitochondrial function. CONCLUSIONS: This study suggests that ropivacaine causes cellular injury and death in HUVECs and TBs via different signaling pathways. The detrimental effects induced by ropivacaine are only partially blunted by dexamethasone. This observation strengthens the importance of inflammation in ERMF.

ERS statement on chest imaging in acute respiratory failure.

Chest imaging in patients with acute respiratory failure plays an important role in diagnosing, monitoring and assessing the underlying disease. The available modalities range from plain chest X-ray to computed tomography, lung ultrasound, electrical impedance tomography and positron emission tomography. Surprisingly, there are presently no clear-cut recommendations for critical care physicians regarding indications for and limitations of these different techniques.The purpose of the present European Respiratory Society (ERS) statement is to provide physicians with a comprehensive clinical review of chest imaging techniques for the assessment of patients with acute respiratory failure, based on the scientific evidence as identified by systematic searches. For each of these imaging techniques, the panel evaluated the following items: possible indications, technical aspects, qualitative and quantitative analysis of lung morphology and the potential interplay with mechanical ventilation. A systematic search of the literature was performed from inception to September 2018. A first search provided 1833 references. After evaluating the full text and discussion among the committee, 135 references were used to prepare the current statement.These chest imaging techniques allow a better assessment and understanding of the pathogenesis and pathophysiology of patients with acute respiratory failure, but have different indications and can provide additional information to each other.

PO2 oscillations induce lung injury and inflammation.

BACKGROUND: Mechanical ventilation can lead to ventilator-induced lung injury (VILI). In addition to the well-known mechanical forces of volutrauma, barotrauma, and atelectrauma, non-mechanical mechanisms have recently been discussed as contributing to the pathogenesis of VILI. One such mechanism is oscillations in partial pressure of oxygen (PO2) which originate in lung tissue in the presence of within-breath recruitment and derecruitment of alveoli. The purpose of this study was to investigate this mechanism's possible independent effects on lung tissue and inflammation in a porcine model. METHODS: To separately study the impact of PO2 oscillations on the lungs, an in vivo model was set up that allowed for generating mixed-venous PO2 oscillations by the use of veno-venous extracorporeal membrane oxygenation (vvECMO) in a state of minimal mechanical stress. While applying the identical minimal-invasive ventilator settings, 16 healthy female piglets (weight 50 ± 4 kg) were either exposed for 6 h to a constant mixed-venous hemoglobin saturation (SmvO2) of 65% (which equals a PmvO2 of 41 Torr) (control group), or an oscillating SmvO2 (intervention group) of 40-90% (which equals PmvO2 oscillations of 30-68 Torr)-while systemic normoxia in both groups was maintained. The primary endpoint of histologic lung damage was assessed by ex vivo histologic lung injury scoring (LIS), the secondary endpoint of pulmonary inflammation by qRT-PCR of lung tissue. Cytokine concentration of plasma was carried out by ELISA. A bioinformatic microarray analysis of lung samples was performed to generate hypotheses about underlying pathomechanisms. RESULTS: The LIS showed significantly more severe damage of lung tissue after exposure to PO2 oscillations compared to controls (0.53 [0.51; 0.58] vs. 0.27 [0.23; 0.28]; P = 0.0025). Likewise, a higher expression of TNF-α (P = 0.0127), IL-1ß (P = 0.0013), IL-6 (P = 0.0007), and iNOS (P = 0.0013) in lung tissue was determined after exposure to PO2 oscillations. Cytokines in plasma showed a similar trend between the groups, however, without significant differences. Results of the microarray analysis suggest that inflammatory (IL-6) and oxidative stress (NO/ROS) signaling pathways are involved in the pathology linked to PO2 oscillations. CONCLUSIONS: Artificial mixed-venous PO2 oscillations induced lung damage and pulmonary inflammation in healthy animals during lung protective ventilation. These findings suggest that PO2 oscillations represent an independent mechanism of VILI.

Detection of inspiratory recruitment of atelectasis by automated lung sound analysis as compared to four-dimensional computed tomography in a porcine lung injury model.

BACKGROUND: Cyclic recruitment and de-recruitment of atelectasis (c-R/D) is a contributor to ventilator-induced lung injury (VILI). Bedside detection of this dynamic process could improve ventilator management. This study investigated the potential of automated lung sound analysis to detect c-R/D as compared to four-dimensional computed tomography (4DCT). METHODS: In ten piglets (25 ± 2 kg), acoustic measurements from 34 thoracic piezoelectric sensors (Meditron ASA, Norway) were performed, time synchronized to 4DCT scans, at positive end-expiratory pressures of 0, 5, 10, and 15 cmH2O during mechanical ventilation, before and after induction of c-R/D by surfactant washout. 4DCT was post-processed for within-breath variation in atelectatic volume (Δ atelectasis) as a measure of c-R/D. Sound waveforms were evaluated for: 1) dynamic crackle energy (dCE): filtered crackle sounds (600-700 Hz); 2) fast Fourier transform area (FFT area): spectral content above 500 Hz in frequency and above -70 dB in amplitude in proportion to the total amount of sound above -70 dB amplitude; and 3) dynamic spectral coherence (dSC): variation in acoustical homogeneity over time. Parameters were analyzed for global, nondependent, central, and dependent lung areas. RESULTS: In healthy lungs, negligible values of Δ atelectasis, dCE, and FFT area occurred. In lavage lung injury, the novel dCE parameter showed the best correlation to Δ atelectasis in dependent lung areas (R2 = 0.88) where c-R/D took place. dCE was superior to FFT area analysis for each lung region examined. The analysis of dSC could predict the lung regions where c-R/D originated. CONCLUSIONS: c-R/D is associated with the occurrence of fine crackle sounds as demonstrated by dCE analysis. Standardized computer-assisted analysis of dCE and dSC seems to be a promising method for depicting c-R/D.

Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial.

BACKGROUND: High-permeability pulmonary edema is a hallmark of acute respiratory distress syndrome (ARDS) and is frequently accompanied by impaired alveolar fluid clearance (AFC). AP301 enhances AFC by activating epithelial sodium channels (ENaCs) on alveolar epithelial cells, and we investigated its effect on extravascular lung water index (EVLWI) in mechanically ventilated patients with ARDS. METHODS: Forty adult mechanically ventilated patients with ARDS were included in a randomized, double-blind, placebo-controlled trial for proof of concept. Patients were treated with inhaled AP301 (n = 20) or placebo (0.9% NaCl; n = 20) twice daily for 7 days. EVLWI was measured by thermodilution (PiCCO®), and treatment groups were compared using the nonparametric Mann-Whitney U test. RESULTS: AP301 inhalation was well tolerated. No differences in mean baseline-adjusted change in EVLWI from screening to day 7 were found between the AP301 and placebo group (p = 0.196). There was no difference in the PaO2/FiO2 ratio, ventilation pressures, Murray lung injury score, or 28-day mortality between the treatment groups. An exploratory subgroup analysis according to severity of illness showed reductions in EVLWI (p = 0.04) and ventilation pressures (p < 0.05) over 7 days in patients with initial sequential organ failure assessment (SOFA) scores ≥11 inhaling AP301 versus placebo, but not in patients with SOFA scores ≤10. CONCLUSIONS: There was no difference in mean baseline-adjusted EVLWI between the AP301 and placebo group. An exploratory post-hoc subgroup analysis indicated reduced EVLWI in patients with SOFA scores ≥11 receiving AP301. These results suggest further confirmation in future clinical trials of inhaled AP301 for treatment of pulmonary edema in patients with ARDS. TRIAL REGISTRATION: The study was prospectively registered at clinicaltrials.gov, NCT01627613 . Registered 20 June 2012.

Moderate hyperoxia induces inflammation, apoptosis and necrosis in human umbilical vein endothelial cells: An in-vitro study.

BACKGROUND: Perioperative oxygen (O2) therapy can cause hyperoxia. Extreme hyperoxia can injure the cardiovascular system and remote organs. OBJECTIVE: Our primary objective was to test the hypothesis that exposure to moderate hyperoxia will induce injury to human umbilical vein endothelial cells (HUVECs), a model for studying the vascular endothelium under controlled conditions. DESIGN: In-vitro cell culture study. SETTING: Department of Anaesthesia, General Intensive Care and Pain Management, Medical University of Vienna, Austria. Study period from the beginning of October 2013 to the end of July 2014. CELLS: HUVECs were isolated from fresh umbilical cords. INTERVENTIONS: HUVECs were exposed to constant hyperoxia (40% O2), cyclic hyperoxia/anoxia (40%/0% O2, average 20% O2), constant normoxia (21% O2) and constant anoxia (0% O2) using a cell culture bioreactor. MAIN OUTCOME MEASURES: Cell growth, viability and release of IL-6, IL-8 and macrophage migration inhibitory factor were assessed at baseline and after 6, 12, 24 and 48 h of treatment. A phosphokinase array was performed after 60 min of treatment to identify activated cellular signalling pathways. RESULTS: Constant hyperoxia and cyclic hyperoxia/anoxia impeded cell growth, reduced viability, triggered a proinflammatory response, proven by IL-6, IL-8 and migration inhibitory factor release, and induced apoptosis and necrosis. The inflammatory and cytotoxicity responses were highest in the constant hyperoxia group. Phosphokinase arrays revealed that different O2 concentrations activated distinct sets of cytoprotective and cell death-associated kinases, including mitogen-activated protein kinases, Src kinases, p53, Akt, mitogen-activated and stress-activated kinase, Lyn, Lck, p70S6, signal transducers and activators of transcription 5b and 6, glycogen synthase kinase 3a/b and 5' AMP-activated protein kinases 1/2. CONCLUSION: Continuous moderate hyperoxia and cyclic moderate hyperoxia/anoxia-induced endothelial inflammation, apoptosis and necrosis. Given the large surface area of the vascular endothelium, moderately elevated O2 levels may contribute to cardiovascular inflammation and injury. TRIAL REGISTRATION: This in-vitro study was not registered in a database.

Intermittent Hypoxia Causes Inflammation and Injury to Human Adult Cardiac Myocytes.

BACKGROUND: Intermittent hypoxia may occur in a number of clinical scenarios, including interruption of myocardial blood flow or breathing disorders such as obstructive sleep apnea. Although intermittent hypoxia has been linked to cardiovascular and cerebrovascular disease, the effect of intermittent hypoxia on the human heart is not fully understood. Therefore, in the present study, we compared the cellular responses of cultured human adult cardiac myocytes (HACMs) exposed to intermittent hypoxia and different conditions of continuous hypoxia and normoxia. METHODS: HACMs were exposed to intermittent hypoxia (0%-21% O2), constant mild hypoxia (10% O2), constant severe hypoxia (0% O2), or constant normoxia (21% O2), using a novel cell culture bioreactor with gas-permeable membranes. Cell proliferation, lactate dehydrogenase release, vascular endothelial growth factor release, and cytokine (interleukin [IL] and macrophage migration inhibitory factor) release were assessed at baseline and after 8, 24, and 72 hours of exposure. A signal transduction pathway finder array was performed to determine the changes in gene expression. RESULTS: In comparison with constant normoxia and constant mild hypoxia, intermittent hypoxia induced earlier and greater inflammatory response and extent of cell injury as evidenced by lower cell numbers and higher lactate dehydrogenase, vascular endothelial growth factor, and proinflammatory cytokine (IL-1ß, IL-6, IL-8, and macrophage migration inhibitory factor) release. Constant severe hypoxia showed more detrimental effects on HACMs at later time points. Pathway analysis demonstrated that intermittent hypoxia primarily altered gene expression in oxidative stress, Wnt, Notch, and hypoxia pathways. CONCLUSIONS: Intermittent and constant severe hypoxia, but not constant mild hypoxia or normoxia, induced inflammation and cell injury in HACMs. Cell injury occurred earliest and was greatest after intermittent hypoxia exposure. Our in vitro findings suggest that intermittent hypoxia exposure may produce rapid and substantial damage to the human heart.

Argon Preconditioning Protects Airway Epithelial Cells against Hydrogen Peroxide-Induced Oxidative Stress.

BACKGROUND: Oxidative stress is the predominant pathogenic mechanism of ischaemia-reperfusion (IR) injury. The noble gas argon has been shown to alleviate oxidative stress-related myocardial and cerebral injury. The risk of lung IR injury is increased in some major surgeries, reducing clinical outcome. However, no study has examined the lung-protective efficacy of argon preconditioning. The present study investigated the protective effects of argon preconditioning on airway epithelial cells exposed to hydrogen peroxide (H2O2) to induce oxidative stress. METHODS: A549 airway epithelial cells were treated with a cytotoxic concentration of H2O2 after exposure to standard air or 30 or 50% argon/21% oxygen/5% carbon dioxide/rest nitrogen for 30, 45 or 180 min. Cells were stained with annexin V/propidium iodide, and apoptosis was evaluated by fluorescence-activated cell sorting. Protective signalling pathways activated by argon exposure were identified by Western blot analysis for phosphorylated candidate molecules of the mitogen-activated protein kinase and protein kinase B (Akt) pathways. RESULTS: Preconditioning with 50% argon for 30, 45 and 180 min and 30% argon for 180 min caused significant protection of A549 cells against H2O2-induced apoptosis, with increases in cellular viability of 5-47% (p < 0.0001). A small adverse effect was also observed, which presented as a 12-15% increase in cellular necrosis in argon-treated groups. Argon exposure resulted in early activation of c-Jun N-terminal kinase (JNK) and p38, peaking 10- 30 min after the start of preconditioning, and delayed activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, peaking after 60-90 min. CONCLUSIONS: Argon preconditioning protects airway epithelial cells from H2O2-induced apoptotic cell death. Argon activates the JNK, p38, and ERK1/2 pathways, but not the Akt pathway. The cytoprotective properties of argon suggest possible prophylactic applications in surgery-related IR injury of the lungs.

Influence of inspiration to expiration ratio on cyclic recruitment and derecruitment of atelectasis in a saline lavage model of acute respiratory distress syndrome.

OBJECTIVE: Cyclic recruitment and derecruitment of atelectasis can occur during mechanical ventilation, especially in injured lungs. Experimentally, cyclic recruitment and derecruitment can be quantified by respiration-dependent changes in PaO2 (ΔPaO2), reflecting the varying intrapulmonary shunt fraction within the respiratory cycle. This study investigated the effect of inspiration to expiration ratio upon ΔPaO2 and Horowitz index. DESIGN: Prospective randomized study. SETTING: Laboratory investigation. SUBJECTS: Piglets, average weight 30 ± 2 kg. INTERVENTIONS: At respiratory rate 6 breaths/min, end-inspiratory pressure (Pendinsp) 40 cm H2O, positive end-expiratory pressure 5 cm H2O, and FIO2 1.0, measurements were performed at randomly set inspiration to expiration ratios during baseline healthy and mild surfactant depletion injury. Lung damage was titrated by repetitive surfactant washout to induce maximal cyclic recruitment and derecruitment as measured by multifrequency phase fluorimetry. Regional ventilation distribution was evaluated by electrical impedance tomography. Step changes in airway pressure from 5 to 40 cm H2O and vice versa were performed after lavage to calculate PO2-based recruitment and derecruitment time constants (TAU). MEASUREMENTS AND MAIN RESULTS: In baseline healthy, cyclic recruitment and derecruitment could not be provoked, whereas in model acute respiratory distress syndrome, the highest ΔPaO2 were routinely detected at an inspiration to expiration ratio of 1:4 (range, 52-277 torr [6.9-36.9 kPa]). Shorter expiration time reduced cyclic recruitment and derecruitment significantly (158 ± 85 torr [21.1 ± 11.3 kPa] [inspiration to expiration ratio, 1:4]; 25 ± 12 torr [3.3 ± 1.6 kPa] [inspiration to expiration ratio, 4:1]; p < 0.0001), whereas the PaO2/FIO2 ratio increased (267 ± 50 [inspiration to expiration ratio, 1:4]; 424 ± 53 [inspiration to expiration ratio, 4:1]; p < 0.0001). Correspondingly, regional ventilation redistributed toward dependent lung regions (p < 0.0001). Recruitment was much faster (TAU: fast 1.6 s [78%]; slow 9.2 s) than derecruitment (TAU: fast 3.1 s [87%]; slow 17.7 s) (p = 0.0078). CONCLUSIONS: Inverse ratio ventilation minimizes cyclic recruitment and derecruitment of atelectasis in an experimental model of surfactant-depleted pigs. Time constants for recruitment and derecruitment, and regional ventilation distribution, reflect these findings and highlight the time dependency of cyclic recruitment and derecruitment.

Real-time in-vivo imaging of pulmonary capillary perfusion using probe-based confocal laser scanning endomicroscopy in pigs: An interventional laboratory study.

BACKGROUND: Little is known about real-time in-vivo microscopy of pulmonary capillary perfusion because current microscopy requires direct access to lung tissue with surgical intervention such as the thoracic-window technique and open-lung model. OBJECTIVES: To evaluate if probe-based confocal laser scanning endomicroscopy (pCLE) via the trachea allows for real-time in-vivo visualisation of pulmonary capillary density and red blood cell (RBC) velocity in pigs. DESIGN: An interventional animal study. SETTING: European University Hospital. ANIMALS: Nine female domestic pigs (50 to 60 kg) were used. MAIN OUTCOME MEASURES: A pCLE probe was positioned in non-dependent, central and dependent lung zones in nine anaesthetised pigs (Alveoflex, Cellvizio, Maunakea, France). After intravenous administration of fluorescein isothiocyanate dextran as contrast agent repetitive pCLE videos were recorded during pressure-controlled ventilation (PCV) or continuous positive airway pressure for 3 min each. Using fluorescein isothiocyanate-labelled RBC erythrocyte velocities in pulmonary capillaries were quantified. Data are expressed as mean ± SD or median with interquartile range (IQR). RESULTS: Capillary density was greater in dependent and central as compared with non-dependent lung zones [[32 (29 to 34) %] and 32 (30 to 34) % vs. 28 (26 to 28) %, respectively, P < 0.05]. During PCV, RBC velocities were higher in larger lung capillaries [diameter >20 µm, 309 µm s(-1) (209 to 397)] than intermediate [diameter 10.1 to 20 µm, 146 µm s(-1) (118 to 235)] and small [diameter <10 µm, 153 µm s(-1) (117 to 236), P <  .05]. During continuous positive airway pressure of 1.5 kPa, RBC velocities in dependent lung areas decreased to 47 µm s(-1) (30 to 82) compared with 198 µm s(-1) (148 to 290) during PCV (P < 0.05). CONCLUSION: pCLE allows endoscopic real-time in-vivo imaging of pulmonary capillary morphology and perfusion. Alterations in pulmonary capillary blood flow induced by different ventilator regimens can be detected. This minimally invasive approach via the endotracheal route is feasible in an experimental setting and may help to understand changes in regional pulmonary capillary perfusion.

Hints for cyclical recruitment of atelectasis during ongoing mechanical ventilation in lavage and oleic acid lung injury detected by SpO2 oscillations and electrical impedance tomography.

PURPOSE OF THE STUDY: Detection of cyclical recruitment of atelectasis after induction of lavage (LAV) or oleic acid injury (OAI) in mechanically ventilated pigs. Primary hypothesis is that oxygen oscillations within the respiratory cycle can be detected by SpO2 recordings (direct hint). SpO2 oscillations reflect shunt oscillations that can only be explained by cyclical recruitment of atelectasis. Secondary hypothesis is that electrical impedance tomography (EIT) depicts specific regional changes of lung aeration and of pulmonary mechanical properties (indirect hint). MATERIALS AND METHODS: Three groups (each n = 7) of mechanically ventilated pigs were investigated applying above mentioned methods before and repeatedly after induction of lung injury: (1) sham treated animals (SHAM), (2) LAV, and (3) OAI. RESULTS: Early oxygen oscillations occurred in the LAV group (mean calculated amplitude: 73.8 mmHg reflecting shunt oscillation of 11.2% in mean). In the OAI group oxygen oscillations occurred hours after induction of lung injury (mean calculated amplitude: 57.1 mmHg reflecting shunt oscillations of 8.4% in mean). The SHAM group had no relevant oxygen oscillations (<30 mmHg, shunt oscillations < 1.5%). Synchronously to oxygen oscillations, EIT depicted (1) a decrease of ventilation in dorsal areas, (2) an increase in ventral areas, (3) a decrease of especially dependent expiratory impedance, 3) an increase in late inspiratory flow especially in the dependant areas, (4) an increase in the speed of peak expiratory flow (PEF), and (5) a decrease of dorsal late expiratory flow. CONCLUSIONS: SpO2 and EIT recordings detect events that are interpreted as cyclical recruitment of atelectasis.

Determination of respiratory gas flow by electrical impedance tomography in an animal model of mechanical ventilation.

BACKGROUND: A recent method determines regional gas flow of the lung by electrical impedance tomography (EIT). The aim of this study is to show the applicability of this method in a porcine model of mechanical ventilation in healthy and diseased lungs. Our primary hypothesis is that global gas flow measured by EIT can be correlated with spirometry. Our secondary hypothesis is that regional analysis of respiratory gas flow delivers physiologically meaningful results. METHODS: In two sets of experiments n = 7 healthy pigs and n = 6 pigs before and after induction of lavage lung injury were investigated. EIT of the lung and spirometry were registered synchronously during ongoing mechanical ventilation. In-vivo aeration of the lung was analysed in four regions-of-interest (ROI) by EIT: 1) global, 2) ventral (non-dependent), 3) middle and 4) dorsal (dependent) ROI. Respiratory gas flow was calculated by the first derivative of the regional aeration curve. Four phases of the respiratory cycle were discriminated. They delivered peak and late inspiratory and expiratory gas flow (PIF, LIF, PEF, LEF) characterizing early or late inspiration or expiration. RESULTS: Linear regression analysis of EIT and spirometry in healthy pigs revealed a very good correlation measuring peak flow and a good correlation detecting late flow. PIFEIT = 0.702 · PIFspiro + 117.4, r(2) = 0.809; PEFEIT = 0.690 · PEFspiro-124.2, r(2) = 0.760; LIFEIT = 0.909 · LIFspiro + 27.32, r(2) = 0.572 and LEFEIT = 0.858 · LEFspiro-10.94, r(2) = 0.647. EIT derived absolute gas flow was generally smaller than data from spirometry. Regional gas flow was distributed heterogeneously during different phases of the respiratory cycle. But, the regional distribution of gas flow stayed stable during different ventilator settings. Moderate lung injury changed the regional pattern of gas flow. CONCLUSIONS: We conclude that the presented method is able to determine global respiratory gas flow of the lung in different phases of the respiratory cycle. Additionally, it delivers meaningful insight into regional pulmonary characteristics, i.e. the regional ability of the lung to take up and to release air.

TIP peptide inhalation in experimental acute lung injury: effect of repetitive dosage and different synthetic variants.

BACKGROUND: Inhalation of TIP peptides that mimic the lectin-like domain of TNF-α is a novel approach to attenuate pulmonary oedema on the threshold to clinical application. A placebo-controlled porcine model of acute respiratory distress syndrome (ARDS) demonstrated a reduced thermodilution-derived extravascular lung water index (EVLWI) and improved gas exchange through TIP peptide inhalation within three hours. Based on these findings, the present study compares a single versus a repetitive inhalation of a TIP peptide (TIP-A) and two alternate peptide versions (TIP-A, TIP-B). METHODS: Following animal care committee approval ARDS was induced by bronchoalveolar lavage followed by injurious ventilation in 21 anaesthetized pigs. A randomised-blinded three-group setting compared the single-dosed peptide variants TIP-A and TIP-B as well as single versus repetitive inhalation of TIP-A (n = 7 per group). Over two three-hour intervals parameters of gas exchange, transpulmonary thermodilution, calculated alveolar fluid clearance, and ventilation/perfusion-distribution were assessed. Post-mortem measurements included pulmonary wet/dry ratio and haemorrhage/congestion scoring. RESULTS: The repetitive TIP-A inhalation led to a significantly lower wet/dry ratio than a single dose and a small but significantly lower EVLWI. However, EVLWI changes over time and the derived alveolar fluid clearance did not differ significantly. The comparison of TIP-A and B showed no relevant differences. Gas exchange and ventilation/perfusion-distribution significantly improved in all groups without intergroup differences. No differences were found in haemorrhage/congestion scoring. CONCLUSIONS: In comparison to a single application the repetitive inhalation of a TIP peptide in three-hour intervals may lead to a small additional reduction the lung water content. Two alternate TIP peptide versions showed interchangeable characteristics.

Influence of fluid and volume state on PaO2 oscillations in mechanically ventilated pigs.

Varying pulmonary shunt fractions during the respiratory cycle cause oxygen oscillations during mechanical ventilation. In artificially damaged lungs, cyclical recruitment of atelectasis is responsible for varying shunt according to published evidence. We introduce a complimentary hypothesis that cyclically varying shunt in healthy lungs is caused by cyclical redistribution of pulmonary perfusion. Administration of crystalloid or colloid infusions would decrease oxygen oscillations if our hypothesis was right. Therefore, n=14 mechanically ventilated healthy pigs were investigated in 2 groups: crystalloid (fluid) versus no-fluid administration. Additional volume interventions (colloid infusion, blood withdrawal) were carried out in each pig. Intra-aortal PaO2 oscillations were recorded using fluorescence quenching technique. Phase shift of oxygen oscillations during altered inspiratory to expiratory (I:E) ventilation ratio and electrical impedance tomography (EIT) served as control methods to exclude that recruitment of atelectasis is responsible for oxygen oscillations. In hypovolemia relevant oxygen oscillations could be recorded. Fluid and volume state changed PaO2 oscillations according to our hypothesis. Fluid administration led to a mean decline of 105.3 mmHg of the PaO2 oscillations amplitude (P<0.001). The difference of the amplitudes between colloid administration and blood withdrawal was 62.4 mmHg in pigs not having received fluids (P=0.0059). Fluid and volume state also changed the oscillation phase during altered I:E ratio. EIT excluded changes of regional ventilation (i.e., recruitment of atelectasis) to be responsible for these oscillations. In healthy pigs, cyclical redistribution of pulmonary perfusion can explain the size of respiratory-dependent PaO2 oscillations.

[Infection prevention in the operating theater: practice-oriented recommendations for anesthesiologists]. / Infektionsprävention im OP: praxisorientierte Empfehlungen für AnästhesistInnen.

This article is intended to provide clinically working anesthesiologists with a practice-oriented overview of selected important current guidelines and recommendations pertaining to intraoperative prevention of infection. The contents of this article are based on the guidelines or recommendation of the World Health Organization (WHO) and the Association of the Scientific Medical Societies in Germany (AWMF) as well as the Commission for Hospital Hygiene and Infection Prevention (KRINKO) at the Robert Koch Institute (RKI). The authors' objective is to foster and support the standard of infection prevention and control in the operating theater by optimizing the standard of hygiene in daily practice to reduce the number of perioperative infections.

The Effect of Prone Positioning After Lung Transplantation.

BACKGROUND: Prone positioning has become a standard therapy in acute respiratory distress syndrome to improve oxygenation and decrease mortality. However, little is known about prone positioning in lung transplant recipients. This large, singe-center analysis investigated whether prone positioning improves gas exchange after lung transplantation. METHODS: Clinical data of 583 patients were analyzed. Prone position was considered in case of impaired gas exchange Pao2/fraction of oxygen in inhaled air (<250), signs of edema after lung transplantation, and/or evidence of reperfusion injury. Patients with hemodynamic instability or active bleeding were not proned. Impact of prone positioning (n = 165) on gas exchange, early outcome and survival were determined and compared with patients in supine positioning (n = 418). RESULTS: Patients in prone position were younger, more likely to have interstitial lung disease, and had a higher lung allocation score. Patients were proned for a median of 19 hours (interquartile range,15-26) hours). They had significantly lower Pao2/fraction of oxygen in inhaled air (227 ± 96 vs 303 ± 127 mm Hg, P = .004), and lower lung compliance (24.8 ± 9.1 mL/mbar vs 29.8 ± 9.7 mL/mbar, P < .001) immediately after lung transplantation. Both values significantly improved after prone positioning for 24 hours (Pao2/fraction of oxygen ratio: 331 ± 91 mm Hg; lung compliance: 31.7 ± 20.2 mL/mbar). Survival at 90 days was similar between the 2 groups (93% vs 96%, P = .105). CONCLUSIONS: Prone positioning led to a significant improvement in lung compliance and oxygenation after lung transplantation. Prospective studies are needed to confirm the benefit of prone positioning in lung transplantation.

Influence of respiratory rate and end-expiratory pressure variation on cyclic alveolar recruitment in an experimental lung injury model.

INTRODUCTION: Cyclic alveolar recruitment/derecruitment (R/D) is an important mechanism of ventilator-associated lung injury. In experimental models this process can be measured with high temporal resolution by detection of respiratory-dependent oscillations of the paO2 (ΔpaO2). A previous study showed that end-expiratory collapse can be prevented by an increased respiratory rate in saline-lavaged rabbits. The current study compares the effects of increased positive end-expiratory pressure (PEEP) versus an individually titrated respiratory rate (RRind) on intra-tidal amplitude of Δ paO2 and on average paO2 in saline-lavaged pigs. METHODS: Acute lung injury was induced by bronchoalveolar lavage in 16 anaesthetized pigs. R/D was induced and measured by a fast-responding intra-aortic probe measuring paO2. Ventilatory interventions (RRind (n=8) versus extrinsic PEEP (n=8)) were applied for 30 minutes to reduce Δ paO2. Haemodynamics, spirometry and Δ paO2 were monitored and the Ventilation/Perfusion distributions were assessed by multiple inert gas elimination. The main endpoints average and Δ paO2 following the interventions were analysed by Mann-Whitney-U-Test and Bonferroni's correction. The secondary parameters were tested in an explorative manner. RESULTS: Both interventions reduced Δ paO2. In the RRind group, ΔpaO2 was significantly smaller (P<0.001). The average paO2 continuously decreased following RRind and was significantly higher in the PEEP group (P<0.001). A sustained difference of the ventilation/perfusion distribution and shunt fractions confirms these findings. The RRind application required less vasopressor administration. CONCLUSIONS: Different recruitment kinetics were found compared to previous small animal models and these differences were primarily determined by kinetics of end-expiratory collapse. In this porcine model, respiratory rate and increased PEEP were both effective in reducing the amplitude of paO2 oscillations. In contrast to a recent study in a small animal model, however, increased respiratory rate did not maintain end-expiratory recruitment and ultimately resulted in reduced average paO2 and increased shunt fraction.