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.

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.

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.

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.

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.

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.

Perfusion index and plethysmographic variability index in patients with interscalene nerve catheters.

BACKGROUND: Interscalene nerve blocks provide adequate analgesia, but there are no objective criteria for early assessment of correct catheter placement. In the present study, pulse oximetry technology was used to evaluate changes in the perfusion index (PI) in both blocked and unblocked arms, and changes in the plethysmographic variability index (PVI) were evaluated once mechanical ventilation was instituted. METHODS: The PI and PVI values were assessed using a Radical-7™ finger pulse oximetry device (Masimo Corp., Irvine, CA, USA) in both arms of 30 orthopedic patients who received an interscalene catheter at least 25 min before induction of general anesthesia. Data were evaluated at baseline, on application of local anesthetics; five, ten, and 15 min after onset of interscalene nerve blocks; after induction of general anesthesia; before and after a 500 mL colloid fluid challenge; and five minutes thereafter. RESULTS: In the 25 patients with successful blocks, the difference between the PI values in the blocked arm and the PI values in the contralateral arm increased within five minutes of the application of the local anesthetics (P < 0.05) and increased progressively until 15 min. After induction of general anesthesia, the PI increased in the unblocked arm while it remained relatively constant in the blocked arm, thus reducing the difference in the PI. A fluid challenge resulted in a decrease in PVI values in both arms. CONCLUSION: The perfusion index increases after successful interscalene nerve blockade and may be used as an indicator for successful block placement in awake patients. The PVI values before and after a fluid challenge can be useful to detect changes in preload, and this can be performed in both blocked and unblocked arms.

Novel technologies to detect atelectotrauma in the injured lung.

Cyclical recruitment and derecruitment of lung parenchyma (R/D) remains a serious problem in ALI/ARDS patients, defined as atelectotrauma. Detection of cyclical R/D to titrate the optimal respiratory settings is of high clinical importance. Image-based technologies that are capable of detecting changes of lung ventilation within a respiratory cycle include dynamic computed tomography (dCT), synchrotron radiation computed tomography (SRCT), and electrical impedance tomography (EIT). Time-dependent intra-arterial oxygen tension monitoring represents an alternative approach to detect cyclical R/D, as cyclical R/D can result in oscillations of PaO2 within a respiratory cycle. Continuous, ultrafast, on-line in vivo measurement of PaO2 can be provided by an indwelling PaO2 probe. In addition, monitoring of fast changes in SaO2 by pulse oximetry technology at the bedside could also be used to detect those fast changes in oxygenation.

Observation of ventilation-induced Spo(2) oscillations in pigs: first step to noninvasive detection of cyclic recruitment of atelectasis?

High arterial partial oxygen pressure (Pao(2)) oscillations within the respiratory cycle were described recently in experimental acute lung injury. This phenomenon has been related to cyclic recruitment of atelectasis and varying pulmonary shunt fractions. Noninvasive detection of Spo(2) (oxygen saturation measured by pulse oximetry) as an indicator of cyclic collapse of atelectasis, instead of recording Pao(2) oscillations, could be of clinical interest in critical care. Spo(2) oscillations were recorded continuously in three different cases of lung damage to demonstrate the technical feasibility of this approach. To deduce Pao(2) from Spo(2), a mathematical model of the hemoglobin dissociation curve including left and right shifts was derived from the literature and adapted to the dynamic changes of oxygenation. Calculated Pao(2) amplitudes (derived from Spo(2) measurements) were compared to simultaneously measured fast changes of Pao(2), using a current standard method (fluorescence quenching of ruthenium). Peripheral hemoglobin saturation was capable to capture changes of Spo(2) within each respiratory cycle. For the first time, Spo(2) oscillations due to cyclic recruitment of atelectasis within a respiratory cycle were determined by photoplethysmography, a technology that can be readily applied noninvasively in clinical routine. A mathematic model to calculate the respective Pao(2) changes was developed and its applicability tested.

Cerebral Gaseous Microemboli are Detectable During Continuous Venovenous Hemodialysis in Critically Ill Patients: An Observational Pilot Study.

BACKGROUND: Continuous venovenous hemodialysis (CVVHD) may generate microemboli that cross the pulmonary circulation and reach the brain. The aim of the present study was to quantify (load per time interval) and qualify (gaseous vs. solid) cerebral microemboli (CME), detected as high-intensity transient signals, using transcranial Doppler ultrasound. MATERIALS AND METHODS: Twenty intensive care unit (ICU group) patients requiring CVVHD were examined. CME were recorded in both middle cerebral arteries for 30 minutes during CVVHD and a CVVHD-free interval. Twenty additional patients, hospitalized for orthopedic surgery, served as a non-ICU control group. Statistical analyses were performed using the Mann-Whitney U test or the Wilcoxon matched-pairs signed-rank test, followed by Bonferroni corrections for multiple comparisons. RESULTS: In the non-ICU group, 48 (14.5-169.5) (median [range]) gaseous CME were detected. In the ICU group, the 67.5 (14.5-588.5) gaseous CME detected during the CVVHD-free interval increased 5-fold to 344.5 (59-1019) during CVVHD (P<0.001). The number of solid CME was low in all groups (non-ICU group: 2 [0-5.5]; ICU group CVVHD-free interval: 1.5 [0-14.25]; ICU group during CVVHD: 7 [3-27.75]). CONCLUSIONS: This observational pilot study shows that CVVHD was associated with a higher gaseous but not solid CME burden in critically ill patients. Although the differentiation between gaseous and solid CME remains challenging, our finding may support the hypothesis of microbubble generation in the CVVHD circuit and its transpulmonary translocation toward the intracranial circulation. Importantly, the impact of gaseous and solid CME generated during CVVHD on brain integrity of critically ill patients currently remains unknown and is highly debated.

Effects of individualized electrical impedance tomography and image reconstruction settings upon the assessment of regional ventilation distribution: Comparison to 4-dimensional computed tomography in a porcine model.

Electrical impedance tomography (EIT) is a promising imaging technique for bedside monitoring of lung function. It is easily applicable, cheap and requires no ionizing radiation, but clinical interpretation of EIT-images is still not standardized. One of the reasons for this is the ill-posed nature of EIT, allowing a range of possible images to be produced-rather than a single explicit solution. Thus, to further advance the EIT technology for clinical application, thorough examinations of EIT-image reconstruction settings-i.e., mathematical parameters and addition of a priori (e.g., anatomical) information-is essential. In the present work, regional ventilation distribution profiles derived from different EIT finite-element reconstruction models and settings (for GREIT and Gauss Newton) were compared to regional aeration profiles assessed by the gold-standard of 4-dimensional computed tomography (4DCT) by calculating the root mean squared error (RMSE). Specifically, non-individualized reconstruction models (based on circular and averaged thoracic contours) and individualized reconstruction models (based on true thoracic contours) were compared. Our results suggest that GREIT with noise figure of 0.15 and non-uniform background works best for the assessment of regional ventilation distribution by EIT, as verified versus 4DCT. Furthermore, the RMSE of anteroposterior ventilation profiles decreased from 2.53±0.62% to 1.67±0.49% while correlation increased from 0.77 to 0.89 after embedding anatomical information into the reconstruction models. In conclusion, the present work reveals that anatomically enhanced EIT-image reconstruction is superior to non-individualized reconstruction models, but further investigations in humans, so as to standardize reconstruction settings, is warranted.

Assessment of regional ventilation distribution: comparison of vibration response imaging (VRI) with electrical impedance tomography (EIT).

BACKGROUND: Vibration response imaging (VRI) is a bedside technology to monitor ventilation by detecting lung sound vibrations. It is currently unknown whether VRI is able to accurately monitor the local distribution of ventilation within the lungs. We therefore compared VRI to electrical impedance tomography (EIT), an established technique used for the assessment of regional ventilation. METHODOLOGY/PRINCIPAL FINDINGS: Simultaneous EIT and VRI measurements were performed in the healthy and injured lungs (ALI; induced by saline lavage) at different PEEP levels (0, 5, 10, 15 mbar) in nine piglets. Vibration energy amplitude (VEA) by VRI, and amplitudes of relative impedance changes (rel.ΔZ) by EIT, were evaluated in seven regions of interest (ROIs). To assess the distribution of tidal volume (VT) by VRI and EIT, absolute values were normalized to the VT obtained by simultaneous spirometry measurements. Redistribution of ventilation by ALI and PEEP was detected by VRI and EIT. The linear correlation between pooled VT by VEA and rel.ΔZ was R(2) = 0.96. Bland-Altman analysis showed a bias of -1.07±24.71 ml and limits of agreement of -49.05 to +47.36 ml. Within the different ROIs, correlations of VT-distribution by EIT and VRI ranged between R(2) values of 0.29 and 0.96. ALI and PEEP did not alter the agreement of VT between VRI and EIT. CONCLUSIONS/SIGNIFICANCE: Measurements of regional ventilation distribution by VRI are comparable to those obtained by EIT.

Multi frequency phase fluorimetry (MFPF) for oxygen partial pressure measurement: ex vivo validation by polarographic clark-type electrode.

BACKGROUND: Measurement of partial pressure of oxygen (PO2) at high temporal resolution remains a technological challenge. This study introduces a novel PO2 sensing technology based on Multi-Frequency Phase Fluorimetry (MFPF). The aim was to validate MFPF against polarographic Clark-type electrode (CTE) PO2 measurements. METHODOLOGY/PRINCIPAL FINDINGS: MFPF technology was first investigated in N = 8 anaesthetised pigs at FIO2 of 0.21, 0.4, 0.6, 0.8 and 1.0. At each FIO2 level, blood samples were withdrawn and PO2 was measured in vitro with MFPF using two FOXY-AL300 probes immediately followed by CTE measurement. Secondly, MFPF-PO2 readings were compared to CTE in an artificial circulatory setup (human packed red blood cells, haematocrit of 30%). The impacts of temperature (20, 30, 40°C) and blood flow (0.8, 1.6, 2.4, 3.2, 4.0 L min(-1)) on MFPF-PO2 measurements were assessed. MFPF response time in the gas- and blood-phase was determined. Porcine MFPF-PO2 ranged from 63 to 749 mmHg; the corresponding CTE samples from 43 to 712 mmHg. Linear regression: CTE = 15.59+1.18*MFPF (R(2) = 0.93; P<0.0001). Bland Altman analysis: meandiff 69.2 mmHg, rangediff -50.1/215.6 mmHg, 1.96-SD limits -56.3/194.8 mmHg. In artificial circulatory setup, MFPF-PO2 ranged from 20 to 567 mmHg and CTE samples from 11 to 575 mmHg. Linear regression: CTE = -8.73+1.05*MFPF (R(2) = 0.99; P<0.0001). Bland-Altman analysis: meandiff 6.6 mmHg, rangediff -9.7/20.5 mmHg, 1.96-SD limits -12.7/25.8 mmHg. Differences between MFPF and CTE-PO2 due to variations of temperature were less than 6 mmHg (range 0-140 mmHg) and less than 35 mmHg (range 140-750 mmHg); differences due to variations in blood flow were less than 15 mmHg (all P-values>0.05). MFPF response-time (monoexponential) was 1.48±0.26 s for the gas-phase and 1.51±0.20 s for the blood-phase. CONCLUSIONS/SIGNIFICANCE: MFPF-derived PO2 readings were reproducible and showed excellent correlation and good agreement with Clark-type electrode-based PO2 measurements. There was no relevant impact of temperature and blood flow upon MFPF-PO2 measurements. The response time of the MFPF FOXY-AL300 probe was adequate for real-time sensing in the blood phase.

TIP peptide inhalation in oleic acid-induced experimental lung injury: a post-hoc comparison.

BACKGROUND: The lectin-like domain of TNF-α mimicked by an inhaled TIP peptide represents a novel approach to attenuate a pulmonary edema in respiratory failure, which is on the threshold to clinical application. In extension to a previously published study, which reported an improved pulmonary function following TIP peptide inhalation in a porcine model of lavage-induced lung injury, a post-hoc comparison to additional experiments was conducted. This analysis addresses the hypothesis that oleic acid injection-induced capillary leakage and alveolar necrosis blunts the previously reported beneficial effects of TIP peptide inhalation in a porcine model. FINDINGS: Following animal care committee approval lung injury was induced by oleic acid injection in six pigs with a setting strictly according to a previously published protocol that was used for lung-lavaged pigs. Ventilation/perfusion-distribution by multiple inert gas elimination, parameters of gas exchange and pulmonary edema were assessed as surrogates of the pulmonary function. A significantly improved ventilation/perfusion-distribution following TIP inhalation was recognized only in the bronchoalveolar lavage model but not following oleic acid injection. The time course after oleic acid injection yielded no comparable impact of the TIP peptide on gas exchange and edema formation. CONCLUSIONS: Reported beneficial effects of the TIP peptide on gas exchange and pulmonary edema were not reproducible in the oleic acid injection model. This analysis assumes that sustained alveolar epithelial necrosis as induced by oleic acid injection may inhibit the TIP-induced edema resolution. Regarding the on-going clinical development of the TIP peptide this approach should hardly be effective in states of severe alveolar epithelial damage.

Influence of crystalloid and colloid fluid infusion and blood withdrawal on pulmonary bioimpedance in an animal model of mechanical ventilation.

Electrical impedance tomography (EIT) is considered useful for monitoring regional ventilation and aeration in intensive-care patients during mechanical ventilation. Changes in their body fluid state modify the electrical properties of lung tissue and may interfere with the EIT measurements of lung aeration. The aim of our study was to assess the effects of crystalloid and colloid infusion and blood withdrawal on bioimpedance determined by EIT in a chest cross-section. Fourteen anaesthetized mechanically ventilated pigs were subjected to interventions affecting the volume state (crystalloid and colloid infusion, blood withdrawal). Six animals received additional crystalloid fluids (fluid group) whereas eight did not (no-fluid group). Global and regional relative impedance changes (RIC, dimensionless unit) were determined by backprojection at end-expiration. Regional ventilation distribution was analyzed by calculating the tidal RIC in the same regions. Colloid infusion led to a significant fall in the global end-expiratory RIC (mean differences: fluid: -91.2, p < 0.001, no-fluid: -38.9, p < 0.001), which was partially reversed after blood withdrawal (mean differences, fluid: +45.1, p = 0.047 and no-fluid: +26.2, p = 0.009). The RIC was significantly lower in the animals with additional crystalloids (mean group difference: 45.5, p < 0.001). Global and regional tidal volumes were not significantly affected by the fluid and volume states.