Clinical dosage of lidocaine does not impact the biomedical outcome of sepsis-induced acute respiratory distress syndrome in a porcine model.

Background: Sepsis is a common disease in intensive care units worldwide, which is associated with high morbidity and mortality. This process is often associated with multiple organ failure including acute lung injury. Although massive research efforts have been made for decades, there is no specific therapy for sepsis to date. Early and best treatment is crucial. Lidocaine is a common local anesthetic and used worldwide. It blocks the fast voltage-gated sodium (Na+) channels in the neuronal cell membrane responsible for signal propagation. Recent studies show that lidocaine administered intravenously improves pulmonary function and protects pulmonary tissue in pigs under hemorrhagic shock, sepsis and under pulmonary surgery. The aim of this study is to show that lidocaine inhalative induces equivalent effects as lidocaine intravenously in pigs in a lipopolysaccharide (LPS)-induced sepsis with acute lung injury. Methods: After approval of the local State and Institutional Animal Care Committee, to induce the septic inflammatory response a continuous infusion of lipopolysaccharide (LPS) was administered to the pigs in deep anesthesia. Following induction and stabilisation of sepsis, the study medication was randomly assigned to one of three groups: (1) lidocaine intravenously, (2) lidocaine per inhalation and (3) sham group. All animals were monitored for 8 h using advanced and extended cardiorespiratory monitoring. Postmortem assessment included pulmonary mRNA expression of mediators of early inflammatory response (IL-6 & TNF-alpha), wet-to-dry ratio and lung histology. Results: Acute respiratory distress syndrome (ARDS) was successfully induced after sepsis-induction with LPS in all three groups measured by a significant decrease in the PaO2/FiO2 ratio. Further, septic hemodynamic alterations were seen in all three groups. Leucocytes and platelets dropped statistically over time due to septic alterations in all groups. The wet-to-dry ratio and the lung histology showed no differences between the groups. Additionally, the pulmonary mRNA expression of the inflammatory mediators IL-6 and TNF-alpha showed no significant changes between the groups. The proposed anti-inflammatory and lung protective effects of lidocaine in sepsis-induced acute lung injury could not be proven in this study.

Non-invasive assessment of Pulse Wave Transit Time (PWTT) is a poor predictor for intraoperative fluid responsiveness: a prospective observational trial (best-PWTT study).

BACKGROUND: Aim of this study is to test the predictive value of Pulse Wave Transit Time (PWTT) for fluid responsiveness in comparison to the established fluid responsiveness parameters pulse pressure (ΔPP) and corrected flow time (FTc) during major abdominal surgery. METHODS: Forty patients undergoing major abdominal surgery were enrolled with continuous monitoring of PWTT (LifeScope® Modell J BSM-9101 Nihon Kohden Europe GmbH, Rosbach, Germany) and stroke volume (Esophageal Doppler Monitoring CardioQ-ODM®, Deltex Medical Ltd, Chichester, UK). In case of hypovolemia (difference in pulse pressure [∆PP] ≥ 9%, corrected flow time [FTc] ≤ 350 ms) a fluid bolus of 7 ml/kg ideal body weight was administered. Receiver operating characteristics (ROC) curves and corresponding areas under the curve (AUCs) were used to compare different methods of determining PWTT. A Wilcoxon test was used to discriminate fluid responders (increase in stroke volume of ≥ 10%) from non-responders. The predictive value of PWTT for fluid responsiveness was compared by testing for differences between ROC curves of PWTT, ΔPP and FTc using the methods by DeLong. RESULTS: AUCs (area under the ROC-curve) to predict fluid responsiveness for PWTT-parameters were 0.61 (raw c finger Q), 0.61 (raw c finger R), 0.57 (raw c ear Q), 0.53 (raw c ear R), 0.54 (raw non-c finger Q), 0.52 (raw non-c finger R), 0.50 (raw non-c ear Q), 0.55 (raw non-c ear R), 0.63 (∆ c finger Q), 0.61 (∆ c finger R), 0.64 (∆ c ear Q), 0.66 (∆ c ear R), 0.59 (∆ non-c finger Q), 0.57 (∆ non-c finger R), 0.57 (∆ non-c ear Q), 0.61 (∆ non-c ear R) [raw measurements vs. ∆ = respiratory variation; c = corrected measurements according to Bazett's formula vs. non-c = uncorrected measurements; Q vs. R = start of PWTT-measurements with Q- or R-wave in ECG; finger vs. ear = pulse oximetry probe location]. Hence, the highest AUC to predict fluid responsiveness by PWTT was achieved by calculating its respiratory variation (∆PWTT), with a pulse oximeter attached to the earlobe, using the R-wave in ECG, and correction by Bazett's formula (AUC best-PWTT 0.66, 95% CI 0.54-0.79). ∆PWTT was sufficient to discriminate fluid responders from non-responders (p = 0.029). No difference in predicting fluid responsiveness was found between best-PWTT and ∆PP (AUC 0.65, 95% CI 0.51-0.79; p = 0.88), or best-PWTT and FTc (AUC 0.62, 95% CI 0.49-0.75; p = 0.68). CONCLUSION: ΔPWTT shows poor ability to predict fluid responsiveness intraoperatively. Moreover, established alternatives ΔPP and FTc did not perform better. TRIAL REGISTRATION: Prior to enrolement on clinicaltrials.gov (NC T03280953; date of registration 13/09/2017).

Resveratrol influences pulmonary mechanics and inflammatory response in a porcine ARDS model.

AIMS: Influencing the inflammatory response represents an important branch in ARDS research. The naturally occurring polyphenol derivative resveratrol has already been confirmed to have strong anti-inflammatory effects on the cardiac and metabolic system. In the present study, we investigated the propagated anti-inflammatory effects of intravenous resveratrol in a porcine ARDS model. MAIN METHODS: 20 domestic pigs (30 ± 2 kg; approval G20-1-135), divided into three groups: 1. resveratrol high dose (HD; n = 8), single bolus of 20 mg/kg over 15 min. 2. resveratrol low dose (LD; n = 8), single bolus of 10 mg/kg over 15 min. 3. Vehicle (n = 4), with the carrier solution DMSO over 15 min administered after ARDS induction. ARDS induction: using BAL/oleic acid and a subsequent test period of 8 h. Measurement parameters: Hemodynamics/spirometry data were collected continuously, BGA/laboratory parameters repetitively. Post-mortem: analysis of pulmonary inflammatory markers. STATISTICS: Two-way analysis of variance (repeated measurement) and Student-Newman-Keuls method. KEY FINDINGS: Resveratrol HD significantly reduced the expression of TNF-alpha in lung tissue compared to the LD group (p < 0.05). A significantly increased functional residual capacity (FRC) could be demonstrated for the HD group at the end of the test (p < 0.05 for HD vs. LD/vehicle). Further, resveratrol HD reduced statistically the EVLWI compared to LD/vehicle (p < 0.05 at T4/T8). SIGNIFICANCE: In this study, resveratrol HD ameliorated pulmonary mechanics as reported for the FRC and EVLWI. Further, the proposed anti-inflammatory effects of resveratrol, a significant reduction in the expression of TNF-alpha was observed in the HD group.

Lung-brain 'cross-talk': systemic propagation of cytokines in the ARDS via the bloodstream using a blood transfusion model does not influence cerebral inflammatory response in pigs.

Background: Interorgan cross-talk describes the phenomenon in which a primarily injured organ causes secondary damage to a distant organ. This cross-talk is well known between the lung and brain. One theory suggests that the release and systemic distribution of cytokines via the bloodstream from the primarily affected organ sets in motion proinflammatory cascades in distant organs. In this study, we analysed the role of the systemic distribution of cytokines via the bloodstream in a porcine ARDS model for organ cross-talk and possible inflammatory changes in the brain. Methods: After approval of the State and Institutional Animal Care Committee, acute respiratory distress syndrome (ARDS) induction with oleic acid injection was performed in seven animals. Eight hours after ARDS induction, blood (35-40 ml kg-1) was taken from these seven 'ARDS donor' pigs. The collected 'ARDS donor' blood was transfused into seven healthy 'ARDS-recipient' pigs. Three animals served as a control group, and blood from these animals was transfused into three healthy pigs after an appropriate ventilation period. All animals were monitored for 8 h using advanced cardiorespiratory monitoring. Postmortem assessment included cerebral (hippocampal and cortex) mediators of early inflammatory response (IL-6, TNF-alpha, iNOS, sLCN-2), wet-to-dry ratio and lung histology. TNF-alpha serum concentration was measured in all groups. Results: ARDS was successfully induced in the 'ARDS donor' group, and serum TNF-alpha levels were elevated compared with the 'ARDS-recipient' group. In the 'ARDS-recipient' group, neither significant ARDS alterations nor upregulation of inflammatory mediators in the brain tissue were detected after high-volume random allogenic 'ARDS-blood' transfusion. The role of the systemic distribution of inflammatory cytokines from one affected organ to another could not be confirmed in this study.

Bi-Level ventilation decreases pulmonary shunt and modulates neuroinflammation in a cardiopulmonary resuscitation model.

BACKGROUND: Optimal ventilation strategies during cardiopulmonary resuscitation are still heavily debated and poorly understood. So far, no convincing evidence could be presented in favour of outcome relevance and necessity of specific ventilation patterns. In recent years, alternative models to the guideline-based intermittent positive pressure ventilation (IPPV) have been proposed. In this randomized controlled trial, we evaluated a bi-level ventilation approach in a porcine model to assess possible physiological advantages for the pulmonary system as well as resulting changes in neuroinflammation compared to standard measures. METHODS: Sixteen male German landrace pigs were anesthetized and instrumented with arterial and venous catheters. Ventricular fibrillation was induced and the animals were left untreated and without ventilation for 4 minutes. After randomization, the animals were assigned to either the guideline-based group (IPPV, tidal volume 8-10 ml/kg, respiratory rate 10/min, FiO21.0) or the bi-level group (inspiratory pressure levels 15-17 cmH2O/5cmH2O, respiratory rate 10/min, FiO21.0). Mechanical chest compressions and interventional ventilation were initiated and after 5 minutes, blood samples, including ventilation/perfusion measurements via multiple inert gas elimination technique, were taken. After 8 minutes, advanced life support including adrenaline administration and defibrillations were started for up to 4 cycles. Animals achieving ROSC were monitored for 6 hours and lungs and brain tissue were harvested for further analyses. RESULTS: Five of the IPPV and four of the bi-level animals achieved ROSC. While there were no significant differences in gas exchange or hemodynamic values, bi-level treated animals showed less pulmonary shunt directly after ROSC and a tendency to lower inspiratory pressures during CPR. Additionally, cytokine expression of tumour necrosis factor alpha was significantly reduced in hippocampal tissue compared to IPPV animals. CONCLUSION: Bi-level ventilation with a constant positive end expiratory pressure and pressure-controlled ventilation is not inferior in terms of oxygenation and decarboxylation when compared to guideline-based IPPV ventilation. Additionally, bi-level ventilation showed signs for a potentially ameliorated neurological outcome as well as less pulmonary shunt following experimental resuscitation. Given the restrictions of the animal model, these advantages should be further examined.

Lung injury does not aggravate mechanical ventilation-induced early cerebral inflammation or apoptosis in an animal model.

INTRODUCTION: The acute respiratory distress syndrome is not only associated with a high mortality, but also goes along with cognitive impairment in survivors. The cause for this cognitive impairment is still not clear. One possible mechanism could be cerebral inflammation as result of a "lung-brain-crosstalk". Even mechanical ventilation itself can induce cerebral inflammation. We hypothesized, that an acute lung injury aggravates the cerebral inflammation induced by mechanical ventilation itself and leads to neuronal damage. METHODS: After approval of the institutional and state animal care committee 20 pigs were randomized to one of three groups: lung injury by central venous injection of oleic acid (n = 8), lung injury by bronchoalveolar lavage in combination with one hour of injurious ventilation (n = 8) or control (n = 6). Brain tissue of four native animals from a different study served as native group. For six hours all animals were ventilated with a tidal volume of 7 ml kg-1 and a scheme for positive end-expiratory pressure and inspired oxygen fraction, which was adapted from the ARDS network tables. Afterwards the animals were killed and the brains were harvested for histological (number of neurons and microglia) and molecular biologic (TNFalpha, IL-1beta, and IL-6) examinations. RESULTS: There was no difference in the number of neurons or microglia cells between the groups. TNFalpha was significantly higher in all groups compared to native (p < 0.05), IL-6 was only increased in the lavage group compared to native (p < 0.05), IL-1beta showed no difference between the groups. DISCUSSION: With our data we can confirm earlier results, that mechanical ventilation itself seems to trigger cerebral inflammation. This is not aggravated by acute lung injury, at least not within the first 6 hours after onset. Nevertheless, it seems too early to dismiss the idea of lung-injury induced cerebral inflammation, as 6 hours might be just not enough time to see any profound effect.

Endexpiratory lung volume measurement correlates with the ventilation/perfusion mismatch in lung injured pigs.

BACKGROUND: In acute respiratory respiratory distress syndrome (ARDS) a sustained mismatch of alveolar ventilation and perfusion (VA/Q) impairs the pulmonary gas exchange. Measurement of endexpiratory lung volume (EELV) by multiple breath-nitrogen washout/washin is a non-invasive, bedside technology to assess pulmonary function in mechanically ventilated patients. The present study examines the association between EELV changes and VA/Q distribution and the possibility to predict VA/Q normalization by means of EELV in a porcine model. METHODS: After approval of the state and institutional animal care committee 12 anesthetized pigs were randomized to ARDS either by bronchoalveolar lavage (n = 6) or oleic acid injection (n = 6). EELV, VA/Q ratios by multiple inert gas elimination and ventilation distribution by electrical impedance tomography were assessed at healthy state and at five different positive endexpiratory pressure (PEEP) steps in ARDS (0, 20, 15, 10, 5 cmH2O; each maintained for 30 min). RESULTS: VA/Q, EELV and tidal volume distribution all displayed the PEEP-induced recruitment in ARDS. We found a close correlation between VA/Q < 0.1 (representing shunt and low VA/Q units) and changes in EELV (spearman correlation coefficient -0.79). Logistic regression reveals the potential to predict VA/Q normalization (VA/Q < 0.1 less than 5%) from changes in EELV with an area under the curve of 0.89 with a 95%-CI of 0.81-0.96 in the receiver operating characteristic. Different lung injury models and recruitment characteristics did not influence these findings. CONCLUSION: In a porcine ARDS model EELV measurement depicts PEEP-induced lung recruitment and is strongly associated with normalization of the VA/Q distribution in a model-independent fashion. Determination of EELV could be an intriguing addition in the context of lung protection strategies.

Inhalation therapy with the synthetic TIP-like peptide AP318 attenuates pulmonary inflammation in a porcine sepsis model.

BACKGROUND: The lectin-like domain of TNF-α can be mimicked by synthetic TIP peptides and represents an innovative pharmacologic option to treat edematous respiratory failure. TIP inhalation was shown to reduce pulmonary edema and improve gas exchange. In addition to its edema resolution effect, TIP peptides may exert some anti-inflammatory properties. The present study therefore investigates the influence of the inhaled TIP peptide AP318 on intrapulmonary inflammatory response in a porcine model of systemic sepsis. METHODS: In a randomized-blinded setting lung injury was induced in 18 pigs by lipopolysaccharide-infusion and a second hit with a short period of ventilator-induced lung stress, followed by a six-hour observation period. The animals received either two inhalations with the peptide (AP318, 2×1 mg kg(-1)) or vehicle. Post-mortem pulmonary expression of inflammatory and mechanotransduction markers were determined by real-time polymerase chain reaction (IL-1ß, IL-6, TNF-α, COX-2, iNOS, amphiregulin, and tenascin-c). Furthermore, regional histopathological lung injury, edema formation and systemic inflammation were quantified. RESULTS: Despite similar systemic response to lipopolysaccharide infusion in both groups, pulmonary inflammation (IL-6, TNF-α, COX-2, tenascin-c) was significantly mitigated by AP318. Furthermore, a Western blot analysis shows a significantly lower of COX-2 protein level. The present sepsis model caused minor lung edema formation and moderate gas exchange impairment. Six hours after onset pathologic scoring showed no improvement, while gas exchange parameters and pulmonary edema formation were similar in the two groups. CONCLUSION: In summary, AP318 significantly attenuated intrapulmonary inflammatory response even without the presence or resolution of severe pulmonary edema in a porcine model of systemic sepsis-associated lung injury. These findings suggest an anti-inflammatory mechanism of the lectin-like domain beyond mere edema reabsorption in endotoxemic lung injury in vivo.

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.

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 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.

Influence of platelet-rich plasma on the anterior fusion in spinal injuries: a qualitative and quantitative analysis using computer tomography.

INTRODUCTION: The effects of platelet-rich plasma (PRP) were monitored by performing a controlled cohort study of patients undergoing an anterior spinal fusion. One group was treated with the addition of PRP. The growth factors contained within the blood platelets are known to play an important role in the new formation of bone following fractures or the implantation of bone grafts. But the results following the use of PRP in spinal fusion are not yet published. METHOD: The study involved a group of 15 patients, who had suffered an injury of the thoracic or lumbar spine and had undergone an anterior fusion using cages. They had received an additional posterior stabilisation and/or anterior implants as well as bone graft combined with PRP. A control group made up of 20 patients received a similar treatment, but without the addition of PRP. A CT scan was performed of all patients during follow-up examinations. The area on the left side of the cage, where the bone graft with or without PRP had been applied, was analysed and the patients were divided into three classes, depending upon the rate of fusion: complete fusion, incomplete fusion and no/minimal ossification. In cases which were classified as complete or incomplete ossification, an additional CT volumetry and densitometry was performed. The patient-referred outcome was documented using the VAS spinal score. RESULTS: In both groups, 40% of the patients had reached a complete fusion in the CT scans. No or minimal fusion was documented in 20% of the PRP group and 30% of the control group. When measuring the density within the newly formed bone mass, both groups showed nearly identical percentages with a density of over 100 Hounsfield units (HU). The share of bone with a density of over +500 HU was 29.33% in the PRP group and 23.57% in the control group. Within the partition of over +100 HU, the absolute density was significantly higher in the PRP group (639.7 vs. 514.2 HU). Similar results could be shown within the partition of over +500 HU (930.7 vs. 846 HU). The VAS scores showed no significant differences between the two groups. CONCLUSION: The additional application of autologous PRP involves very little risk for the patients. The study implies that the use of PRP provides a faster fusion and higher density values within the fusion mass. A clear advancement in spinal fusion in terms of a clinical benefit remains questionable.