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.

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.

Endotracheal Intubation Using a Flexible Intubation Endoscope As a Standardized Model for Safe Airway Management in Swine.

Endotracheal intubation is often a basic requirement for translational research in porcine models for various interventions that require a secured airway or high ventilation pressures. Endotracheal intubation is a challenging skill, requiring a minimum number of successful endotracheal intubations to achieve a high success rate under optimal conditions, which is often unachievable for non-anaesthesiology researchers. Due to the specific porcine airway anatomy, a difficult airway can usually be assumed. The impossibility of establishing a secure airway can result in injury, adverse events, or death of the laboratory animal. Using a prospective, randomized, controlled evaluation approach, it has been shown that fiberoptic-assisted endotracheal intubation takes longer but has a higher first-pass success rate than conventional intubation without causing clinically relevant drops in oxygen saturation. This model presents a standardized regimen for endoscopically guided endotracheal intubation, providing a secured airway, especially for researchers who are inexperienced in the technique of endotracheal intubation via direct laryngoscopy. This procedure is expected to minimize animal suffering and unnecessary animal losses.

Comparison of two porcine acute lung injury models: a post-hoc analysis.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a common disease in intensive care medicine. Despite intensive research, mortality rates are high, not even in COVID-19 ARDS. Thereby, pigs offer some advantages to study the characteristics of ARDS. Many different ARDS models exist. Most of the articles published focused on histopathological and microscopic lung alterations to identify the most suitable animal ARDS model. "Macroscopic" observations and descriptions are often missing. Therefore, we performed a post-hoc comparison of two common ARDS models for pigs: lipopolysaccharide (LPS) vs. a double-hit model (bronchoalveolar lavage + oleic acid infusion). We investigated hemodynamic, spirometric and laboratory changes as another main clinical part of ARDS. RESULTS: The groups were compared by two-way analysis of variance (ANOVA) with a post-hoc Student-Newman-Keuls test. A p value lower than 0.05 was accepted as significant. All animals (n = 8 double-hit ARDS; n = 8 LPS ARDS) survived the observation period of 8 h. ARDS induction with reduced oxygen indices was successful performed in both models (76 ± 35/225 ± 54/212 ± 79 vs. 367 ± 64; T0/T4/T8 vs. BLH for double-hit; 238 ± 57/144 ± 59 vs. 509 ± 41; T4/T8 vs. BLH for LPS; p < 0.05). ARDS induced with LPS leads to more hemodynamic (mean arterial pulmonary pressure 35 ± 3/30 ± 3 vs. 28 ± 4/23 ± 4; T4/T8 LPS vs. double-hit; p < 0.05; doses of norepinephrine 1.18 ± 1.05 vs. 0.11 ± 0.16; LPS vs. double-hit for T8; p < 0.05) and inflammatory (pulmonary IL-6 expression: 2.41e-04 ± 1.08e-04 vs. 1.45e-05 ± 7.26e-06; LPS vs. double-hit; p < 0.05) alterations. ARDS induced by double-hit requires a more invasive ventilator strategy to maintain a sufficient oxygenation (PEEP at T4: 8 ± 3 vs. 6 ± 2; double-hit vs. LPS; p < 0.05). CONCLUSIONS: Both animal ARDS models are feasible and are similar to human presentation of ARDS. If your respiratory research focus on hemodynamic/inflammation variables, the LPS-induced ARDS is a feasible model. Studying different ventilator strategies, the double-hit ARDS model offers a suitable approach.

Levosimendan Ameliorates Cardiopulmonary Function but Not Inflammatory Response in a Dual Model of Experimental ARDS.

The calcium sensitiser levosimendan, which is used as an inodilator to treat decompensated heart failure, may also exhibit anti-inflammatory properties. We examined whether treatment with levosimendan improves cardiopulmonary function and is substantially beneficial to the inflammatory response in acute respiratory response syndrome (ARDS). Levosimendan was administered intravenously in a new experimental porcine model of ARDS. For comparison, we used milrinone, another well-known inotropic agent. Our results demonstrated that levosimendan intravenously improved hemodynamics and lung function in a porcine ARDS model. Significant beneficial alterations in the inflammatory response and lung injury were not detected.

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.

Hyaluronic acid plasma levels during high versus low tidal volume ventilation in a porcine sepsis model.

BACKGROUND: Shedding of the endothelial glycocalyx can be observed regularly during sepsis. Moreover, sepsis may be associated with acute respiratory distress syndrome (ARDS), which requires lung protective ventilation with the two cornerstones of application of low tidal volume and positive end-expiratory pressure. This study investigated the effect of a lung protective ventilation on the integrity of the endothelial glycocalyx in comparison to a high tidal volume ventilation mode in a porcine model of sepsis-induced ARDS. METHODS: After approval by the State and Institutional Animal Care Committee, 20 male pigs were anesthetized and received a continuous infusion of lipopolysaccharide to induce septic shock. The animals were randomly assigned to either low tidal volume ventilation, high tidal volume ventilation, or no-LPS-group groups and observed for 6 h. In addition to the gas exchange parameters and hematologic analyses, the serum hyaluronic acid concentrations were determined from central venous blood and from pre- and postpulmonary and pre- and postcerebral circulation. Post-mortem analysis included histopathological evaluation and determination of the pulmonary and cerebral wet-to-dry ratios. RESULTS: Both sepsis groups developed ARDS within 6 h of the experiment and showed significantly increased serum levels of hyaluronic acid in comparison to the no-LPS-group. No significant differences in the hyaluronic acid concentrations were detected before and after pulmonary and cerebral circulation. There was also no significant difference in the serum hyaluronic acid concentrations between the two sepsis groups. Post-mortem analysis showed no significant difference between the two sepsis groups. CONCLUSION: In a porcine model of septic shock and ARDS, the serum hyaluronic acid levels were significantly elevated in both sepsis groups in comparison to the no-LPS-group. Intergroup comparison between lung protective ventilated and high tidal ventilated animals revealed no significant differences in the serum hyaluronic acid levels.

Influence of rosuvastatin treatment on cerebral inflammation and nitro-oxidative stress in experimental lung injury in pigs.

BACKGROUND: Many patients with acute respiratory distress syndrome (ARDS) suffer from cognitive impairment after hospital discharge. Different mechanisms have been implicated as potential causes for this impairment, inter alia cerebral inflammation. A class of drugs with antioxidant and anti-inflammatory properties are ß-HMG-CoA-reductase inhibitors ("statins"). We hypothesized that treatment with rosuvastatin attenuates cerebral cytokine mRNA expression and nitro-oxidative stress in an animal model of acute lung injury. METHODS: After approval of the institutional and state animal care committee, we performed this prospective randomized controlled animal study in accordance with the international guidelines for the care and use of laboratory animals. Thirty-two healthy male pigs were randomized to one of four groups: lung injury by central venous injection of oleic acid (n = 8), statin treatment before and directly after lung injury (n = 8), statin treatment after lung injury (n = 8), or ventilation-only controls (n = 8). About 18 h after lung injury and standardized treatment, the animals were euthanised, and the brains and lungs were collected for further examinations. We determined histologic lung injury and cerebral and pulmonal cytokine and 3-nitrotyrosine production. RESULTS: We found a significant increase in hippocampal IL-6 mRNA after lung injury (p < 0.05). Treatment with rosuvastatin before and after induction of lung injury led to a significant reduction of hippocampal IL-6 mRNA (p < 0.05). Cerebral 3-nitrotyrosine was significantly higher in lung-injured animals compared with all other groups (p < 0.05 vs. animals treated with rosuvastatin after lung injury induction; p < 0.001 vs. all other groups). 3-Nitrotyrosine was also increased in the lungs of the lung-injured pigs compared to all other groups (p < 0.05 each). CONCLUSIONS: Our findings highlight cerebral cytokine production and nitro-oxidative stress within the first day after induction of lung injury. The treatment with rosuvastatin reduced IL-6 mRNA and 3-nitrotyrosine concentration in the brains of the animals. In earlier trials, statin treatment did not reduce mortality in ARDS patients but seemed to improve quality of life in ARDS survivors. Whether this is attributable to better cognitive function because of reduced nitro-oxidative stress and inflammation remains to be elucidated.

Levosimendan increases brain tissue oxygen levels after cardiopulmonary resuscitation independent of cardiac function and cerebral perfusion.

Prompt reperfusion is important to rescue ischemic tissue; however, the process itself presents a key pathomechanism that contributes to a poor outcome following cardiac arrest. Experimental data have suggested the use of levosimendan to limit ischemia-reperfusion injury by improving cerebral microcirculation. However, recent studies have questioned this effect. The present study aimed to investigate the influence on hemodynamic parameters, cerebral perfusion and oxygenation following cardiac arrest by ventricular fibrillation in juvenile male pigs. Following the return of spontaneous circulation (ROSC), animals were randomly assigned to levosimendan (12 µg/kg, followed by 0.3 µg/kg/min) or vehicle treatment for 6 h. Levosimendan-treated animals showed significantly higher brain PbtO2 levels. This effect was not accompanied by changes in cardiac output, preload and afterload, arterial blood pressure, or cerebral microcirculation indicating a local effect. Cerebral oxygenation is key to minimizing damage, and thus, current concepts are aimed at improving impaired cardiac output or cerebral perfusion. In the present study, we showed that NIRS does not reliably detect low PbtO2 levels and that levosimendan increases brain oxygen content. Thus, levosimendan may present a promising therapeutic approach to rescue brain tissue at risk following cardiac arrest or ischemic events such as stroke or traumatic brain injury.

Effect of fluid resuscitation on cerebral integrity: A prospective randomised porcine study of haemorrhagic shock.

BACKGROUND: The treatment of haemorrhagic shock is a challenging task. Colloids have been regarded as standard treatment, but their safety and benefit have been the subject of controversial debates. Negative effects, including renal failure and increased mortality, have resulted in restrictions on their administration. The cerebral effects of different infusion regimens are largely unknown. OBJECTIVES: The current study investigated the impact of gelatine-polysuccinate, hydroxyethyl starch (HES) and balanced electrolyte solution (BES) on cerebral integrity, focusing on cerebral inflammation, apoptosis and blood flow in pigs. DESIGN: Randomised experimental study. SETTING: University-affiliated large animal research unit. ANIMALS: Twenty-four juvenile pigs aged 8 to 12 weeks. INTERVENTION: Haemorrhagic shock was induced by controlled arterial blood withdrawal to achieve a combination of relevant blood loss (30 to 40 ml kg-1) and haemodynamic deterioration. After 30 min of shock, fluid resuscitation was started with either gelatine-polysuccinate, HES or BES. The animals were then monitored for 4 h. MAIN OUTCOME MEASURES: Cerebral perfusion and diffusion were measured via arterial-spin-labelling MRI. Peripheral tissue perfusion was evaluated via white light spectroscopy. Cortical and hippocampal samples were collected at the end of the experiment. The numbers of cerebral cell nuclei were counted and mRNA expression of markers for cerebral apoptosis [glucose transporter protein type 1 (SLC2A), lipocalin 2 (LCN-2), aquaporin-4 (AQP4)] and inflammation [IL-6, TNF-α, glial fibrillary acidic protein (GFAP)] were determined. RESULTS: The three fluid protocols all stabilised the macrocirculation. Fluid resuscitation significantly increased the cerebral perfusion. Gelatine-polysuccinate and HES initially led to a higher cardiac output but caused haemodilution. Cerebral cell counts (as cells µm-2) were lower after colloid administration in the cortex (gelatine-polysuccinate, 1.8 ±â€Š0.3; HES, 1.9 ±â€Š0.4; each P < 0.05 vs. BES, 2.3 ±â€Š0.2) and the hippocampus (gelatine-polysuccinate, 0.8 ±â€Š0.2; HES, 0.9 ±â€Š0.2; each P < 0.05 vs. BES, 1.1 ±â€Š0.1). After gelatine-polysuccinate, the hippocampal SLC2A and GFAP were lower. After gelatine-polysuccinate, the cortical LCN-2 and TNF-α expression levels were increased (each P < 0.05 vs. BES). CONCLUSION: In a porcine model, fluid resuscitation by colloids, particularly gelatine-polysuccinate, was associated with the occurrence of cerebral injury. ETHICAL APPROVAL NUMBER: 23 177-07/G 15-1-092; 01/2016.

Targeted fibre-optical intrabronchial lipopolysaccharide administration in pigs - a methodical refinement for improved accuracy in respiratory research.

OBJECTIVE: To establish and evaluate a standardized method of targeted, intrabronchial drug delivery in pigs. STUDY DESIGN: Randomized controlled trial. ANIMALS: A total of 16 German Landrace pigs (Sus scrofa), age range 12‒16 weeks, and weighing 28‒35 kg. METHODS: The animals were anaesthetized, intubated, and instrumented with extended cardiovascular monitoring. Lung injury was induced by administering via a flexible fibre-optic endoscope using 100 mL saline solution containing either 20 mg of Escherichia coli lipopolysaccharide (E. coli LPS) (n = 8) or no additive (sham, n = 8) into the two distal mainstem bronchi. The animals were monitored for 8 hours and arterial oxygenation, inspiratory pressure and arterial blood pressure were measured repeatedly. Post-mortem, lung tissue was prepared for histologic damage scoring and determination of proinflammatory cytokines Interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFα). Statistical analyses were performed using inter-group analysis of variance and Student's t tests. Data are presented as mean ± standard deviation. A p value <0.05 was considered significant. RESULTS: The targeted application of LPS led to significant deterioration of oxygenation consistent with mild-to-moderate acute respiratory distress syndrome (ARDS) and hypotension (Horowitz ratio: sham 2 hour, 300 ± 39; LPS 2 hour, 193.7 ± 52; p < 0.001). Histologic analyses identified increased inflammation and oedema in the tissues of the animals in the LPS group IL-6 sham: 6.4 ± 4.4 × 10-5 pg mL-1; IL-6 LPS: 2.8 ± 2.4 × 10-4 pg mL-1, p = 0.015. CONCLUSIONS: The targeted application of agents via flexible fibre-optic endoscopy is a valid, reliable method of causing controlled lung damage in a porcine model. The data presented suggest the feasibility and possible advantages of controlled application and could expand the array of techniques used to help understand the critical condition of ARDS. In addition, a targeted approach could help reduce animal numbers used for this purpose.

Experimental lung injury induces cerebral cytokine mRNA production in pigs.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is an important disease with a high incidence among patients admitted to intensive care units. Over the last decades, the survival of critically ill patients has improved; however, cognitive deficits are among the long-term sequelae. We hypothesize that acute lung injury leads to upregulation of cerebral cytokine synthesis. METHODS: After approval of the institutional and animal care committee, 20 male pigs were randomized to one of three groups: (1) Lung injury by oleic acid injection (OAI), (2) ventilation only (CTR) or (3) untreated. We compared neuronal numbers, proportion of neurons with markers for apoptosis, activation state of Iba-1 stained microglia cells and cerebral mRNA levels of different cytokines between the groups 18 hours after onset of lung injury. RESULTS: We found an increase in hippocampal TNFalpha (p < 0.05) and IL-6 (p < 0.05) messenger RNA (mRNA) in the OAI compared to untreated group as well as higher hippocampal IL-6 mRNA compared to control (p < 0.05). IL-8 and IL-1beta mRNA showed no differences between the groups. We found histologic markers for beginning apoptosis in OAI compared to untreated (p < 0.05) and more active microglia cells in OAI and CTR compared to untreated (p < 0.001 each). CONCLUSION: Hippocampal cytokine transcription increases within 18 hours after the induction of acute lung injury with histological evidence of neuronal damage. It remains to be elucidated if increased cytokine mRNA synthesis plays a role in the cognitive decline observed in survivors of ARDS.

Bronchoalveolar Lavage and Oleic Acid-Injection in Pigs as a Double-Hit Model for Acute Respiratory Distress Syndrome (ARDS).

The treatment of ARDS continues to pose major challenges for intensive care physicians in the 21st century with mortality rates still reaching up to 50% in severe cases. Further research efforts are needed to better understand the complex pathophysiology of this disease. There are different well-established animal models to induce acute lung injury but none has been able to adequately mimic the complex pathomechanisms of ARDS. The most crucial factor for the development of this condition is the damage to the alveolar capillary unit. The combination of two well-established lung injury models allow us to mimic in more detail the underlying pathomechanism. Bronchoalveolar lavage (BAL) leads to surfactant depletion as well as alveolar collapse. The repeated instillation of fluid volumes causes subsequent hypoxemia. Surfactant depletion is a key factor of ARDS in humans. BAL is often combined with other lung injury approaches, but not with a second hit followed by oleic acid injection (OAI) yet. Oleic acid injection leads to severely impaired gas exchange, a deterioration of lung mechanics and disruption of the alveolo-capillary barrier. The OAI mimics most of the expected effects of ARDS consisting of extended inflammation of lung tissue with an increase of alveolar leakage and gas exchange impairment. A disadvantage of the combination of different models is the difficulty to determine the influence to the lung injury caused by BAL alone, OAI alone or both together. The model presented in this report represents the combination of BAL and OAI as a new double-hit lung injury model. This new model is easy to implement and an alternative to study different therapeutic approaches in ARDS in the future.

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.

Standardized Model of Ventricular Fibrillation and Advanced Cardiac Life Support in Swine.

Cardiopulmonary resuscitation after cardiac arrest, independent of its origin, is a regularly encountered medical emergency in hospitals as well as preclinical settings. Prospective randomized trials in human subjects are difficult to design and ethically ambiguous, which results in a lack of evidence-based therapies. The model presented in this report represents one of the most common causes of cardiac arrests, ventricular fibrillation, in a standardized setting in a large animal model. This allows for reproducible observations and various therapeutic interventions under clinically accurate conditions, hence facilitating the generation of better evidence and eventually the potential for improved medical treatment.

Fluid resuscitation-related coagulation impairment in a porcine hemorrhagic shock model.

BACKGROUND: Fast and effective treatment of hemorrhagic shock is one of the most important preclinical trauma care tasks e.g., in combat casualties in avoiding severe end-organ damage or death. In scenarios without immediate availability of blood products, alternate regimens of fluid resuscitation represent the only possibility of maintaining sufficient circulation and regaining adequate end-organ oxygen supply. However, the fluid choice alone may affect the extent of the bleeding by interfering with coagulation pathways. This study investigates the impact of hydroxyethyl starch (HES), gelatine-polysuccinate (GP) and balanced electrolyte solution (BES) as commonly used agents for fluid resuscitation on coagulation using a porcine hemorrhagic shock model. METHODS: Following approval by the State and Institutional Animal Care Committee, life-threatening hemorrhagic shock was induced via arterial blood withdrawal in 24 anesthetized pigs. Isovolumetric fluid resuscitation with either HES, GP or BES (n = 3 × 8) was performed to compensate for the blood loss. Over four hours, hemodynamics, laboratory parameters and rotational thromboelastometry-derived coagulation were analyzed. As secondary endpoint the porcine values were compared to human blood. RESULTS: All the agents used for fluid resuscitation significantly affected coagulation. We measured a restriction of laboratory parameters, clot development and clot firmness, particularly in HES- and GP-treated animals. Hemoglobin content dropped in all groups but showed a more pronounced decline in colloid-treated pigs. This effect was not maintained over the four-hour monitoring period. CONCLUSION: HES, GP, and BEL sufficiently stabilized the macrocirculation, but significantly affected coagulation. These effects were most pronounced after colloid and particularly HES administration. Despite suitability for rapid hemodynamic stabilization, colloids have to be chosen with caution, because their molecular properties may affect coagulation directly and as a consequence of pronounced hemodilution. Our comparison of porcine and human coagulation showed increased coagulation activity in pig blood.

Random allogeneic blood transfusion in pigs: characterisation of a novel experimental model.

BACKGROUND: Organ cross-talk describes interactions between a primary affected organ and a secondarily injured remote organ, particularly in lung-brain interactions. A common theory is the systemic distribution of inflammatory mediators that are released by the affected organ and transferred through the bloodstream. The present study characterises the baseline immunogenic effects of a novel experimental model of random allogeneic blood transfusion in pigs designed to analyse the role of the bloodstream in organ cross-talk. METHODS: After approval of the State and Institutional Animal Care Committee, 20 anesthetized pig were randomized in a donor and an acceptor (each n = 8): the acceptor animals each received high-volume whole blood transfusion from the donor (35-40 ml kg-1). Four animals received balanced electrolyte solution instead of blood transfusion (control group; n = 4). Afterwards the animals underwent extended cardiorespiratory monitoring for eight hours. Post mortem assessment included pulmonary, cerebral and systemic mediators of early inflammatory response (IL-6, TNF-alpha, iNOS), wet to dry ratio, and lung histology. RESULTS: No adverse events or incompatibilities occurred during the blood transfusion procedures. Systemic cytokine levels and pulmonary function were unaffected. Lung histopathology scoring did not display relevant intergroup differences. Neither within the lung nor within the brain an up-regulation of inflammatory mediators was detected. High volume random allogeneic blood transfusion in pigs neither impaired pulmonary integrity nor induced systemic, lung, or brain inflammatory response. CONCLUSION: This approach can represent a novel experimental model to characterize the blood-bound transmission in remote organ injury.

Standardized Hemorrhagic Shock Induction Guided by Cerebral Oximetry and Extended Hemodynamic Monitoring in Pigs.

Hemorrhagic shock ranks among the main reasons for severe injury-related death. The loss of circulatory volume and oxygen carriers can lead to an insufficient oxygen supply and irreversible organ failure. The brain exerts only limited compensation capacities and is particularly at high risk of severe hypoxic damage.This article demonstrates the reproducible induction of life-threatening hemorrhagic shock in a porcine model by means of calculated blood withdrawal. We titrate shock induction guided by near-infrared spectroscopy and extended hemodynamic monitoring to display systemic circulatory failure, as well as cerebral microcirculatory oxygen depletion. In comparison to similar models that primarily focus on predefined removal volumes for shock induction, this approach highlights a titration by means of the resulting failure of macro- and microcirculation.

Oleic Acid-Injection in Pigs As a Model for Acute Respiratory Distress Syndrome.

The acute respiratory distress syndrome is a relevant intensive care disease with an incidence ranging between 2.2% and 19% of intensive care unit patients. Despite treatment advances over the last decades, ARDS patients still suffer mortality rates between 35 and 40%. There is still a need for further research to improve the outcome of patients suffering from ARDS. One problem is that no single animal model can mimic the complex pathomechanism of the acute respiratory distress syndrome, but several models exist to study different parts of it. Oleic acid injection (OAI)-induced lung injury is a well-established model for studying ventilation strategies, lung mechanics and ventilation/perfusion distribution in animals. OAI leads to severely impaired gas exchange, deterioration of lung mechanics and disruption of the alveolo-capillary barrier. The disadvantage of this model is the controversial mechanistic relevance of this model and the necessity for central venous access, which is challenging especially in smaller animal models. In summary, OAI-induced lung injury leads to reproducible results in small and large animals and hence represents a well-suited model for studying ARDS. Nevertheless, further research is necessary to find a model that mimics all parts of ARDS and lacks the problems associated with the different models existing today.

Ultra-low tidal volume ventilation-A novel and effective ventilation strategy during experimental cardiopulmonary resuscitation.

BACKGROUND: The effects of different ventilation strategies during CPR on patient outcomes and lung physiology are still poorly understood. This study compares positive pressure ventilation (IPPV) to passive oxygenation (CPAP) and a novel ultra-low tidal volume ventilation (ULTVV) regimen in an experimental ventricular fibrillation animal model. STUDY DESIGN: Prospective randomized controlled trial. ANIMALS: 30 male German landrace pigs (16-20 weeks). METHODS: Ventricular fibrillation was induced in anesthetized and instrumented pigs and the animals were randomized into three groups. Mechanical CPR was initiated and ventilation was either provided by means of standard IPPV (RR: 10/min, Vt: 8-9 ml/kg, FiO2: 1,0, PEEP: 5 mbar), CPAP (O2-Flow: 10 l/min, PEEP: 5 mbar) or ULTVV (RR: 50/min, Vt: 2-3 ml/kg, FiO2: 1,0, PEEP: 5 mbar). Guideline-based advanced life support was applied for a maximum of 4 cycles and animals achieving ROSC were monitored for 6 h before terminating the experiment. Ventilation/perfusion ratios were performed via multiple inert gas elimination, blood gas analyses were taken hourly and extended cardiovascular measurements were collected constantly. Brain and lung tissue samples were taken and analysed for proinflammatory cytokine expression. RESULTS: ULTVV provided sufficient oxygenation and ventilation during CPR while demanding significantly lower respiratory and intrathoracic pressures. V/Q mismatch was significantly decreased and lung injury was mitigated in surviving animals compared to IPPV and CPAP. Additionally, cerebral cytokine expression was dramatically reduced. CONCLUSION: Ultra-low-volume ventilation during CPR in a porcine model is feasible and may provide lung-protective benefits as well as neurological outcome improvement due to lower inflammation. Our results warrant further studies and might eventually lead to new therapeutic options in the resuscitation setting.