Rolf Dembinski

Simvastatin Reduces Endotoxin-Induced Acute Lung Injury by Decreasing Neutrophil Recruitment and Radical Formation

Introduction Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. As simvastatin exerts protective effects in inflammatory diseases we explored its effects on development of ALI and due to the importance of neutrophils in ALI also on neutrophil effector functions. Methods C57Bl/6 mice were exposed to aerosolized LPS (500 µg/ml) for 30 min. The count of alveolar, interstitial, and intravasal neutrophils were assessed 4 h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and albumin content in the BAL fluid. In vitro, we analyzed the effect of simvastatin on neutrophil adhesion, degranulation, apoptosis, and formation of reactive oxygen species. To monitor effects of simvastatin on bacterial clearance we performed phagocytosis and bacterial killing studies in vitro as well as sepsis experiments in mice. Results Simvastatin treatment before and after onset of ALI reduces neutrophil influx into the lung as well as lung permeability indicating the protective role of simvastatin in ALI. Moreover, simvastatin reduces the formation of ROS species and adhesion of neutrophils without affecting apoptosis, bacterial phagocytosis and bacterial clearance. Conclusion Simvastatin reduces recruitment and activation of neutrophils hereby protecting from LPS-induced ALI. Our results imply a potential role for statins in the management of ALI.

Respiratory compliance but not gas exchange correlates with changes in lung aeration after a recruitment maneuver: an experimental study in pigs with saline lavage lung injury

IntroductionAtelectasis is a common finding in acute lung injury, leading to increased shunt and hypoxemia. Current treatment strategies aim to recruit alveoli for gas exchange. Improvement in oxygenation is commonly used to detect recruitment, although the assumption that gas exchange parameters adequately represent the mechanical process of alveolar opening has not been proven so far. The aim of this study was to investigate whether commonly used measures of lung mechanics better detect lung tissue collapse and changes in lung aeration after a recruitment maneuver as compared to measures of gas exchangeMethodsIn eight anesthetized and mechanically ventilated pigs, acute lung injury was induced by saline lavage and a recruitment maneuver was performed by inflating the lungs three times with a pressure of 45 cmH2O for 40 s with a constant positive end-expiratory pressure of 10 cmH2O. The association of gas exchange and lung mechanics parameters with the amount and the changes in aerated and nonaerated lung volumes induced by this specific recruitment maneuver was investigated by multi slice CT scan analysis of the whole lung.ResultsNonaerated lung correlated with shunt fraction (r = 0.68) and respiratory system compliance (r = 0.59). The arterial partial oxygen pressure (PaO2) and the respiratory system compliance correlated with poorly aerated lung volume (r = 0.57 and 0.72, respectively). The recruitment maneuver caused a decrease in nonaerated lung volume, an increase in normally and poorly aerated lung, but no change in the distribution of a tidal breath to differently aerated lung volumes. The fractional changes in PaO2, arterial partial carbon dioxide pressure (PaCO2) and venous admixture after the recruitment maneuver did not correlate with the changes in lung volumes. Alveolar recruitment correlated only with changes in the plateau pressure (r = 0.89), respiratory system compliance (r = 0.82) and parameters obtained from the pressure-volume curve.ConclusionA recruitment maneuver by repeatedly hyperinflating the lungs led to an increase of poorly aerated and a decrease of nonaerated lung mainly. Changes in aerated and nonaerated lung volumes were adequately represented by respiratory compliance but not by changes in oxygenation or shunt.

Effects of partial ventilatory support modalities on respiratory function in severe hypoxemic lung injury.

Objective:The early phase of acute respiratory distress syndrome (ARDS) is characterized by impaired respiratory mechanics, ventilation-perfusion mismatch, and severe hypoxemia. Partial ventilatory support can effectively unload the respiratory workload and improve pulmonary gas exchange with less hemodynamic compromise. The partial ventilatory support mode most indicated in early phases of ARDS has not been determined. This study compares the effects of assisted ventilatory techniques on breathing pattern, gas exchange, hemodynamic function, and respiratory effort with those of controlled mechanical ventilation in similarly sedated subjects. Design:Prospectively randomized crossover animal study. Setting:Animal research laboratory. Subjects:Eleven anesthetized and mechanically ventilated pigs. Interventions:Acute lung injury was induced by lung lavage. Pressure-controlled ventilation (PCV), pressure-controlled assisted ventilation (P-ACV), bilevel positive airway pressure (BIPAP), and pressure support ventilation (PSV) with equal airway pressures and sedation were applied in random order. Measurements and Main Results:Gas exchange, respiratory effort, and hemodynamic function were measured, and ventilation-perfusion distributions were calculated by multiple inert-gas-elimination techniques. The results revealed that partial ventilatory support was superior to PCV in maintaining adequate oxygenation and hemodynamic function with reduced sedation. The effects of P-ACV, BIPAP, and PSV were comparable with respect to gas exchange and hemodynamic function, except for a more pronounced reduction in shunt during BIPAP. P-ACV and PSV were superior to BIPAP to reduce respiratory drive and work of breathing. PSV affected the pattern of breathing and deadspace to a greater degree than did P-ACV. Conclusions:In acute lung injury, P-ACV preserves oxygenation and hemodynamic function with less respiratory effort compared with BIPAP and reduces the need for sedation compared with PCV.

Effect of inhaled prostacyclin in combination with almitrine on ventilation-perfusion distributions in experimental lung injury.

Objective: To investigate a possible additive effect of combined nitric oxide (NO) and almitrine bismesylate (ALM) on pulmonary ventilation-perfusion (V˙.A/Q˙) ratio.¶Design: Prospective, controlled animal study.¶Setting: Animal research facility of a university hospital.¶Interventions: Three conditions were studied in ten female pigs with experimental acute lung injury (ALI) induced by repeated lung lavage: 1) 10 ppm NO, 2) 10 ppm NO with 1 μg/kg per min ALM, 3) 1 μg/kg per min ALM. For each condition, gas exchange, hemodynamics and V˙.A/Q˙ distributions were analyzed using the multiple inert gas elimination technique (MIGET).¶Measurement and results: With NO + ALM, arterial oxygen partial pressure (PaO2) increased from 63 ± 18 mmHg to 202 ± 97 mmHg while intrapulmonary shunt decreased from 50 ± 15 % to 26 ± 12 % and blood flow to regions with a normal V˙.A/Q˙ ratio increased from 49 ± 16 % to 72 ± 15 %. These changes were significant when compared to untreated ALI (p < 0.05) and NO or ALM alone (p < 0.05), although improvements due to NO or ALM also reached statistical significance compared to ALI values (p < 0.05).¶Conclusions: We conclude that NO + ALM results in an additive improvement of pulmonary gas exchange in an experimental model of ALI by diverting additional blood flow from non-ventilated lung regions towards those with normal V˙.A/Q˙ relationships.

Pressure support compared with controlled mechanical ventilation in experimental lung injury.

UNLABELLED It has been suggested that, in acute lung injury (ALI), spontaneous breathing activity may increase oxygenation because of an improvement of ventilation-perfusion distribution. Pressure support ventilation (PSV) is one of the assisted spontaneous breathing modes often used in critical care medicine. We sought to determine the prolonged effects of PSV on gas exchange in experimental ALI. We hypothesized that PSV may increase oxygenation because of an improvement in ventilation-perfusion distribution. Thus, ALI was induced in 20 pigs by using repetitive lung lavage. Thereafter, the animals were randomized to receive either PSV with a pressure level set to achieve a tidal volume >4 mL/kg and a respiratory rate <40 min(-1) (n = 10) or controlled mechanical ventilation (CMV) with a tidal volume of 10 mL/kg and a respiratory rate of 20 min(-1) (n = 10). Positive end-expiratory pressure was set at 10 cm H(2)O in both groups. Blood gas analyses and determination of ventilation-perfusion (.V(A)/.Q) distribution were performed at the onset of ALI and after 2, 4, 8, and 12 h. The main result was an improvement of oxygenation because of a decrease of pulmonary shunt and an increase of areas with normal .V(A)/.Q ratios during PSV (P < 0.005). However, during CMV, a more pronounced reduction of shunt was observed compared with PSV (P < 0.005). We conclude that, in this model of ALI, PSV improves gas exchange because of a reduction of .V(A)/.Q inequality. However, improvements in .V(A)/.Q distribution may be more effective with CMV than with PSV. IMPLICATIONS Assisted spontaneous breathing may have beneficial effects on gas exchange in acute lung injury. We tested this hypothesis for pressure support ventilation in an animal model of acute lung injury. Our results demonstrate that pressure support does not necessarily provide better gas exchange than controlled mechanical ventilation.

Effect of aerosolized prostacyclin and inhaled nitric oxide on experimental hypoxic pulmonary hypertension

Objective: To compare the effect of different concentrations of inhaled nitric oxide and doses of nebulized prostacyclin on hypoxia-induced pulmonary hypertension in pigs.¶Design: Prospective, controlled animal study.¶Setting: Animal research facilities of an university hospital.¶Interventions: After reducing the fraction of inspired oxygen (FIO2) from 1.0 to 0.1, two groups of five pigs each were submitted to inhalation of three concentrations of nitric oxide (5, 10 and 20 ppm) or three doses of prostacyclin (2.5, 5, 10 ng × kg–1× min–1).¶Results: All doses of prostacyclin and concentrations of nitric oxide resulted in a decrease in mean pulmonary arterial pressure and pulmonary vascular resistance when compared to hypoxic ventilation (p < 0.001) which was independent of the dose or concentration of either drug used. While inhalation of nitric oxide caused a reduction in mean pulmonary arterial pressure back to values obtained during ventilation with FIO2 1.0, values achieved with prostacyclin were still significantly higher when compared to measurements prior to the initiation of hypoxic ventilation. However, direct comparison of the effect of 20 ppm nitric oxide and 10 ng × kg–1× min–1 prostacyclin on mean pulmonary arterial pressure revealed no differences between the drugs. All other hemodynamic and gas exchange parameters remained stable throughout the study.¶Conclusions: Inhalation of clinically used concentrations of nitric oxide and doses of prostacyclin can decrease elevated pulmonary arterial pressure in an animal model of hypoxic pulmonary vasoconstriction without impairing systemic hemodynamics or gas exchange.

S-100 protein and neurohistopathologic changes in a porcine model of acute lung injury

Background: Survivors of acute respiratory distress syndrome exhibit neuropsychological sequelae that might be attributable to hippocampal damage. The authors sought to determine the effects of hypoxemia in a pig model of acute lung injury on the hippocampal region and the release of S-100 protein in comparison to a control group in which hypoxemia was induced by reducing the inspired oxygen fraction. Methods: Hypoxemia was induced in 14 female pigs by repeated lung lavages (lung injury group; n = 7) or by reducing the inspired oxygen fraction (hypoxia-only group; n = 7). Hemodynamic variables, gas exchange, and serum concentrations of S-100 protein were measured at baseline, after induction of acute lung injury, and subsequently for 12 h. Animals were euthanized, and the brains were removed for histopathologic examination. Results: Comparable blood gases were seen in both groups. Serum S-100 protein concentrations were comparable for both groups at baseline. At all other time points, S-100 concentrations were significantly higher in the lung injury group. Neuropathologic examination showed basophilic and shrunken neurons of the pyramidal cell layer in the hippocampal CA1 subregion of all pigs in the lung injury group. Few abnormalities were seen in the hypoxia-only group. Conclusions: The same degree of hypoxemia induced in a lavage model of acute lung injury results in greater brain damage assessed by S-100 protein and histopathologic findings when compared to a group in which hypoxemia at the same degree was induced by reducing the inspired oxygen fraction. This suggests that acute lung injury leads to neuropathologic changes independent of hypoxemia.

Treatment of burns in the first 24 hours: simple and practical guide by answering 10 questions in a step-by-step form

Residents in training, medical students and other staff in surgical sector, emergency room (ER) and intensive care unit (ICU) or Burn Unit face a multitude of questions regarding burn care. Treatment of burns is not always straightforward. Furthermore, National and International guidelines differ from one region to another. On one hand, it is important to understand pathophysiology, classification of burns, surgical treatment, and the latest updates in burn science. On the other hand, the clinical situation for treating these cases needs clear guidelines to cover every single aspect during the treatment procedure. Thus, 10 questions have been organised and discussed in a step-by-step form in order to achieve the excellence of education and the optimal treatment of burn injuries in the first 24 hours. These 10 questions will clearly discuss referral criteria to the burn unit, primary and secondary survey, estimation of the total burned surface area (%TBSA) and the degree of burns as well as resuscitation process, routine interventions, laboratory tests, indications of Bronchoscopy and special considerations for Inhalation trauma, immediate consultations and referrals, emergency surgery and admission orders. Understanding and answering the 10 questions will not only cover the management process of Burns during the first 24 hours but also seems to be an interactive clear guide for education purpose.

Extrakorporale Membranoxygenierung beim akuten Lungenversagen

ZusammenfassungDie extrakorporale Membranoxygenierung (ECMO) stellt heute im Rahmen klinischer Algorithmen einen wichtigen Baustein in der Therapie des schweren akuten Lungenversagens (ARDS) dar, nachdem sich in observationellen Studien der Wert dieses Verfahrens für die ARDS-Therapie trotz fehlender positiver kontrollierter Studien gezeigt hat. In spezialisierten Zentren wird bei Patienten mit drohender Hypoxie nach Anwendung verschiedener konservativer Therapieverfahren die ECMO unter Integration von Blutpumpen und künstlichen Membranlungen (Oxygenatoren) als Lungenersatzverfahren angewandt. Die Neuentwicklung von Oberflächenbeschichtungen, optimierten Oxygenatoren und miniaturisierten Blutpumpen sollte in der Zukunft sowohl die Hämokompatibilität steigern als auch die klinische Anwendung vereinfachen und komplikationsärmer machen. Die Entwicklung von Oxygenatoren mit deutlich niedrigeren Strömungswiderständen ermöglicht dabei die klinische Anwendung als pumpenloses, durch die arteriovenöse Druckdifferenz getriebenes Lungenunterstützungsverfahren (ECLA). Diese Neuentwicklungen könnten in der Zukunft zur Anwendung der ECMO nicht mehr nur als „ultima ratio“, sondern auch bei weniger schwerem ARDS führen, um lungenprotektivere, weniger invasive Beatmungsformen zu ermöglichen.AbstractAfter various observational studies demonstrated a benefit of extracorporeal membrane oxygenation (ECMO) in the therapy of severe acute respiratory distress syndrome (ARDS), ECMO now represents an important contribution for ARDS therapy using clinical algorithms despite a lack of positive controlled studies. In specialized centers patients with severe ARDS and imminent hypoxia despite intensive conventional therapy, are treated with ECMO using blood pumps and artificial membrane lungs (oxygenators) for extracorporeal lung assist. The development of new surface modifications, optimized oxygenators and miniaturized blood pumps should increase hemocompatibility and lead to simplified treatment as well as less complications. New oxygenators with significantly decreased blood resistance allow the clinical application of pumpless arteriovenous extracorporeal lung assist (ECLA). After these new developments indications for ECMO could be extended from use not only as ultima ratio but to less severe ARDS to enable lung protective, less invasive mechanical ventilation.

Low tidal volume ventilation in a porcine model of acute lung injury improves cerebral tissue oxygenation.

BACKGROUND:In study, we investigated the effects of different tidal volumes on cerebral tissue oxygenation and cerebral metabolism in a porcine model of acute lung injury (ALI). We hypothesized that mechanical ventilation with low tidal (LT) volumes improves cerebral tissue oxygenation and metabolism after experimentally induced ALI. METHODS:After inducing experimental ALI by surfactant depletion, we studied two conditions in 10 female pigs: 1) LT volume ventilation with 6 mL/kg body weight, and 2) high tidal (HT) volume ventilation with 12 mL/kg body weight. Variables of gas exchange, hemodynamic, continuous cerebral tissue oxygen tension (ptiO2), cerebral microdialysis, and systemic cytokines were analyzed. After induction of ALI, data were collected at 2, 4, and 8 h. The primary end point was the change in ptiO2. For group comparisons, a t-test was used. A value of <0.05 was considered to indicate statistical significance. RESULTS:At baseline and after induction of ALI, no differences between groups were found in ptiO2; however, ptiO2 was significantly lower in the HT group after 4 and 8 h. Pao2 and Paco2 showed no significant differences between the groups at all timepoints. Regarding cerebral microdialysis, a significantly higher level of extracellular lactate could be demonstrated after 2, 4, and 8 h in the HT group. The release of cytokines resulted in higher values for interleukin-6 and interleukin-8 in the HT group. CONCLUSION:Protective ventilation with LT yielded a significant improvement in cerebral tissue oxygenation and metabolism compared to HT ventilation in a porcine model of ALI. There was dissociation between arterial and cerebral tissue oxygenation. Cerebral oxygenation and metabolism might have possibly been impaired by a more distinctive inflammatory response in the HT group.