Rosiglitazone dampens pulmonary inflammation in a porcine model of acute lung injury.

The hallmarks of acute lung injury (ALI) are the compromised alveolar-capillary barrier and the extravasation of leukocytes into the alveolar space. Given the fact that the peroxisome proliferator-activated receptor-γ agonist rosiglitazone holds significant anti-inflammatory properties, we aimed to evaluate whether rosiglitazone could dampen these hallmarks of local pulmonary inflammation in a porcine model of lung injury. For this purpose, we used a model of lipopolysaccharide (LPS, 50 µg/kg)-induced ALI. One hundred twenty minutes following the infusion of LPS, we started the exposure to rosiglitazone through inhalation or infusion. We found that intravenous rosiglitazone significantly controlled local pulmonary inflammation as determined through the expression of cytokines within the alveolar compartment. Furthermore, we found a significant reduction of the protein concentration and neutrophil activity within the alveolar space. In summary, we therefore conclude that the treatment with rosiglitazone might dampen local pulmonary inflammation during the initial stages of ALI.

The neuronal guidance protein netrin-1 reduces alveolar inflammation in a porcine model of acute lung injury.

INTRODUCTION: Acute lung injury (ALI) is an inflammatory disorder of pulmonary or extrapulmonary origin. We have previously demonstrated that netrin-1 dampens murine ALI, and in an attempt to advance this finding into future clinical practice we evaluated whether netrin-1 would reduce alveolar inflammation during porcine ALI. METHODS: This was a controlled in vivo experimental study in pigs. We induced ALI through lipoploysaccharide (LPS) infusion (50 µg/kg) for 2 hours. Following this, we exposed animals to either vehicle, intravenous netrin-1 (netrin-1 i.v.) or inhaled netrin-1 (netrin-1 inh.). Serum samples and bronchoalveolar lavage (BAL) were obtained to determine levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, interleukin-6 and interleukin-8 at baseline and 6 hours following treatment. Myeloperoxidase activity (MPO) and protein levels were determined in the BAL, and tissue samples were obtained for histological evaluation. Finally, animals were scanned with spiral CT. RESULTS: Following LPS infusion, animals developed acute pulmonary injury. Serum levels of TNF-α and IL-6 were significantly reduced in the netrin-1 i.v. group. BAL demonstrated significantly reduced cytokine levels 6 hours post-netrin-1 treatment (TNF-α: vehicle 633 ± 172 pg/ml, netrin-1 i.v. 84 ± 5 pg/ml, netrin-1 inh. 168 ± 74 pg/ml; both P < 0.05). MPO activity and protein content were significantly reduced in BAL samples from netrin-1-treated animals. Histological sections confirmed reduced inflammatory changes in the netrin-1-treated animals. Computed tomography corroborated reduced pulmonary damage in both netrin-1-treated groups. CONCLUSIONS: We conclude that treatment with the endogenous anti-inflammatory protein netrin-1 reduces pulmonary inflammation during the initial stages of ALI and should be pursued as a future therapeutic option.

Thoracic epidural anesthesia in sepsis--is it harmful or protective?

Research interest in epidural anesthesia during sepsis has grown over the past years and studies have tried to determine its mechanisms, which should, theoretically, protect organs and reduce morbidity and mortality. However, different experimental approaches in different animal models have provided conflicting results over whether epidural anesthesia has protective or harmful effects and whether these alter depending on the phase of sepsis, the spread of epidural anesthesia or additional supportive therapies. In the future, more standardized research is necessary to integrate the results of all studies, which have been published.

A double blind, single centre, sub-chronic reperfusion trial evaluating FX06 following haemorrhagic shock in pigs.

OBJECTIVE: Haemorrhagic shock causes ischaemia and subsequent fluid resuscitation causes reperfusion injury, jointly resulting in high morbidity and mortality. We tested whether the anti-inflammatory fibrin-derived peptide, Bbeta(15-42), also called FX06, is tissue protective in a model of haemorrhagic shock. METHODS: In a pig model, we standardised the severity of haemorrhagic shock by achieving a cumulative oxygen deficit of approximately 100ml/kg body weight by withdrawing blood over a period of 1h. This was followed by resuscitation with shed blood and full electrolyte solution, and pigs were monitored for 3 days. At reperfusion, 17 pigs were randomly assigned to FX06 or solvent treatment. RESULTS: FX06-treated pigs demonstrated improved cardiac function (stroke volume index: 67ml/m(2) versus 33ml/m(2)), decreased troponin T release in the early reperfusion (0.24ng/ml versus 0.78ng/ml), decreased AST levels after 24h (106U/l versus 189U/l) and decreased creatinine levels after 24h (108micromol/l versus 159micromol/l). Furthermore, FX06-treated pigs demonstrated preservation of the gut/blood barrier, while controls demonstrated high endotoxin plasma levels indicating translocation of bacteria and/or its products (0.2EU/ml versus 24.3EU/ml) after 24h. This study also demonstrates a significantly improved neurological performance in the FX06 group as determined by S100beta serum levels (0.72microg/l versus 1.25microg/l) after 48h and neurological deficit scores (11 versus 70) after 24h. CONCLUSION: FX06 - when administered as an adjunct to fluid resuscitation therapy - is organ protective in pigs. Further investigations are warranted to reveal the protective mechanism of FX06.

Successful transtracheal lung ventilation using a manual respiration valve: an in vitro and in vivo study.

BACKGROUND: Lung ventilation through a thin transtracheal cannula may be attempted in patients with laryngeal stenosis or "cannot intubate, cannot ventilate" situations. It may be impossible to achieve sufficient ventilation if the lungs are spontaneously emptying only through the thin transtracheal cannula, which imposes high resistance to airflow, resulting in dangerous hyperinflation. Therefore, the authors describe the use of a manual respiration valve that serves as a bidirectional pump providing not only inflation but also active deflation of the lungs in case of emergency transtracheal lung ventilation. METHODS: The effectiveness of such a valve was tested in vitro using mechanical lungs in combination with two different cannula sizes and various gas flows. The valve was then tested in five pigs using a transtracheal 16-gauge cannula with three different combinations of inspiratory/expiratory times and gas flows and an occluded upper airway. RESULTS: In the mechanical lungs, the valve permitted higher minute volumes compared with spontaneous lung emptying. In vivo, the arterial oxygen and carbon dioxide partial pressures increased initially and then remained stable over 1 h (arterial oxygen tension, 470.8 +/- 86.8; arterial carbon dioxide tension, 63.0 +/- 7.2 mmHg). The inspiratory pressures measured in the trachea remained below 10 cm H2O and did not substantially influence central venous and pulmonary artery pressures. Mean arterial pressure and cardiac output were unaffected by the ventilation maneuvers. CONCLUSIONS: This study demonstrated in vitro and in vivo in adult pigs that satisfactory lung ventilation can be assured with transtracheal ventilation through a 16-gauge cannula for a prolonged period of time if combined with a bidirectional manual respiration valve.

Graft survival and graft function of pediatric en bloc kidneys in paraaortal position.

BACKGROUND: En bloc kidneys from pediatric donors are regarded as questionable with respect to the safety and quality of the transplant outcome. Therefore, we retrospectively studied graft outcome and graft function of our 56 en bloc kidneys transplanted in paraaortal position between 1992 and 1999. METHODS: Graft outcome of en bloc kidneys (group A) was compared with graft outcome of single cadaveric adult donor kidneys (group B). Matched pairs were generated regarding HLA-missmatch, cold ischemic time, recipient age, body mass index, and systolic arterial blood pressure. RESULTS: Allograft survival rates of pediatric en bloc kidneys at 1, 3, and 5 years were significantly lower (group A: 78, 70, 70% vs. group B: 92, 92, 81%, P<0.05). Lower survival rate was caused by a higher number of graft losses in the early postoperative period (group A: 21% vs. group B: 4%, P<0.01) due to vascular complications. Main risk factor for graft loss was donor age of less than 12 months. Five years after transplantation serum creatinine of pediatric en bloc kidneys was significantly better than of adult kidneys (0.9+/-0.06 vs. 1.8+/-0.2 mg/dl, P<0.001). CONCLUSION: En bloc kidneys show a high percentage of graft survival with excellent long-term graft function. However, the early postoperative period carries a higher risk of graft loss in very young donors due to vascular complications. In the face of donor shortage en bloc kidneys from pediatric donors can successfully be transplanted in a paraaortal position.