Thomas Iber

Bβ15-42 (FX06) reduces pulmonary, myocardial, liver, and small intestine damage in a pig model of hemorrhagic shock and reperfusion

Objective:The fibrin-derived peptide Bβ15-42 (also called FX06) has been shown to reduce myocardial infarct size following ischemia/reperfusion. Hemorrhagic shock (HS) followed by volume resuscitation represents a similar scenario, whereby a whole organism is vulnerable to reperfusion injury. Design:We subjected male farm-bred landrace pigs (∼30 kg) to HS by withdrawing blood to a mean arterial pressure of 40 mm Hg for 60 minutes. Pigs were then resuscitated with shed blood and crystalloids for 60 minutes, and at this time, FX06 (2.4 mg/kg, n = 8) or vehicle control (phosphate buffered saline; 2.4 mg/kg, n = 7) was injected as an intravenous bolus. Setting:University hospital laboratory. Subjects:Anesthetized male farm-bred landrace pigs. Measurements and Main Results:Data are presented as mean ± sd. Five hours after resuscitation, controls presented acute lung injury (Pao2/Fio2-ratio <300 mm Hg; extra-vascular lung water index (marker for lung injury): 9.0 ± 1.8 mL/kg) and myocardial dysfunction/damage (cardiac index: 4.3 ± 0.25 L/min/m2; stroke volume index: 30 ± 6 mL/m2; cardiac TnT levels: 0.58 ± 0.25 ng/mL). In contrast, FX06-treated animals showed significantly improved pulmonary and circulatory function (Pao2/Fio2-ratio >*400 mm Hg; extra-vascular lung water index: *5.2 ± 2.1 mL/kg, cardiac index: *6.3 ± 1.4 L/min/m2; stroke volume index: *51 ± 11 mL/m2; cardiac TnT levels: *0.11 ± 0.09 ng/mL; *p < 0.05). Also, tissue oxygenation (tpO2; mm Hg) was significantly improved during reperfusion in FX06-treated pigs when compared with controls (liver 51 ± 4 vs. *65 ± 4; serosa 44 ± 5 vs. *55 ± 7; mucosa 14 ± 4 vs. *26 ± 4). Finally, FX06 reduced accumulation of myeloperoxidase-positive cells (mainly neutrophils) in myocardium, liver, and small intestine and reduced interleukin-6 plasma levels (*p < 0.05; compared with controls). Conclusion:We conclude that in a pig model of HS and reperfusion, administration of FX06 during reperfusion protects shock- susceptible organs such as heart, lung, liver, and small intestine.

Superimposed high-frequency jet ventilation combined with continuous positive airway pressure/assisted spontaneous breathing improves oxygenation in patients with H1N1-associated ARDS

BackgroundNumerous cases of swine-origin 2009 H1N1 influenza A virus (H1N1)-associated acute respiratory distress syndrome (ARDS) bridged by extracorporeal membrane oxygenation (ECMO) therapy have been reported; however, complication rates are high. We present our experience with H1N1-associated ARDS and successful bridging of lung function using superimposed high-frequency jet ventilation (SHFJV) in combination with continuous positive airway pressure/assisted spontaneous breathing (CPAP/ASB).MethodsWe admitted five patients with H1N1 infection and ARDS to our intensive care unit. Although all patients required pure oxygen and controlled ventilation, oxygenation was insufficient. We applied SHFJV/CPAP/ASB to improve oxygenation.ResultsInitial PaO2/FiO2 ratio prior SHFJV was 58-79 mmHg. In all patients, successful oxygenation was achieved by SHFJV (PaO2/FiO2 ratio 105-306 mmHg within 24 h). Spontaneous breathing was set during first hours after admission. SHFJV could be stopped after 39, 40, 72, 100, or 240 h. Concomitant pulmonary herpes simplex virus (HSV) infection was observed in all patients. Two patients were successfully discharged. The other three patients relapsed and died within 7 weeks mainly due to combined HSV infection and in two cases reoccurring H1N1 infection.ConclusionsSHFJV represents an alternative to bridge lung function successfully and improve oxygenation in the critically ill.

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.

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.