High permeability pulmonary edema is a key feature of acute lung injury (ALI) and is worsened by mechanical ventilation. Although ALI represents a significant cause of morbidity and mortality in critically ill patients, specific adjunctive therapies are not well characterized. As sphingosine-1-phosphate (Sph-1-P), a biologically active phospholipid, enhances endothelial layer barrier function in vitro, we hypothesized that Sph-1-P would attenuate alveolar edema formation in a canine model of endotoxin (LPS)-induced ALI.
11 male beagles (10-15 kg) were anesthetized, intubated, and mechanically ventilated. LPS (2 mg/kg in 0.9 NS) was segmentally instilled intrabronchially via fiberoptic bronchoscope in four control dogs and in four dogs treated concomitantly with intravenous Sph-1-P (85 μg/kg). Sham intrabronchial saline instillation was performed in three animals. Supportive care including mechanical ventilation (Vt=17cc/kg, PEEP=5 cm H2O, FiO2=30%), fluid resuscitation, and hemodynamic monitoring was provided for six hours. ALI was quantified by shunt formation (Qs/Qt), bronchoalveolar lavage (BAL) protein concentration, and Evan’s Blue Dye (EB) extravasation.
Beagles remained hemodynamically stable throughout each experiment. Qs/Qt increased rapidly following LPS instillation and continued to rise over time in control dogs (solid circles). Sph-1-P attenuated increases in shunt fraction following an initial exacerbation of LPS-induced injury (open circles, p<0.05 at 90 min, p=0.05 at 330 min). Saline instillation evoked mild increases in shunt (squares). BAL protein concentration was lower in Sph-1-P treated dogs (dark grey bars) compared to controls (black bars) at 150 min (p<0.05) and at 330 min. BAL protein was attenuated in Sph-1-P animals compared to sham injured dogs (light grey bars, p<0.05 at 330 min). Finally, EB extravasation was decreased in sham and Sph-1-P dogs compared to LPS controls.CONCLUSIONS: Intravenous Sph-1-P attenuates vascular leak associated with LPS-induced ALI.
Sph-1-P may shorten the duration of mechanical ventilation and thereby limit morbidity associated with ALI.
B.J. McVerry, None.