Plasma expansion by polyethylene-glycol-modified albumin

Abstract

Systemic inflammatory response conditions are associated with capillary leak and haemodynamic compromise. Fluid resuscitation to reverse the ensuing hypovolaemia is, however, complicated by the decreased endothelium reflection coefficient to albumin and other colloids. We developed PEG–Alb (albumin covalently linked to polyethylene glycol) as a potential resuscitative agent. PEG was covalently linked to human albumin at multiple sites on the protein. The modified protein was heterogeneous when examined by SDS/PAGE, size-exclusion chromatography and SELDI–TOF MS (surface-enhanced laser-desorption ionization–time of flight MS). Based on size-exclusion chromatography and osmotic pressure data, the effective volume of PEG–Alb is increased 13- to 16-fold compared with unmodified albumin. In an LPS (lipopolysaccharide) model of shock, rats treated with PEG–Alb showed better blood pressure, lower Hct (haematocrit) consistent with haemodilution and less lung injury than rats treated with unmodified albumin or saline. In a CLP (caecal ligation and puncture) model of sepsis, PEG–Alb was more effective than albumin or saline in maintaining blood pressure and in decreasing Hct. When fluorescein-labelled PEG–Alb and Texas Red-labelled albumin were administered to rats with LPS- or CLP-induced shock, PEG–Alb was retained within blood vessels, whereas albumin extravasates into the interstitial space. Based on these data, PEG–Alb appears to be retained within blood vessels in models of capillary leak. PEG–Alb may ultimately be effective in the clinical treatment of shock associated with capillary leak.