PATHOBIOLOGY OF INTRAVENOUS LIPID EMULSIONS IN CHILDREN

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Intravenous lipid emulsions are an important part of total parenteral nutrition (TPN). Complications of TPN with lipid emulsions are seen, however, and include fever and "pyrogen reactions," abnormal pulmonary function, and thrombocytopenia. It had been our clinical impression that thrombocytopenia is a particular problem of lipid emulsion therapy in some neonates and children with burns. We believe that C-reactive protein (CRP), present in trace amounts in normal plasma but markedly elevated with infection, inflammation, or trauma, combines with the phosphocholine emulsifier of lipid emulsion to create liposomes capable of activating complement, generating anaphylatoxins C3a and C5a, thereby aggregating platelets and causing fever. In clinical studies, we will define the incidence of thrombocytopenia and other adverse reactions in neonates and burned children receiving lipid emulsion therapy, and attempt to correlate these reactions with CRP, anaphylatoxin levels, and a quantitative plasma "creaming" reaction that we have developed. We will also study a small number of adult patients, from whom a larger number of sequential samples can be drawn. We will purify CRP by column chromatography to give us adequate amounts of CRP for in vitro experimentation. In vitro experiments are designed to study the effects of lipid emulsion on two target cells of adverse reactions, the macrophage and the platelets. We will study the elaboraton of IL-1 by monocytes challenged with lipid incubated in different types of plasma. Normal plasma, plasma supplemented with varying concentraions of CRP, various complement deficient plasmas will be used to study the relative contributions of CRP and complement in the elaboration of the endogenous pyrogen, Il-1. We will study platelet activation by lipid-plasma interactions. Complement deficient plasma and F (ab') anti-CRP will be used to determine whether platelet activation involves liposome-CRP binding, C3a generation, or liposome-CRP-Clq binding, or some combination. Finally, we will attempt to further study the pathologic events in rabbits with both normal and elevated CRP levels infused with lipid emulsion, to determine the role of CRP and of complement activation in producing these reactions (fever, neutropenia, thrombocytopenia).