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(Circulation. 1999;99:2302-2309.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Hemodynamic Changes Induced by Liposomes and Liposome-Encapsulated Hemoglobin in Pigs

A Model for Pseudoallergic Cardiopulmonary Reactions to Liposomes: Role of Complement and Inhibition by Soluble CR1 and Anti-C5a Antibody

Janos Szebeni, MD, PhD; John L. Fontana, MD; Nabila M. Wassef, PhD; Paul D. Mongan, MD; David S. Morse, MD; David E. Dobbins, PhD; Gregory L. Stahl, PhD; Rolf Bünger, MD, PhD; Carl R. Alving, MD

From the Departments of Membrane Biochemistry, Walter Reed Army Institute of Research, Washington, DC (J.S., N.M.W., C.R.A.); Anesthesiology and Physiology, Uniformed Services University of the Health Sciences, Bethesda, Md (J.L.F., P.D.M., D.E.D., R.B.); and Anesthesia, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (D.S.M., G.L.S.).

Correspondence to Janos Szebeni, MD, PhD, Department of Membrane Biochemistry, Walter Reed Army Institute of Research, Washington, DC 20307-5100.

Background—Intravenous administration of some liposomal drugs can trigger immediate hypersensitivity reactions that include symptoms of cardiopulmonary distress. The mechanism underlying the cardiovascular changes has not been clarified.

Methods and Results—Anesthetized pigs (n=18) were injected intravenously with 5-mg boluses of large multilamellar liposomes, and the ensuing hemodynamic, hematologic, and laboratory changes were recorded. The significant (P<0.01) alterations included 79±9% (mean±SEM) rise in pulmonary arterial pressure, 30±7% decline in cardiac output, 11±2% increase in heart rate, 236±54% increase in pulmonary vascular resistance, 71±27% increase in systemic vascular resistance, and up to a 100-fold increase in plasma thromboxane B₂. These changes peaked between 1 and 5 minutes after injection, subsided within 10 to 20 minutes, were lipid dose–dependent (ED₅₀=4.5±1.4 mg), and were quantitatively reproducible in the same animal several times over 7 hours. The liposome-induced rises of pulmonary arterial pressure showed close quantitative and temporal correlation with elevations of plasma thromboxane B₂ and were inhibited by an anti-C5a monoclonal antibody (GS1), by sCR1, or by indomethacin. Liposomes caused C5a production in pig serum in vitro through classic pathway activation and bound IgG and IgM natural antibodies. Zymosan- and hemoglobin-containing liposomes and empty liposomes caused essentially identical pulmonary changes.

Conclusions—The intense, nontachyphylactic, highly reproducible, complement-mediated pulmonary hypertensive effect of minute amounts of intravenous liposomes in pigs represents a unique, unexplored phenomenon in circulation physiology. The model provides highly sensitive detection and study of cardiopulmonary side effects of liposomal drugs and many other pharmaceutical products due to "complement activation–related pseudoallergy" (CARPA).

Key Words: thromboxane • hemodynamics • hypertension, pulmonary • immune system • blood cells

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