An Animal Model for the Detection of Hypotensive Side Effects of Immunoglobulin Preparations

Intravenous administration of certain immunoglobulin preparations may cause severe adverse reactions, especially in immunodeficient patients. These reactions are generally assumed to be related to the anticomplementary activity of the preparations, caused by IgG aggregates. Because the exact mechanism of the adverse reaction is unknown, we investigated the reactions induced in anesthetized rats on rapid intravenous administration of different human immunoglobulin preparations. The most conspicuous observation was a severe, long-lasting hypotension, induced by standard immunoglobulin preparations (for intramuscular use), which appeared to be independent from the concomitant complement and neutrophil activation. The long-lasting hypotension was not related to the presence of prekallikrein activator, which induced a transient hypotensive reaction only after sensitizing the rats to bradykinin. The reactions appeared to be associated with IgG aggregates. It was found that certain aggregates induced mainly complement activation, whereas others had mainly a hypotensive effect or no effect at all. It was concluded that the rat model provides a sensitive and reproducible test system for vasoactive properties of immunoglobulin preparations for intravenous administration that cannot be predicted from in vitro measurements, such as anticomplementary activity, aggregate content or prekallikrein activator activity. It is suggested that the test may also be used for other plasma products for intravenous administration.