Anaphylactoid reactions in children receiving high-dose intravenous cyclosporine for reversal of tumor resistance: The causative role of improper dissolution of Cremophor EL

Purpose: An unusually high incidence of anaphylactoid reactions was observed during a phase I/II trial of high-dose intravenous cyclosporine (CsA) therapy to attenuate tumor multidrug resistance (MDR). Five of 21 children experienced severe anaphylactoid reactions shortly after initiation of the first or second CsA infusion. We hypothesized that improper dissolution of the vehicle Cremophar EL may have been a cause for these anaphylactoid reactions. Methods: All nurses who had administered intravenous CsA were interviewed regarding their technique of preparing the infusion and the occurrence of an anaphylactoid reaction. The responses were statistically analyzed. The effect of various mixing techniques on the distribution of Cremophor EL in the infusion was experimentally evaluated. Different mixing techniques were used to assess their effect an the distribution of Cremophor EL in the solution. Results: Analysis of the preparation techniques of the CsA infusion showed significant correlation between suboptimal mixing of CsA by nurses and the occurrence of anaphylactoid reactions (P = .02). Experimental simulation showed that suboptimal mixing results in an uneven distribution of Cremophor EL, which subsequently sinks to the bottom of the vial. Conclusion: Improper mixing of high-dose CsA infusions causes nonsolubilized Cremophor EL to sink to the outflow area of the bottle. An initial bolus infusion of highly concentrated Cremophor EL may produce an anaphylactoid-like response. This mechanism of toxicity is important to recognize, because it is easily preventable by proper preparation of the infusion, thus reducing the incidence of potentially life-threatening anaphylactoid reactions.