Hemolysis and Renal Failure Associated with Inappropriate use of Sterile Water to Dilute 25% Albumin Solution

The FDA is aware of four cases of hemolysis that have occurred since 1994, during or following plasmapheresis when Albumin (Human) 25% was diluted to a 5% final protein concentration using Sterile Water for Injection. One case is the subject of a previously published letter to the editor.⁽¹⁾ Clinical details of the three additional cases that were reported to medWatch may be found in references 2 and 3.

Hemolysis, which was observed in all four cases and which was followed by acute renal failure in two of them, resulted from infusion, during plasmapheresis, of varying amounts of hypotonic albumin solutions that had been prepared with Sterile Water for Injection. Albumin (Human) solutions of all concentrations are formulated to have a sodium concentration between 130 and 160 mEq/L. Thus, a fivefold dilution in sterile water would produce about one-fifth that of 0.9% sodium chloride (isotonic saline). The large volumes used in plasmapheresis/plasma exchange were likely a contributing factor, in view of the fact that the hypotonic plasma replacement mixture would have accounted for a significant fraction of the patient's calculated blood volume. In the hypotonic environment, shear forces in the plasmapheresis device may have contributed to the observed hemolysis.

The hospital pharmacies in the above cases apparently relied on information contained in the widely distributed 1994 edition of Trissel's Handbook on Injectable Drugs.⁽⁴⁾ The section of this monograph that deals with Albumin (Human) 25% states in part, "A 5% solution may be prepared from the 25% product by adding 1 volume of 25% albumin to 4 volumes of sterile water or an infusion solution such as dextrose 5% in water or sodium chloride 0.9%." This section was revised in 1996 to read, "A 5% solution may be prepared from the 25% product by adding 1 volume of 25% albumin to 4 volumes of an infusion solution, such as dextrose 5% in water or sodium chloride 0.9%. If sterile water for injection is the diluent, the tonicity of the diluted solution must be considered. Substantial reduction in tonicity creates the potential for hemolysis."⁽⁵⁾

We do not know how often this dilution error is occurring in pharmacies. However, the current short supply of Albumin (Human) may lead to increasingly frequent instances of dilution of more concentrated solutions, creating an increased potential for error. The medical community needs to be aware of this potentially serious problem. FDA is recommending to manufacturers of Albumin (Human) 25% that the package inserts for their products be revised to include (1) a warning statement about the risk of potentially fatal hemolysis and acute renal failure when Sterile Water for Injection is used as a diluent for albumin and (2) information on acceptable diluents, such as 0.9% saline or 5% dextrose in water. The importance of consulting up-to-date references is also emphasized. The risk of serious morbidity and mortality can be reduced by remembering that, whenever drugs for intravenous infusion are diluted, the tonicity of the final solution must be considered.

Health care professionals should report any serious adverse events, including cases like those described above, to FDA's medWatch Program at 1-800-FDA-1088 or (FAX) 1-800-FDA-0178, and/or to the respective pharmaceutical manufacturers.

5. Trissel LA. Handbook on Injectable Drugs. 9th ed. Bethesda, MD: American Society of Health System Pharmacists; 1996.