Correspondence

A Dangerous Error in the Dilution of 25 Percent Albumin

N Engl J Med 1998; 338:1226-1227April 23, 1998

Article

To the Editor:

Physicians and pharmacists should be alert to a serious error that can occur in the preparation of replacement albumin solutions for plasmapheresis.

Plasmapheresis was performed in an elderly man who had myeloma with renal insufficiency. One plasma volume exchange was ordered, with 5 percent albumin as the replacement solution, with calcium, potassium, and magnesium supplements. Because of the lack of availability of 5 percent albumin, the hospital pharmacy used 25 percent albumin and diluted this solution 1:4 with sterile water to achieve a 5 percent solution. Reference was made to Trissel's Handbook on Injectable Drugs, the 1994 edition of which states, “A 5% solution may be prepared from the 25% product by adding 1 volume of the 25% albumin to 4 volumes of sterile water or an infusion solution such as dextrose 5% in water or sodium chloride 0.9%.”1 The pharmacist used sterile water as described by the handbook, resulting in a hypo-osmolar solution that caused severe hemolysis in the patient. The hematocrit dropped 7.3 points, and renal failure developed.

This flagrant error in instructing dilution with water was only partially corrected in the 1996 edition of Trissel's handbook. This edition states, “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.” In view of the osmolarity of the 25 percent albumin solution diluted with sterile water (approximately 36 mOsm per liter), one should never use water to dilute 25 percent albumin.

The problem is aggravated by the label on the 25 percent albumin solution. The label states that 100 ml of 25 percent albumin is “osmotically equivalent to 500 ml of plasma.” This statement is not true. It confuses the osmotic and oncotic effects. The oncotic effect of 100 ml of the 25 percent solution is equivalent to 500 ml of plasma, but since the concentration of saline in the 25 percent solution is isotonic with plasma, the osmotic effect of 100 ml of the 25 percent is equivalent to only 100 ml of plasma.

The handbook and product label need to be corrected as soon as possible to prevent this error in the future. Pharmacies and the medical community should be alert to this potentially life-threatening error.

Donald R. Steinmuller, M.D.
800 N. Westmoreland Rd., Lake Forest, IL 60045

1 References

1. 1

   Trissel LA. Handbook on injectable drugs. 8th ed. Bethesda, Md.: American Society of Health-System Pharmacists, 1994.
   

The above letter was referred to representatives of the Food and Drug Administration (FDA), who reply below:

To the Editor: Including the case reported by Dr. Steinmuller, the FDA is aware of four cases of hemolysis that have occurred since 1994 during or after plasmapheresis when albumin (human) 25 percent was diluted to a 5 percent solution with the use of sterile water for injection. The dilutions resulted in markedly hypotonic plasma-replacement infusions, which produced osmotic hemolysis in all four cases and acute renal failure in two of them. One case was reported previously,1 and two additional cases were reported to the FDA's post-marketing reporting system for adverse drug experiences (MEDWatch).2

Human albumin solutions of all concentrations are formulated to have a sodium concentration between 130 and 160 mmol per liter. Thus, a 1:4 dilution in sterile water produces a solution with osmolarity (tonicity) of only about one fifth that of 0.9 percent sodium chloride (isotonic saline). The large volumes used in plasmapheresis and plasma exchange probably contributed to the hemolysis, since the hypotonic plasma-replacement mixture accounted for a substantial fraction of the patient's calculated blood volume. In the hypotonic environment, shear forces of the plasmapheresis device may have contributed to the observed hemolysis.

We do not know how often this dilution error is occurring in pharmacies. However, the current short supply of human albumin may lead to increasingly frequent instances of dilution of more concentrated solutions, creating an increased potential for error.

In the two cases most recently reported to MEDWatch, the hospital pharmacies relied on information contained in an out-of-date (1994) edition of Trissel's widely distributed Handbook on Injectable Drugs. The section that deals with albumin (human) 25 percent has been partly corrected in the 1996 edition but, in our view, remains somewhat ambiguous with respect to the unacceptability of sterile water for injection as a diluent for the product.

The FDA has taken the following steps to advise the medical community of this potentially serious problem. First, the FDA is recommending to manufacturers of albumin (human) 25 percent that the package inserts for their products be revised to include a warning statement concerning the risk of potentially fatal hemolysis and acute renal failure when sterile water for injection is used as a diluent for albumin, plus information on acceptable diluents, such as 0.9 percent sodium chloride or 5 percent dextrose in water. Second, the FDA has submitted a letter to the editor regarding these cases to the American Journal of Health-System Pharmacists, to alert pharmacists who dispense albumin and plasmapheresis infusions. Third, the FDA has submitted a drug warning for publication in the FDA Medical Bulletin. Fourth, efforts are under way to notify the manufacturers of plasmapheresis devices of this preventable serious error. Finally, the American Society of Health-System Pharmacists, publisher of Trissel's Handbook on Injectable Drugs, has been asked to further revise the monograph to eliminate any ambiguity concerning the fact that sterile water for injection should not be used as a diluent for albumin (human) 25 percent.

Health care professionals should report any serious adverse events, including events such as those described above, to the FDA's MEDWatch program (telephone, 800-FDA-1088; fax, 800-FDA-0178), the pharmaceutical manufacturer, or both.

L. Ross Pierce, M.D.
Ann Gaines, Ph.D.
Frederick Varricchio, M.D., Ph.D.
Jay S. Epstein, M.D.
Food and Drug Administration, Rockville, MD 20852

2 References

1. 1

   Forte FJ, Caravone D, Coyne MJ. Albumin dilution as a cause of hemolysis during plasmapheresis. Am J Health Syst Pharm 1995;52:207-207
   Web of Science | Medline

2. 2

   Kessler DA. Introducing MEDWatch: a new approach to reporting medication and device adverse effects and product problems. JAMA 1993;269:2765-2768
   CrossRef | Web of Science | Medline

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   Frederick Varricchio, John Reed. (2006) Follow-up Study of Medication Errors Reported to the Vaccine Adverse Event Reporting System (VAERS). Southern Medical Journal 99:5, 486-489
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   Rahul K. Shah, Erna Kentala, Gerald B. Healy, David W. Roberson. (2004) Classification and Consequences of Errors in Otolaryngology. The Laryngoscope 114:8, 1322-1335
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   Mark E. Brecher. (2002) Plasma exchange: Why we do what we do. Journal of Clinical Apheresis 17:4, 207-211
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4. 4

   (1999) Hemolysis and acute renal failure due to the administration of albumin diluted in sterile water. Transfusion 39:1, 110-111
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5. 5

   (1998) More on Dangerous Dilution of 25 Percent Albumin. New England Journal of Medicine 339:9, 634-635
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