Correspondence
More on Dangerous Dilution of 25 Percent Albumin
N Engl J Med 1998; 339:634-635August 27, 1998
- Article
To the Editor:
The letter by Steinmuller (April 23 issue)1 reports the problems, including hemolysis, that occurred when sterile water was used to dilute 25 percent albumin. The problems occur because although the albumin is concentrated about fivefold in 25 percent albumin, the electrolytes are not, so that the resulting solution is close to isotonic and therefore can be safely administered intravenously. When diluted with water or dextrose in water, it becomes proportionally low in electrolytes.
Although the response by the representatives of the Food and Drug Administration (FDA)2 is correct with regard to the recommendation that dilution with 5 percent glucose, instead of water alone, would prevent hemolysis, use of this solution would not prevent the possible development of hyponatremia and brain swelling if the solution were used rapidly in large volumes, as in plasma exchange. Owing to its oncotic pressure, the albumin would tend to remain in the plasma compartment, whereas the glucose would rapidly leave the circulation, enter the interstitial fluid and then enter cells, become metabolized, and no longer exert an osmotic effect. This would not be a problem if the solution were given in small enough amounts or slowly enough to allow the kidneys to excrete the excess water before it accumulated, but in the case of plasmapheresis, it would certainly be hazardous, since the extra water would dilute the extracellular electrolytes and then shift to the intracellular compartment.
Glucose solutions should not be used to replace plasma or other extracellular fluids. Sodium chloride 0.9 percent (154 mmol per liter) is a reasonable alternative, but a more physiologic solution, one that more closely resembles plasma, would be even better.
2 ReferencesRichard E. Kravath, M.D.
Kings County Hospital Center, Brooklyn, NY 11203-20981
Steinmuller DR . A dangerous error in the dilution of 25 percent albumin. N Engl J Med 1998;338:1226-1226
Full Text | Web of Science | Medline2
Pierce LR ,Gaines A ,Varricchio F ,Epstein JS . A dangerous error in the dilution of 25 percent albumin. N Engl J Med 1998;338:1226-1227
Full Text | Web of Science | Medline
To the Editor:
The letter by Dr. Steinmuller is misleading in that it takes out of context advice from the ninth edition of the Handbook on Injectable Drugs 1 concerning the dilution of 25 percent albumin. That edition states, “A 5% solution may be prepared from the 25% product by adding 1 volume of the 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.”
It is common knowledge that large volumes of very hypotonic solutions should not be administered intravenously. Although the FDA recommended in its Federal Register notice2 that sterile water for injection be used as a diluent for albumin when a lower sodium concentration is indicated, this is undoubtedly suitable only for small volumes of albumin, for partial dilutions, or in the presence of other diluents. There are no pharmaceutical products that should be given in large volumes as very hypotonic solutions. This principle was apparently disregarded in the cases described by Pierce and colleagues.3
In 1995, Forte et al. reported hemolysis in a patient undergoing plasmapheresis.4 The information on albumin in the Handbook on Injectable Drugs was revised as noted in the edition published in 1996. The January 14, 1998, issue of ISMP Medication Safety Alert, 5 published by the Institute for Safe Medication Practices and sent to virtually every hospital pharmacy in the United States, called attention to the dangers of hypotonic albumin solutions.
This situation points to the need for health care practitioners to use up-to-date references. We are continuing our efforts to alert practitioners through collaboration with the Institute for Safe Medication Practices and notices in upcoming issues of the ASHP Newsletter and the American Journal of Health-System Pharmacy as well as on the Web site of the American Society of Hospital Pharmacists (http://www.ashp.org). The 10th edition of the Handbook on Injectable Drugs, released in June 1998, contains a stronger notice about the dilution of albumin.
The Handbook on Injectable Drugs focuses on the stability and compatibility of drugs. Each specific clinical situation requires practitioners to use their training, knowledge, and common sense when interpreting and applying information from any reference.
5 ReferencesLawrence A. Trissel, F.A.S.H.P.
University of Texas M.D. Anderson Cancer Center, Houston, TX 77030Henri R . Manasse, Jr., Ph.D., Sc.D.
American Society of Health-System Pharmacists, Bethesda, MD 208141
Trissel LA. Handbook on injectable drugs. 9th ed. Bethesda, Md.: American Society of Health-System Pharmacists, 1996.
2
Food and Drug Administration 3
Pierce LR ,Gaines A ,Varricchio F ,Epstein JS . A dangerous error in the dilution of 25 percent albumin. N Engl J Med 1998;338:1226-1227
Full Text | Web of Science | Medline4
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 | Medline5
Safety briefsISMP Med Saf Alert 1998;14:3-3
Author/Editor Response
The authors and a colleague reply:
To the Editor: We agree with Dr. Kravath that the use of a replacement solution of albumin (human) 5 percent, prepared by diluting albumin (human) 25 percent with dextrose 5 percent injection (in water), would generally be inappropriate in the context of plasma exchange or plasmapheresis or in other situations involving the administration of very large volumes, because of the attendant risk of hyponatremia. Physicians must always take the patient's fluid and electrolyte balance into consideration in deciding what intravenous replacement solutions to administer. Our statement in responding to Dr. Steinmuller that acceptable diluents for albumin (human) 25 percent include sodium chloride 0.9 percent injection and dextrose 5 percent injection was intended to address avoidance of the risk of hemolysis. Physicians may use normal saline as a diluent for albumin (human) 25 percent in situations in which the fluid and electrolyte status of the patient permits the administration of normal saline. Conversely, in situations in which dextrose 5 percent injection may be safely administered in like volume, the dilution of albumin (human) 25 percent with dextrose 5 percent injection may be appropriate.
Plasma exchange or plasmapheresis represents a unique circumstance because, in formulating the replacement solution, one must take into account not only the loss of endogenous plasma proteins (principally, but not exclusively, albumin) but also the fact that significant quantities of electrolytes such as sodium and chloride are being removed by the procedure. As was evident in our reply to Dr. Steinmuller's letter, the sodium concentration of albumin (human) 5 percent prepared by dilution with dextrose 5 percent injection is only 26 to 32 mmol per liter. We are aware that normal saline is commonly used as a diluent for albumin (human) 25 percent in preparing replacement solutions for plasma exchange or plasmapheresis. In other settings in which sodium load is a concern and the volume to be administered is more limited, dextrose 5 percent injection may be an acceptable choice of diluent for albumin (human) 20 or 25 percent solutions.
We wish to emphasize the final statement by Trissel and Manasse. It is unlikely that any reference book, compendium, or guideline can anticipate all clinical situations. Accordingly, practitioners must continue to use their training, knowledge, and experience when interpreting and applying information from such sources.
L. Ross Pierce, M.D.
John S. Finlayson, Ph.D.
Jay S. Epstein, M.D.
Food and Drug Administration, Rockville, MD 20852
