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Pathochemical Toxicity of Perfluorocarbon-5070, a Liquid Test Performance Fluid Previously Used in Dialyzer Manufacturing, Confirmed in Animal Experiment

Bernard Canaud^*, Pedro Aljama, Christian Tielemans, Vladimir Gasparovic, Alberto Gutierrez^|| and Francesco Locatelli^¶

^* Nephrology, Lapeyronie University Hospital, Montpellier, France; Nephrology, Reina Sofia University Hospital, Cordoba, Spain; Erasme Hospital, Brussels, Belgium; Department of Internal Medicine, Emergency & Intensive Care, Rebro, Zagreb, Croatia; ^|| Department of Clinical Science, Division of Renal Medicine, Huddinge University Hospital, Huddinge, Sweden; and ^¶ Department of Nephrology, Alessandro Manzoni Hospital, Lecco, Italy

Address correspondence to: Dr. Bernard Canaud, Department of Nephrology, Lapeyronie University Hospital, 371 Avenue du Doyen G. Giraud, Montpellier, France LR 34295. Phone: 33-467-338495; Fax: 33-467-603783; E-mail: b-canaud{at}chu-montpellier.fr

Received for publication May 6, 2004. Accepted for publication February 24, 2005.

In the light of clustered deaths in late 2001 associated with hemodialysis (HD), this article analyzes the pathochemical toxicity of the perfluorocarbon-5070 (PF-5070), a liquid used as test performance fluid for detecting capillary leaks during dialyzer manufacturing. Residual PF-5070 in some Athane dialyzers of the involved brands was infused in the injured patients during hemodialysis. The clinical presentation was in contrast with other previously described severe reactions to HD. Foam material was discovered in the right ventricle and caval vein of the patients who underwent postmortem examination. Deaths were attributed to gas embolism without the external causes identified. To explore the pathochemical toxicity of the inert liquid PF-5070, an animal model was developed. In a rabbit model, single slug intravenous injections as bolus of increasing doses of PF-5070 were performed. In a first set of experiments, three groups of three rabbits were administered increasing doses of PF-5070 at 4, 40, or 160 µl/kg. After intravenous injection, the animals were observed for clinical signs of adverse effects and underwent autopsy after death. Doses were normalized to animal body weight to allow comparison with supposed patient exposure. Five of nine rabbits died soon after PF-5070 dosing: One rabbit died within 4 h in the 4 µl/kg group, one rabbit died within 30 min in the 40 µl/kg group, and three rabbits died within 30 min in the 160 µl/kg group. In a second set of experiments, six rabbits were injected with a lethal dose of PF-5070 to analyze clinical symptoms and pathophysiology. All rabbits died on the day of dosing and displayed neurologic disorders (paralysis, nystagmus, rigidity, convulsions), then breathing abnormalities (rapid breathing, salivation, dark mucous membrane), and fatal collapse. Autopsy of rabbits showed evidence of gas retention in the lung tissue and gas bubbles in the right cardiac cavities. Histologic findings included alveolar hemorrhage with pulmonary edema, cerebellum, and cortex patchy areas of infarction. Single-dose intravenous administration of PF-5070 reproduced in a rabbit model the pathophysiologic effects observed in the hemodialysis patients. Severity of the symptoms observed in the animals was dose-dependent. Clinical and pathologic findings can be explained by the capacity of perfluorocarbon to emulsify blood at body temperature, to increase partial pressure in the pulmonary capillary bed, and to form bubbles in the pulmonary capillary circulation, thus blocking lung and visceral perfusion. Such experimental findings indicate the toxicity of PF-5070 administered intravenously and make the pathochemical toxicity link with the hemodialysis-related deaths caused by the presence of residues of PF-5070 in the Althane dialyzers. We conclude, in light of this outbreak and the subsequent investigations, that liquid PF-5070 is a highly toxic compound when administered intravenously because of its emulsifying properties. The use of PF-5070 or any liquid fluorocarbon compounds in medical devices with blood contact and particularly in the dialyzer manufacturing should be considered with caution.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673