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Letters to RenalWEB - May 6, 2002

Regarding Patient Deaths Associated with PF5070

The recent epidemic of deaths associated with the use of the Althane dialyser produced by Baxter International Inc at Ronneby in Sweden (1) has recently attracted two invited editorials in leading journals (2,3). Both editorials are remarkable for what they do not state and also for their attempts to share the responsibility for this epidemic between the manufacturer and the end user. In this letter, I will attempt to better explain the mechanisms involved in this tragedy and to suggest that the end user, dialysis nurse, technician or doctor cannot in anyway be held responsible. Furthermore, I would like to draw attention to the possibility, that there are many patients exposed to the estimated 30,000 "repaired" Althane Dialysers that did not die directly from exposure to PF5070, but may have sustained gas emboli in the cerebral or coronary arteries with consequent infarction of the affected cerebral or myocardial tissue.

The deaths had occurred over a period of months and had one feature in common: all patients were dialysed on the same make of cellulose di-acetate hollow fibre dialyser (manufactured from melt spun fibres made in Miami Lakes Florida and assembled in Ronneby, Sweden) commercialised as the Althane dialyser. The causes of death were finally established following autopsy findings in Croatian patients of massive gas formation in the right side of the heart and the pulmonary-alveolar capillary bed (4). The discovery of residual perfluorocarbon (PF5070 -perfluoroheptane C7F16) in certain lots of the Althane dialyser indicated that this volatile hydrophobic fluid was responsible for the gas formation. The underlying hypothesis explaining these findings requires firstly that PF5070 is insoluble in plasma water and hence fails to traverse the pulmonary alveolar capillary membrane (according to the data sheet of the manufacturer, PF5070 is completely insoluble in water (5)). Thus, PF5070 cannot equilibrate across the pulmonary alveolar capillary membrane and, in consequence, the vapour pressure of PF5070 contributes to the total vapour pressure in the pulmonary capillary blood but does not make a similar contribution to the vapour pressure in the alveolar air. Secondly, the vapour pressure of PF5070 must exceed a limit of approximately 55mmHg at body temperature (the value found by Saas et al below which fatal gas formation did not occur in dogs receiving IV FC80 (a fluorocarbon with very similar properties to PF5070) at a dose of 0.1mg/kg/bodyweight (6)). The vapour pressure of PF5070 at 20ºC is ca. 79 mmHg (5); at body temperature the vapour pressure of PF5070 is even higher. Consequently, the total gas tension in pulmonary capillary blood (containing PF5070) exceeds the total tension of alveolar gases (atmospheric pressure). Bubbles of O2, CO2,N2, PF5070 and water vapour form in the pulmonary capillary bed progressively. Eventually, after some hours, the total volume of gas in the pulmonary capillary bed exceeds the bed's capacity to expand and then retro filling of the pulmonary artery and the right heart with this gas occurs. The reason why this apparently non-toxic perfluorocarbon PF5070 was used is not clearly explained by either editorial (2,3).

The reports do not state why or how the PF5070 was actually used to detect leaks in fibres of the dialyser during the manufacturing process. To my knowledge, this fluid is only used to aid in the repair of dialysers that have failed the initial air pressure test. A simplified explanation of the method was available in the El Pais on 6th November 2001 with a clearly understandable diagram to aid the lay reader in a reported interview with Dr.Jose Divino, Medical Director of Baxter Europe (7). The diagram indicates that if more than five fibres (presumably judged by the rate of loss of pressure) were found to be leaking in the routine air pressure test, the device was discarded. However, it was estimated in the El Pais report (7) that as many as 10% of the dialysers had leaks of less than five fibres. The leaking fibres in these dialysers were repaired and the dialyser was then re-introduced into the production lot. The process of repair of capillary dialysers, "dialyser repair", has been employed for over 30 years in the dialysis industry but is less common today. It was used by Baxter only in their Ronneby plant, which represented less than 30% of their global production (1). The "dialyser repair" process requires that the leaking fibre or fibres are identified and then sealed at both ends. Where this process is used, the standard method of repair is that PF5070 is introduced into the blood compartment after removal of the header caps by plunging one end of the device into a bath of PF5070 and priming the dialyser with this hydrophobic fluid. Air is then pumped under pressure into the dialysate compartment whilst the dialyser is held in the vertical position with the bottom end immersed in PF5070. Inspection of the upper end reveals the approximate area of leakage by seeing where air bubbles appear. This area is then sealed with polyurethane glue (potting material) and the process repeated after turning the dialyser upside down.

As sealing is performed manually with a fine needle and syringe, following marking of the leaking fibres, the probability that more than 5 leaking fibres are sealed is a reasonable assumption. This variable will depend upon the skill and experience of the operator. In any individual dialyser that contained broken hollow fibres, which were filled with PF5070, there is some probability that both ends of one or more intact fibres, adjacent to the leaking fibre, were not sealed, i.e., one end of the fibre was sealed, the other was not. Under such conditions, there is poor accessibility to the PF5070 that is trapped within the fibre. That trapped fluid will only come out very slowly with any rinsing method, whether it be air, solvent, or saline, because the interface for transport is comprised only of the cross sectional area of the fibre and that of the break - if any - within the fibre. Thus, it is likely that any residual PF5070 trapped in a fibre sealed at one end would be incompletely removed by an air rinse unless it was continued for a sufficiently long time. A saline rinse would be ineffective because it would have to rely on dissolution of the trapped PF5070 into the aqueous stream, which cannot occur as the hydrophobic PF5070 is insoluble in water (5). (There is a theoretical possibility of ultrafiltration from dialysate side to lumen, thereby displacing PF5070 out of the lumen, but that too is likely to be very slow.) Thus, a standard rinse/priming procedure which is all the end user could be expected to do without explicit warning by the manufacturer to rinse more extensively because of possible contamination would be highly unlikely to remove trapped PF5070 that remained after an air rinse. It would appear, therefore, to be incorrect to involve the end user in sharing the responsibility for these deaths as is implied by the editorials (2,3).

However, the prolonged contact of blood and especially albumin with the open ended fibres would result in the slow passage of PF5070 into the lungs with the consequent delay of several hours from the end of dialysis until death as was reported in the Croatian epidemic (3). The possibility that there are survivors of this global epidemic seems to have been discounted by both editorials but cannot be excluded. The post mortem evidence from the Spanish outbreak showed multiple organ damage (8) which one could conclude resulted from small gas emboli reaching the micro-capillary circulation of the brain and other vital organs. A histological examination of the organs of rats following IV injection of 100µL of fluorocarbon revealed extensive brain infarction with gas emboli in the cerebral arteries (9). Thus, it is reasonable to postulate that non-fatal systemic emboli may have occurred in some of the population at risk. Finally, although the reports conclude that it is mandatory to banish the use of such compounds" (i.e.PF5070), they both fail to recommend the banishment of "dialyser repair " in dialyser manufacturing.

Stanley Shaldon, MA, MD, FRCP
25 Le Michelangelo
7 Avenue des Papalins
MONACO 98000
e-mail: stanley_shaldon@monaco377.com


References:
1.http://www.baxter.com/utilities/news/releases/2001/10-15dialyzer.html
2.Canaud B. Performance liquid test as a cause for sudden deaths of dialysis patients: perfluorohydrocarbon, a previously unrecognised hazard for dialysis patients. Nephrol Dial Transplant 2002; 17:545-54
3.Ward RA. Ensuring Patient Safety: What lessons can be learned from device related adverse events in hemodialysis. Artificial Organs 2002;26:305-306.
4. Gasparovic V, Ostojic R, Cjenero-Margan , Kes P. Sudden deaths of Croatian hemodialysis patients in October 2001. Croatian Medical Journal 2001;42:606-610
5. Material Safety Data Sheet: PF-5070 3M Brand Performance Fluid. Minnesota Mining and Manufacturing Company St. Paul Minnesota. 1999.
6. Sass DJ, Van Dyke RA, Wood EH, Johanson SA, Didiheim P. Gas embolism due to intravenous FC 80 liquid fluorocarbon. J Appl Physiol 1976; 40:745-751.
7. El Pais. Madrid Tuesday 6th November 2001: report by S Pozzi and J Prats entitled Baxter admite que varias muertes por dialysis pueden deberse al uso sus filtros.
8. El Pais. Madrid Friday 9th November 2002: report by Emilio de Benito entitled
Sanidad concluye que Baxter no garantiza la calidad de sus dializadores. Un informe achaca 11 muertes en dialysis a sustancias "no inocuas" presentes en los filtros.
9. Heinsen H, Mottaghy K and Frömel M. Pulmonary and systemic embolism after deliberate intravenous fluorocarbon administration. Virchows Arch A Path Anat and Histol 1980;386;331-341.



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