Performance liquid test as a cause for sudden deaths of dialysis patients: perfluorohydrocarbon, a previously unrecognized hazard for dialysis patients

Bernard Canaud on behalf of the European Experts Panel*,

Department of Nephrology, Lapeyronie University Hospital, Montpellier, France

Keywords: haemodialysis hazards; life-threatening complications; perfluorocarbon toxicity

Haemodialysis hazards

Over the last two decades, routinely performed haemodialysis (HD) has continued to evolve as a safe procedure of renal replacement therapy (RRT). Despite the apparent overall safety of the HD procedure, the nephrology community must not forget that HD can be the cause of serious reactions leading eventually to life-threatening complications [1,2]. The recent outbreak of clustered deaths in end-stage renal disease (ESRD) patients on RRT has dramatically reinforced the view that even modern HD is not devoid of potential complications requiring permanent vigilance. Strict precautionary measures and continuous quality assessments should be applied along the different steps of the RRT chain that links the manufacturer to the dialysis patient via the care providers. In the light of the recent tragic HD events that have put Baxter on the news forefront, it is our duty to insist on the fact that only strict adherence to quality control protocols, and careful observation to identify new risks, will minimize HD hazards.

Past and recent history of HD may serve to illustrate the fact that severe clinical adverse events may occur in dialysed patients. These include anaphylactic reactions resulting from ethylene oxide (ETO) or formaldehyde (FO) sensitization [35], haemolysis from chloramine intoxication [6], acute and severe fluoride intoxication [7], pyrogenic reactions or bacteraemias related to dialysate contamination [8,9], acute hepatic failure resulting from Cyanobacteria contamination [10], shock syndrome resulting from the interaction of ACE inhibitor and AN-69 membrane [1113], acute pulmonary events with haemodialysers [14], acute loss of vision, red-eye syndrome and eosinophilic pulmonary infiltrates with aged cellulose dialysers [1517]. This non-exhaustive list is merely to acknowledge that HD patients are exposed at dialysis session to the potential hazards of extracorporeal RRT.

The recent outbreak of clustered deaths of ESRD patients is a new event in the long list of severe HD reactions. The mode of clinical presentation differs completely from what has been described in the past.

Acute dialysis-associated death: a new syndrome

This new syndrome must be elucidated and the nephrology community must be aware of its existence. The following questions will assist in understanding what occurred.

The facts have already been reported in the non-specialized press. It is important, however, to relate medical events as they unfolded in order to gain a proper understanding of the scientific facts. This is a serial story that took place in different stages.

The first part of the story occurred in Spain in late August 2001. Ten ESRD patients regularly treated by HD suddenly died a few hours after completion of their dialysis session. An 11th patient died later during an acute dialysis. Patients presented with a variety of symptoms, including chest tightness, shortness of breath and malaise leading to cardiac arrest, which did not respond to resuscitative efforts. The patients were treated in three different dialysis units. The same brand of dialyser was the only common feature shared by this group of patients. Given the clustered nature of events in several dialysis units and the commonality of the dialyser type utilized, the dialyser was suspected even though the nature of the deaths were not typical of a dialyser reaction.

As a precautionary measure, the suspected batches of dialysers were recalled for reassessment. In addition to the testing conducted by the manufacturer, TÜV, the European regulatory agency responsible for medical device approval, proceeded to a complete evaluation of the dialysers. Interestingly, neither set of tests revealed any safety or performance failures in the implicated batches of dialysers, even after completing a battery of internationally recognized tests. Unfortunately, the dialysers were released despite the fact that the causes of patients' deaths were not elucidated.

In mid-October authorities in Croatia reported unexplained deaths in 23 HD patients treated in four independent dialysis facilities over a 6-day period. The patients presented with acute onset of illness a few hours after their HD session using the A (Althane) series dialyser, commercialized by Baxter. The clinical picture also consisted of various degrees of chest tightness, progressive dyspnea and circulatory collapse. As noted in the Spanish patients, also these patients failed to respond to any resuscitation manoeuvre, including mechanical respiratory assistance or inotropic agents. Death of patients occurred both during and within a few hours after the onset of symptoms. In the meantime, around 20 additional dialysis patients treated in the USA, Italy, Germany, Taiwan and Colombia, dialysing with the Althane series dialyser presented a similar dramatic clinical picture. The investigation was conducted at different levels, including country Health Authorities' reports, TÜV audits and tests, review of dialysis centre practices, and examination of Baxter's manufacturing facilities, with the help of a European panel of experts. Given the lack of available clinical facts related to the patients' disease state and treatment history, the clinical picture surrounding the deaths and the practices of the dialysis centres, the expert panel created an extensive questionnaire for the various parties to complete. In this way, the panel hoped to provide a comprehensive picture of the clinical events in an effort to help identify any common threads.

Epidemiological investigation and clinical features

Epidemiological information was crucial to understand the events. They revealed that dialysis injuries occurred simultaneously in several and separate dialysis units in several countries with totally different dialysis practices. Single use dialysers coming from the same manufacturer and sharing similar membranes were the common denominator of all these events. Water treatment systems and haemodialysis machines did not share any common particularities among centres. No specific medication was found to be commonly used in these patients.

The clinical manifestations were relatively uniform although they varied in intensity and severity according to the type of patients. Most involved patients presented with chest tightness, undefined malaise, increasing shortness of breath leading to severe dyspnea within a few hours during or following a regular dialysis session. According to local health authority reports, the clinical situation progressively worsened in most patients, requiring major resuscitation, ventilatory assistance, and the administration of inotropic and vasoactive drugs. Some patients presented with cardiac arrest or myocardial infarction. It would appear that the majority of patients did not respond to resuscitation manoeuvres and death occurred following refractory respiratory distress.

Pulmonary capillary obstruction by foam material

Autopsies performed on certain Croatian patients were quite contributive to the pathophysiological understanding of this new syndrome. Air embolism resulting from the migration of microbubbles was initially suspected but not confirmed since the control of the haemodialysis machine did not reveal any safety failure in the air detection monitoring system. The findings revealed that most pulmonary capillaries were obstructed by foam material. This foam material initially interpreted as the consequence of air embolism was in fact a blood emulsion of unknown origin.

The investigation conducted simultaneously by Baxter and the FDA identified in some dialysers the unusual presence of a liquid substance. This fluid was soon recognized as a performance liquid, and identified as a perfluorohydrocarbon-based fluid (PF5070). PF5070 (3-M) is used to detect fibre leaks during the manufacturing process of the dialysers. Perfluorohydrocarbons are well-known products that are widely used in dialyser manufacturing industry and without previously recognized toxicity. Moreover, perfluorocarbon substances were in general proposed and are currently evaluated as an oxygen carrier in the treatment of lung injury. Up to now, animal studies involving intra-tracheal perfluorocarbon for liquid ventilation showed no direct parenchymal toxicity to the lungs [18,19]. Moreover, histological evaluation of autopsied animals showed no signs of foam material [20]. The toxicity of PF5070 in HD patients appears to be associated with the capacity of fluorocarbon to emulsify blood at normal body temperature and under low oxygen tension. This unusual and interesting phenomenon has been already reported in animal experiments with FC 80 [21]. Preliminary experiments have shown that i.v. injection of PF5070, at comparable doses to those obtained in the dialysers, to normal rabbits induced the animals' death. Toxicity of PF5070 was clearly dose-related. Pathological examination of the injected animals found lesions of foam deposits obstructing lung capillaries, similar to those found in the Croatian patients.

Considering the epidemiological and clinical facts and the animal experimental data, one can consider that the cause of this new syndrome is now elucidated. The causal agent is a performance test liquid (PF5070) used in the dialyser manufacturing process to detect leaks in the bundle fibres. For unclear reasons, this test fluid was not removed adequately after dialyser assembly. Indeed, the presence of such substance after dialyser release clearly indicates a failure of the rinsing or air blowing process at the dialyser manufacturing plant. The i.v. passage of PF5070 at the time of dialysis priming might have emulsified the patient's blood thus creating microbubble aggregates that subsequently plugged pulmonary capillaries and created patchy lung infarction. As a consequence, the oxygen delivery was compromised inducing severe hypoxaemia with fatal consequences.

Haemodialyser quality control: lesson for the future

Several errors might have culminated throughout the different steps of the dialysis chain linking the dialyser manufacturer to the patient, resulting in these consequences. Although it belongs to the legal authorities to assign the different responsibilities it appears that these are distributed at several levels. At the level of the dialyser manufacturer (Baxter), the removal of the fluid was apparently not adequate and quality control tests were not efficient in detecting any residual material. At the level of the regulatory notified body (TÜV), the incriminated dialysers reassessed after the first outbreak episode, were considered safe and in strict accordance with original certified dialysers. Perhaps standard safety (International Standards Organization) testing should be re-evaluated to see if additional testing is warranted. This is an area that the expert panel would like to pursue in the future with the International Standards Organization. At the level of the user (dialysis unit), it is probable that the priming and cleaning procedure of the dialysers was not performed with the adequate amount of saline and/or that not sufficient time of dialysate rinsing was allowed. The severity of the clinical picture might be also the result of advanced age and comorbid conditions of certain dialysis patients.

The dramatic events reported in this editorial will without any doubt convince the dialysis community that continuous quality improvement aiming at reducing HD-related hazards is clearly required. Such an approach must imply all intervening parties from the manufacturer to the user. It is also important to note that the battery of dialyser toxicity tests, that are proposed by notified regulatory bodies are not sensitive enough to detect such risks. In light of these events, it is of course mandatory to banish the use of such compounds, but also it is necessary to establish new criteria of quality in dialyser manufacturing and testing.

Notes

Correspondence and offprint requests to: Prof. Bernard Canaud, Department of Nephrology, Lapeyronie University Hospital, 371 Avenue du Doyen G. Giraud, F-34295 Montpellier, France. Email: b\|[hyphen]\|canaud{at}chu\|[hyphen]\|montpellier.fr Back

* European Experts Panel: 1. Prof. Bernard Canaud, Nephrology, Lapeyronie University Hospital, Montpellier, France; 2. Prof. Pedro Aljama, Nephrology, Reina Sofia University Hospital, Cordoba, Spain; 3. Prof. Dr Francesco Locatelli, Nephrology, Lecco Hospital, Lecco, Italy; 4. Prof. Christian Tielemans, Erasme Hospital, Brussels, Belgium; 5. Prof. Vladimir Gasparovic, Department of Internal Medicine, Emergency and Intensive Care, Rebro, Zagreb, Croatia; 6. Prof. Walter Hörl, Nephrology and Dialysis, University of Vienna, Vienna, Austria; 7. Prof. Conrad Baldamus, Medical Clinic IV, Cologne University Hospital, Cologne, Germany; 8. Prof. Alberto Gutierrez, Dept of Clinical Science, Division of Renal Medicine, Huddinge University Hospital, Huddinge, Sweden; 9. Prof. William Henrich, University of Maryland, Maryland, USA; 10. Prof. Norbert Lameire (appointed as delegate of the International Society of Nephrology), Nephrology, Gent University Hospital, Gent, Belgium. Back

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