Recognizing and Reacting to Product-Related Adverse Events in Hemodialysis

What Does This Important Study Show? 

A recent publication by Blossom et al3 in the New England Journal of Medicine reports an outbreak of severe adverse reactions in patients treated by using extracorporeal therapies, mostly hemodialysis, who underwent systemic anticoagulation with unfractionated heparin from a single supplier. During an 11-week period, 152 allergic-type reactions involving 113 patients from 13 states were reported to the Centers for Disease Control and Prevention (CDC). The reactions were characterized by hypotension (50% of patients), nausea (48.7%), and shortness of breath (37.5%). Hemodialysis patients accounted for 130 reactions, and mean time between administration of heparin and onset of the reaction was 5.1 minutes. In a case-control study comparing dialysis facilities that reported reactions with facilities in the same states that did not report reactions, heparin from 1 supplier was used in 100% (21 of 21) of case facilities compared with 4.3% (1 of 21) of control facilities. Heparin from facilities that reported reactions was found to contain oversulfated chondroitin sulfate,4 which activated the kinin-kallikrein pathway and generated the complement-derived anaphylatoxins C3a and C5a at clinically relevant concentrations.5 For reactions with information available about the manufacturing lot of heparin, 98.5% occurred in facilities in which there was contaminated heparin.

How Does This Study Compare With Prior Studies? 

Clusters of product-related adverse events in hemodialysis patients have been reported previously. Several of these episodes have been associated with the use of contaminated products, including hypersensitivity reactions to residual ethylene oxide in dialyzers sterilized with ethylene oxide,6 reactions to membrane degradation products in dialyzers containing cellulose acetate membranes,7 and toxic reactions to perfluorocarbon-5070, used to detect fiber leaks during dialyzer manufacturing.8 Other product-related adverse events have been associated with the use of contaminated water to prepare dialysate or process dialyzers for reuse9 or allergic reactions to some membrane materials, particularly in patients receiving angiotensin-converting enzyme inhibitors.10 As in the present report, these events can occur in the beginning minutes of dialysis and manifest similar symptoms of hypotension, shortness of breath, and nausea.6, 10

Recognizing that a product-related adverse event is occurring can be difficult because the symptoms may be very similar to those associated with an excessive rate of fluid removal in many patients, although symptoms related to fluid removal generally do not occur in the first few minutes of dialysis. Adverse events also may be unrecognized as being product related because product-related adverse events are rare. There are more than 320,000 hemodialysis patients in the United States; with a thrice-weekly treatment schedule, this number translates into approximately 50 million dialysis treatments per year. The exact number of allergic reactions to contaminated heparin that occurred in the hemodialysis population during the time frame covered by this report is not certain. The Food and Drug Administration (FDA) reported that approximately 350 heparin-related events were reported to the manufacturer in the first 6 weeks of 2008. It is unclear whether all these events were heparin related. However, if this were the case, it would correspond to an incidence rate of approximately 6 events/100,000 dialysis treatments, similar to the reported incidence rate of 3.5 severe events/100,000 dialyzers sold for anaphylactoid reactions to residual ethylene oxide at the height of that outbreak.11

The relative rarity of product-related adverse events may explain in part why it took almost 3 months for federal authorities to issue a warning to dialysis facilities. The first reactions appear to have occurred in St Louis, MO, around November 19, 2007. The CDC was notified of those events by the Missouri State Health Department on January 7, 2008. Based on these cases and information for additional cases provided by dialysis supply companies, the CDC issued an alert on February 1, 2008, in which it was reported that the majority of reactions occurred in patients being treated with heparin from a single manufacturer.12 The CDC alert was followed on February 11, 2008, by a notice from the FDA that the manufacturer was recalling certain lots of heparin and advising health care practitioners to obtain heparin from alternative suppliers and limit the use of the drug until the cause of the reactions was identified.13 The time between the first events and widespread notification of the dialysis community is similar to that of the outbreak of perfluorocarbon-5070 toxicity that occurred in 2001, in which nearly 2 months elapsed between the first cluster of 11 events in late August and recall of the contaminated dialyzers by the manufacturer in mid-October.

What Should Clinicians and Researchers Do? 

In the first instance, the report by Blossom et al3 serves to remind us of long-standing limitations of the use of heparin for systemic anticoagulation of patients receiving hemodialysis or other extracorporeal blood purification therapies. Its complex biological effects make unfractionated heparin difficult to dose and monitor during routine hemodialysis, particularly since the advent of the Clinical Laboratory Improvement Act in the United States in 1988. Moreover, a small, but significant, number of patients cannot undergo systemic anticoagulation with heparin because of heparin-induced thrombocytopenia. Low-molecular-weight heparins have less complex biological effects; however, they also are difficult to monitor, have prolonged half-lives, and are associated with heparin-induced thrombocytopenia. To date, such alternatives to heparin as hirudin derivatives and argatroban have not achieved widespread use, largely because of their cost, and there clearly is a need for new anticoagulants for extracorporeal therapy.

More generally, the report of Blossom et al3 raises important issues related to timely identification of product-related adverse events in hemodialysis patients and initiation of actions to protect patients from further harm.

First, because drug manufacturing is a global industry, there needs to be an internationally accepted system for tracking a drug from manufacture to use. Identifying particular batches of heparin as the culprit in these reactions was difficult because dialysis units do not routinely record the lot number of heparin used for an individual patient. For food safety, it often is said that it should be possible to track food from farm to fork. It also should be possible to track drugs from synthesis to syringe.

Second, there needs to be an international reporting system to monitor adverse events in patients undergoing hemodialysis and other therapies. Rare, but disastrous, events may occur around the world. Without an integrated reporting system, the problem may not be recognized. For example, contaminated heparin also was causing adverse events in Germany at the same time they were occurring in the United States.14 However, different companies supplied the heparin to dialysis facilities in the United States and Germany, and these companies may not have obtained their raw material from the same supplier, making it more difficult to recognize a common problem. Some initial steps toward an international reporting system have been taken. The International Organization for Standardization has published a standardized coding structure for reporting the type and cause of adverse events related to medical devices,15 and the Global Harmonization Task Force on medical device regulation has published a guidance document on adverse-event reporting for medical devices.16

Third, there needs to be established international manufacturing and distribution standards that are supervised by an international agency. The need for international standards is particularly important for such drugs as heparin, which are extracted from a raw material rather than being synthesized de novo and for which the raw material is globally sourced. With such drugs, there is always the potential for contaminants that originate from the crude raw material or that are deliberately introduced, as may have occurred in this case and which occurred in the recent cases of melamine contamination of food products.17 It can be difficult to detect such contaminants by routine analysis of the drug, and this will become an even more critical issue with the proliferation of biosimilars.

The strikingly similar delay between the occurrence of the first adverse event in a cluster to the issuance of alerts by regulatory agencies suggests that the lack of a coordinated system to track drugs and devices from their manufacture to their use and the absence of an international reporting system to monitor adverse events represent important vulnerabilities in our capacity to ensure patient safety. Use of an international electronic infrastructure, similar to that already in place for the banking industry or law enforcement, could facilitate more rapid reporting, tracking, analysis, and notification of rare events.