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. 2008 Dec 18;359(25):2674-84.
doi: 10.1056/NEJMoa0806450. Epub 2008 Dec 3.

Outbreak of adverse reactions associated with contaminated heparin

David B Blossom  1 , Alexander J Kallen, Priti R Patel, Alexis Elward, Luke Robinson, Ganpan Gao, Robert Langer, Kiran M Perkins, Jennifer L Jaeger, Katie M Kurkjian, Marilyn Jones, Sarah F Schillie, Nadine Shehab, Daniel Ketterer, Ganesh Venkataraman, Takashi Kei Kishimoto, Zachary Shriver, Ann W McMahon, K Frank Austen, Steven Kozlowski, Arjun Srinivasan, George Turabelidze, Carolyn V Gould, Matthew J Arduino, Ram Sasisekharan
Affiliations

Outbreak of adverse reactions associated with contaminated heparin

David B Blossom et al. N Engl J Med. .

Erratum in

  • N Engl J Med. 2010 Mar 18;362(11):1056

Abstract

Background: In January 2008, the Centers for Disease Control and Prevention began a nationwide investigation of severe adverse reactions that were first detected in a single hemodialysis facility. Preliminary findings suggested that heparin was a possible cause of the reactions.

Methods: Information on clinical manifestations and on exposure was collected for patients who had signs and symptoms that were consistent with an allergic-type reaction after November 1, 2007. Twenty-one dialysis facilities that reported reactions and 23 facilities that reported no reactions were included in a case-control study to identify facility-level risk factors. Unopened heparin vials from facilities that reported reactions were tested for contaminants.

Results: A total of 152 adverse reactions associated with heparin were identified in 113 patients from 13 states from November 19, 2007, through January 31, 2008. The use of heparin manufactured by Baxter Healthcare was the factor most strongly associated with reactions (present in 100.0% of case facilities vs. 4.3% of control facilities, P<0.001). Vials of heparin manufactured by Baxter from facilities that reported reactions contained a contaminant identified as oversulfated chondroitin sulfate (OSCS). Adverse reactions to the OSCS-contaminated heparin were often characterized by hypotension, nausea, and shortness of breath occurring within 30 minutes after administration. Of 130 reactions for which information on the heparin lot was available, 128 (98.5%) occurred in a facility that had OSCS-contaminated heparin on the premises. Of 54 reactions for which the lot number of administered heparin was known, 52 (96.3%) occurred after the administration of OSCS-contaminated heparin.

Conclusions: Heparin contaminated with OSCS was epidemiologically linked to adverse reactions in this nationwide outbreak. The reported clinical features of many of the cases further support the conclusion that contamination of heparin with OSCS was the cause of the outbreak.

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Figures

Figure 1
Figure 1. Cases of Adverse Reactions Associated with Heparin, According to Week of Onset
The figure shows a total of 152 cases of adverse reactions associated with heparin that were reported to the Centers for Disease Control and Prevention from November 19, 2007, through January 31, 2008.
Figure 2
Figure 2. Association of Oversulfated Chondroitin Sulfate (OSCS) in Unfractionated Heparin with Induction of Kallikrein Activity
Thirteen samples of heparin, including one sample of non–clinical-grade heparin (control heparin 1), representing both suspect heparin lots and control lots, were analyzed in a blinded fashion for both the presence of OSCS and the ability to activate kallikrein. The presence of OSCS was detected and quantified as described elsewhere.6 The amidolytic activity of kallikrein was assessed at various concentrations of heparin, as indicated. Lots A through D and F through J contained OSCS. Samples from Lot E, as well as controls 1 through 3, contained no detectable OSCS. Lots A through G and Lot J were recalled on January 17, 2008. T bars indicate standard deviations of replicate measurements. ND denotes not detected.
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References

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    1. Acute allergic-type reactions among patients undergoing hemodialysis — multiple states, 2007–2008. MMWR Morb Mortal Wkly Rep. 2008;57:124–5. - PubMed
    1. Recall — firm press release: Baxter issues urgent nationwide voluntary recall of heparin 1,000 units/ml 10 and 30ml multidose vials. Food and Drug Administration; Rockville, MD: [Accessed November 24, 2008]. 2008. at http://www.fda.gov/oc/po/firmrecalls/baxter01_08.html.
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