Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis

JAMA. 2008 May 21;299(19):2304-12. doi: 10.1001/jama.299.19.jrv80007. Epub 2008 Apr 28.


Context: Hemoglobin-based blood substitutes (HBBSs) are infusible oxygen-carrying liquids that have long shelf lives, have no need for refrigeration or cross-matching, and are ideal for treating hemorrhagic shock in remote settings. Some trials of HBBSs during the last decade have reported increased risks without clinical benefit.

Objective: To assess the safety of HBBSs in surgical, stroke, and trauma patients.

Data sources: PubMed, EMBASE, and Cochrane Library searches for articles using hemoglobin and blood substitutes from 1980 through March 25, 2008; reviews of Food and Drug Administration (FDA) advisory committee meeting materials; and Internet searches for company press releases.

Study selection: Randomized controlled trials including patients aged 19 years and older receiving HBBSs therapeutically. The database searches yielded 70 trials of which 13 met these criteria; in addition, data from 2 other trials were reported in 2 press releases, and additional data were included in 1 relevant FDA review.

Data extraction: Data on death and myocardial infarction (MI) as outcome variables.

Results: Sixteen trials involving 5 different products and 3711 patients in varied patient populations were identified. A test for heterogeneity of the results of these trials was not significant for either mortality or MI (for both, I2 = 0%, P > or = .60), and data were combined using a fixed-effects model. Overall, there was a statistically significant increase in the risk of death (164 deaths in the HBBS-treated groups and 123 deaths in the control groups; relative risk [RR], 1.30; 95% confidence interval [CI], 1.05-1.61) and risk of MI (59 MIs in the HBBS-treated groups and 16 MIs in the control groups; RR, 2.71; 95% CI, 1.67-4.40) with these HBBSs. Subgroup analysis of these trials indicated the increased risk was not restricted to a particular HBBS or clinical indication.

Conclusion: Based on the available data, use of HBBSs is associated with a significantly increased risk of death and MI.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • Blood Substitutes / adverse effects*
  • Hemoglobins* / adverse effects
  • Humans
  • Mortality
  • Myocardial Infarction / epidemiology
  • Raffinose / adverse effects
  • Raffinose / analogs & derivatives
  • Risk


  • Blood Substitutes
  • Hemoglobins
  • O-raffinose cross-linked human hemoglobin
  • PolyHeme
  • HBOC 201
  • Raffinose