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


METHODS
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.


METHODS
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.


METHODS
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.


CONCLUSIONS
Based on the available data, use of HBBSs is associated with a significantly increased risk of death and MI.
Natanson
Charles
C
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA. cnatanson@cc.nih.gov
Kern
Steven J
SJ
Lurie
Peter
P
Banks
Steven M
SM
Wolfe
Sidney M
SM
D001802:Blood Substitutes / Q000009:adverse effects*; D006454:Hemoglobins / Q000009:adverse effects; D006801:Humans; D009026:Mortality; D009203:Myocardial Infarction / Q000453:epidemiology; D011887:Raffinose / Q000009:adverse effects / Q000031:analogs & derivatives; D012306:Risk
D001802:Blood Substitutes; D006454:Hemoglobins; C097124:O-raffinose cross-linked human hemoglobin; C509893:PolyHeme; C096798:HBOC 201; D011887:Raffinose