A review of blood substitutes: examining the history, clinical trial results, and ethics of hemoglobin-based oxygen carriers.
The complications associated with acquiring and storing whole blood for transfusions have launched substantial efforts to develop a blood substitute. The history of these efforts involves a complicated mixture of science, ethics, and business. This review focuses on clinical trials of the three hemoglobin-based oxygen carriers (HBOC) that have progressed to Phase II or III clinical trials: He-mAssist (Baxter; Deerfield, IL, US), PolyHeme (Northfield; Evanston, IL, US), and Hemopure (Biopure; Cambridge, MA, US). Published animal studies and clinical trials carried out in a perioperative setting have demonstrated that these products successfully transport and deliver oxygen, but all may induce hypertension and lead to unexpectedly low cardiac outputs. Overall, these studies suggest that HBOCs resulted in only modest blood saving during and after surgery, no improvement in mortality and an increased incidence of adverse reactions. To date, the results from these perioperative studies have not led to regulatory approval. All three companies instead chose to focus their efforts on large trials of trauma patients in the pre-hospital setting.Baxter abandoned the development of HemAssist after a trial in the U.S. was prematurely halted when the first 100 patients showed significantly increased mortality rates as compared to patients treated with blood products. Northfield's PolyHeme trial demonstrated a non-significant trend towards increased mortality and a very modest reduction in the subsequent need for blood. The testing of Biopure's Hemopure for trauma patients has been halted for several years because of FDA concerns over trial design and study justification. Ethical concerns have also been raised regarding the design and implementation of all HBOC clinical trials.Thus, the available evidence suggests that HemAssist, Polyheme, and Hemopure are associated with a significant level of cardiovascular dysfunction. The next generation of HBOCs remains under development.
Chen
Jiin-Yu
JY
Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA. jichen1@utmb.edu
Scerbo
Michelle
M
Kramer
George
G
D001802:Blood Substitutes / Q000009:adverse effects*; D002986:Clinical Trials as Topic / Q000941:ethics; D006454:Hemoglobins / Q000009:adverse effects / Q000145:classification*; D006801:Humans
D001802:Blood Substitutes; D006454:Hemoglobins; C509893:PolyHeme; C096798:HBOC 201
J Trauma. 2008 Jun;64(6):1484-97
18545113
Science. 1933 Aug 4;78(2014):106-7
17732672
J Appl Physiol (1985). 1994 Nov;77(5):2348-54
7868454
Transfus Sci. 1995 Mar;16(1):5-17
10155705
Anesth Analg. 1996 Nov;83(5):921-7
8895264
Chron High Educ. 2006 Jun 16;52(41):A14-8
16856301
J Vasc Surg. 2000 Feb;31(2):299-308
10664499
Am J Bioeth. 2006 May-Jun;6(3):18-21
16754441
Stroke. 1999 May;30(5):993-6
10229733
JAMA. 2008 May 21;299(19):2304-12
18443023
Surg Infect (Larchmt). 2004 Winter;5(4):395-404
15744131
Clin Infect Dis. 2003 Jul 1;37(1):88-95
12830413
J Am Coll Surg. 1998 Aug;187(2):113-20; discussion 120-2
9704955
J Lab Clin Med. 1997 Sep;130(3):328-38
9341993
J Appl Physiol. 1949 Jan;1(7):469-89
18104040
Intensive Care Med. 2003 Mar;29(3):378-85
12541156
Anesth Analg. 2003 Aug;97(2):323-332
12873912
J Am Coll Surg. 2002 Oct;195(4):445-52; discussion 452-5
12375748
Am J Surg. 1998 Dec;176(6):612-7
9926800
Proc Natl Acad Sci U S A. 1976 Jun;73(6):2128-31
1064880
JAMA. 1999 Nov 17;282(19):1857-64
10573278
J Thorac Cardiovasc Surg. 2002 Jul;124(1):35-42
12091806
Shock. 2005 Apr;23(4):337-43
15803057
Mil Med. 2004 Jul;169(7):546-50
15291188
Arch Surg. 1997 Jun;132(6):620-4; discussion 624-5
9197854
Anesth Analg. 2002 Apr;94(4):799-808, table of contents
11916776
Trans Assoc Am Physicians. 1968;81:147-52
5721397
Anesthesiology. 2000 Mar;92(3):646-56
10719942