Abstract
Historically, hemoglobin-based oxygen carriers (HBOCs) were being developed as “blood substitutes,” despite their transient circulatory half-life (~ 24 h) vs. transfused red blood cells (RBCs). More recently, HBOC commercial development focused on “oxygen therapeutic” indications to provide a temporary oxygenation bridge until medical or surgical interventions (including RBC transfusion, if required) can be initiated. This included the early trauma trials with HemAssist ® (Baxter), Hemopure ® (Biopure) and PolyHeme ® (Northfield) for resuscitating hypotensive shock. These trials all failed due to safety concerns (e.g., cardiac events, mortality) and certain protocol design limitations. In 2008 the Food and Drug Administration (FDA) put all HBOC trials in the US on clinical hold due to the unfavorable benefit:risk profile demonstrated by various HBOCs in different clinical studies in a meta-analysis published by Natanson et al. (2008). During standard resuscitation in trauma, organ dysfunction and failure can occur due to ischemia in critical tissues, which can be detected by the degree of lactic acidosis. Sangart’s Phase 2 trauma program with MP4OX therefore added lactate >5 mmol/L as an inclusion criterion to enroll patients who had lost sufficient blood to cause a tissue oxygen debt. This was key to the successful conduct of their Phase 2 program (ex-US, from 2009 to 2012) to evaluate MP4OX as an adjunct to standard fluid resuscitation and transfusion of RBCs. In 2013, Sangart shared their Phase 2b results with the FDA, and succeeded in getting the FDA to agree that a planned Phase 2c higher dose comparison study of MP4OX in trauma could include clinical sites in the US. Unfortunately, Sangart failed to secure new funding and was forced to terminate development and operations in Dec 2013, even though a regulatory path forward with FDA approval to proceed in trauma had been achieved.
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References
Epstein JS, Jaffe HW, Alter HJ et al (2013) Blood system changes since recognition of transfusion-associated AIDS. Transfusion 53:2365–2374
Mitchell P, Weiskopf R, Zapol WM (2013) NIH/FDA/DOD interagency working group on oxygen therapeutics. In: Kim HW, Greenburg AG (eds) Hemoglobin-based oxygen carriers as red cell substitutes and oxygen therapeutics. Springer, Berlin, pp 141–147
Kauvar DS, Wade CE (2005) The epidemiology and modern management of traumatic hemorrhage: US and international perspective. Crit Care 9:S1–S9
Abramson D, Scalea TM, Hitchcock R et al (1993) Lactate clearance and survival following injury. J Trauma 35:584–589
Manikis P, Jankowski S, Zhang H et al (1995) Correlation of serial blood lactate levels to organ failure and mortality after trauma. Am J Emerg Med 13:619–622
Regnier MA, Raux M, Le Manach Y et al (2012) Prognostic significance of blood lactate and lactate clearance in trauma patients. Anesthesiology 117:1276–1288
Lefering R, Zielske D, Bouillon B et al (2013) Lactic acidosis is associated with multiple organ failure and need for ventilator support in patients with severe hemorrhage from trauma. Eur J Trauma Emerg Surg 39(5):487–493. doi:10.1007/s00068-013-0285-3
Jahr JS, Akha AS, Holtby RJ (2012) Crosslinked, polymerized, and PEG-conjugated hemoglobin-based oxygen carriers: clinical safety and efficacy of recent and current products. Curr Drug Discov Technol 9:158–165
Brohi K, Plani F, Moeng M et al (2010) Multicenter randomized controlled trial TRA-204 to evaluate the safety and efficacy of MP4OX in lactate clearance following trauma hemorrhage. Crit Care Med 38:749
Brohi K, Levy H, Keipert PE et al (2011) Normalization of lactate within 8 hours or ≥20% clearance in initial 2 hours correlate with outcomes from traumatic hemorrhage. Crit Care Med 39:643
Brohi K, Boffard K, Zielske D et al (2013) Effects of MP4OX, an oxygen therapeutic, on clinical outcomes in trauma patients with hemorrhagic shock: a Phase IIb multi-center randomized placebo-controlled trial. Poster presentation: American Association for the Surgery of Trauma (AAST) meeting, San Francisco
US Food and Drug Administration (2004) Draft guidance for industry: criteria for safety and efficacy evaluation of oxygen therapeutics as red blood cell substitutes. Issued Oct 2004 (www.rsihata.com/updateguidance/usfda2/bio1/ucm080290)
Silverman TA, Weiskopf RB (2009) Hemoglobin-based oxygen carriers: current status and future directions. Anesthesiology 111:946–963
Natanson C, Kerns SJ, Lurie P et al (2008) Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death. A meta-analysis. JAMA 299:2304–2312
Letters to the Editor (2008) Hemoglobin-based blood substitutes and risk of myocardial infarction and death. JAMA 300:1295–1300
Olofsson CI, Górecki AZ, Dirksen R et al (2011) Evaluation of MP4OX for prevention of perioperative hypotension in patients undergoing primary hip arthroplasty with spinal anesthesia: a randomized, double-blind, multicenter study. Anesthesiology 114:1048–1063
Van der Linden P, Gazdzik TS, Jahoda D et al (2011) A double-blind, randomized, multicenter study of MP4OX for treatment of perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia. Anesth Analg 112:759–773
Winslow RM (2006) Clinical indications for blood substitutes and optimal properties. In: Winslow RM (ed) Blood substitutes. Elsevier, London, pp 115–125
Misra H, Lickliter J, Kazo F et al (2014) Pegylated carboxyhemoglobin bovine (Sanguinate): results of a Phase I clinical trial. Artif Organs 38:702–707
Hsia JC, Ma L (2012) Compositions and methods of use of neurovascular protective multifunctional polynitroxylated pegylated carboxy hemoglobins for transfusion and critical care medicine. US Patent 8273857B2 (https://patents.google.com/patent/US8273857B2/en)
Hsia CJC, Ma L (2012) A hemoglobin-based multifunctional therapeutic: polynitroxylated pegylated hemoglobin. Artif Organs 36:215–220
Zhang J, Cao S, Ma L et al (2013) Protection from transient focal cerebral ischemia by transfusion of polynitroxylated pegylated hemoglobin. Stroke 44:A154
Shellington DK, Du L, Wu X et al (2011) Polynitroxylated pegylated hemoglobin: a novel neuroprotective hemoglobin for acute volume-limited fluid resuscitation after combined traumatic brain injury and hemorrhagic hypotension in mice. Crit Care Med 39:494–505
Brockman EC, Bayir H, Blasiole B et al (2012) Polynitroxylated-pegylated hemoglobin attenuates fluid requirements and brain edema in combined traumatic brain injury plus hemorrhagic shock in mice. J Cereb Blood Flow Metab 33:1457–1464
Acknowledgments
PEK was formerly employed by Sangart Inc. (San Diego, CA) as VP, Clinical Development, during the conduct of the MP4OX clinical trials in trauma.
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Keipert, P.E. (2017). Hemoglobin-Based Oxygen Carrier (HBOC) Development in Trauma: Previous Regulatory Challenges, Lessons Learned, and a Path Forward. In: Halpern, H., LaManna, J., Harrison, D., Epel, B. (eds) Oxygen Transport to Tissue XXXIX. Advances in Experimental Medicine and Biology, vol 977. Springer, Cham. https://doi.org/10.1007/978-3-319-55231-6_45
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