Review articleHemoglobin-based oxygen carriers for hemorrhagic shock☆
Introduction
The primary goals of resuscitation in hemorrhagic shock are the restoration of oxygen delivery to end organs and support of intravascular volume to prevent circulatory collapse. The ideal resuscitative fluid would be well-tolerated and accomplish both of these goals. It would have minimal associated adverse effects, be easily stored, universally compatible and in plentiful supply.1 No such fluid exists. Instead, traditional resuscitation relies on transfusion of crystalloids such as normal saline or lactated Ringer's, starch-based artificial colloids such as hetastarch or dextrans, or blood components. These therapies have important roles in the treatment of hemorrhagic shock, but are far from ideal.
A range of alternative agents has been developed in an attempt to design an ideal resuscitation fluid. Perfluorocarbon emulsions, which expand intravascular volume and dramatically increase the solubility of dissolved respiratory gases in blood, are currently licensed for use in Russia.2 Recombinant hemoglobins, liposome-encapsulated hemoglobins and heme-containing nanoparticles are currently in preclinical development.3, 4, 5 While potentially promising, challenges in large-scale production, adverse effects and questionable clinical utility call into question the practicality of these agents.2, 3, 4, 5
We believe the most promising artificial resuscitation fluids are hemoglobin-based oxygen carriers (HBOCs), which are synthesized from chemically modified human or bovine hemoglobin. Although early development of these agents was fraught with setbacks and failures, improved understanding of the mechanisms of toxicity of first generation agents has led to the rational design of a second generation of HBOCs with improved adverse effect profiles.
In this article, we briefly discuss the major limitations of traditional resuscitative fluids (crystalloid, artificial colloids and blood) to provide readers with an understanding of the ongoing impetus to develop alternative agents. We then review the history of early HBOC development and the current understanding of the mechanisms of their toxicity that has informed the design of second-generation agents. Finally, we provide an overview of these newer HBOCs that are under active investigation.
Section snippets
Limitations of crystalloid or artificial colloids
The shortcomings of crystalloids and artificial colloids in the resuscitation of massive hemorrhage are well known.6 While supporting circulatory volume, crystalloids have none of the properties of endogenous blood components and therefore lead to dilutional anemia and coagulopathy. Furthermore, their use activates proinflammatory cascades, causes cellular swelling, acidosis, metabolic dysfunction and apoptosis, and leads to interstitial edema and organ dysfunction.7, 8, 9, 10
Starch-based
Limitations of blood component therapy
Unfortunately, transfusion of human donor-derived blood products is also far from ideal. The drawbacks of blood products may be roughly grouped into four categories: difficulties in supply and availability; development of storage-related defects; infectious potential; and immunomodulatory effects.
Hemoglobin-based oxygen carriers
Almost as soon as the practice of blood transfusion became widespread, scientists have searched for an alternative. Attempts to transfuse cell-free native human hemoglobin were reported as early as 1933 and led to profound hypertension and acute renal failure.33 These early observations led to progressive modification of the hemoglobin molecule beginning with simple intramolecular cross-linking and advancing to complex chemical modifications which attempt to overcome these and other
Dimerization and renal failure
Cell-free hemoglobin exists in equilibrium between tetramers and dimers (Fig. 1).34 Dissociated dimers undergo rapid renal clearance leading to a short serum half-life, renal tubular toxicity and acute renal failure.33, 35 At low physiologic levels, proximal tubule cells reabsorb and catabolize filtered hemoglobin, but upon administration of the large volumes of hemoglobin required to resuscitate patients in shock, this mechanism is quickly overwhelmed.34 This problem is overcome by chemical
Diaspirin cross-linked hemoglobin
As noted above, the realization that dimerization and glomerular filtration of hemoglobin leads to renal failure rapidly led to a strategy of cross-linking to prevent dissociation. The earliest HBOC to use this strategy was a diaspirin cross-linked hemoglobin (DCLHb; HemAssist, Baxter Corporation, Deerfield, IL), in which αα-intramolecular cross-linking was carried out using a brominated salicylate moiety (Fig. 1).55 At the time of development, the mechanisms of extrarenal toxicity reviewed
Second generation HBOCs
As understanding of the mechanisms of HBOC toxicity grew, several refinements were made to the rational design of these molecules, leading to the ongoing development of a second generation of products (Table 1). Specifically increasing molecular size, viscosity and oxygen affinity, developers seek to reduce complications related to NO depletion and hypoxia, creating better tolerated agents.
Conclusion
Hemorrhagic shock is a pathologic state in which intravascular volume and oxygen delivery are impaired, leading to circulatory collapse and cellular ischemia. Current resuscitation strategies rely on administration of crystalloid, starch-based colloids or blood components. Only administration of PRBCs restores oxygen carrying capacity, but their supply is limited and their use is associated with a wide range of adverse effects including immunomodulation. The development of HBOCs designed to
Conflict of interest statement
The authors have no conflicts, financial or personal relationships to disclose.
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2014, Trends in BiotechnologyCitation Excerpt :Nevertheless, similar to other acellular HBOCs, polymerized or conjugated (e.g., PEG-modified) Hbs lack the ability to autoregulate the oxidative state of iron (Fe) in their heme groups, which results in the irreversible conversion of Fe2+-containing Hb to Fe3+-containing methemoglobin (metHb) [26]. MetHb, unlike Hb, has a low O2-carrying capacity and high O2 affinity, which hinders O2 delivery at physiologic oxygen tensions [22] and further results in the induction of adverse effects, such as bradycardia and hypotension [26–28]. Given the need for an artificial RBC substitute, and building on the aforementioned lessons learned through the development of PFCs and acellular HBOCs, research efforts are currently underway to generate synthetic microparticle, nanoparticle, and stem cell-based oxygen carriers.
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2014, Small Animal Critical Care Medicine, Second Edition
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A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2011.09.020.