Blood Substitutes and Transfusion Therapy

Educational Objectives

The goal of this program is to improve the management of patients requiring trauma resuscitation. After hearing and assimilating this program, the clinician will be better able to:

1.   Explain the significance of immunomodulation associated with allogeneic blood transfusion.

2.   Discuss the hemoglobin modification strategies used in the development of blood substitutes.

3.   List the major drawbacks of blood substitutes.

4.   Recognize the disadvantages of the use of crystalloid in resuscitation of trauma patients.

5.   Summarize the evidence showing that whole blood is preferable to modified hemoglobin-based oxygen carri­ers.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Hol­comb is on the advisory board of Novo Nordisk and is a consultant for HemCon. Drs. Hoyt and Scherer and the planning committee reported nothing to disclose.

Acknowledgements

Dr. Hoyt spoke at 16th Annual USC Trauma/Critical Care Symposium, held March 12-13, 2009, in Pasadena, CA, and sponsored by the Keck School of Medicine, University of Southern California. Dr. Holcomb spoke at Detroit Trauma Symposium, held April 6-7, 2009, in Detroit, MI, and sponsored by the Wayne State University School of Medicine. Dr. Scherer was recorded at Las Vegas Trauma, Critical Care, and Acute Care Surgery Conference, held April 5-8, in Las Vegas, NV, and sponsored by the Trauma and Critical Care Foundation. The Audio-Digest Founda­tion thanks the speakers and the sponsors for their cooperation in the production of this program.

What’s New in Blood Substitutes for Trauma Resuscitation

David S. Hoyt, MD, John E. Connolly Professor and Chair, Department of Surgery, University of Califor­nia, Irvine, School of Medicine

Background: »14 million units transfused annually; problems include cross-matching, need for refrigeration, limita­tions of blood supply, transfusion reactions, and infectious disease; immunomodulation  —  most important issue oc­curing with transfusion; definitive evidence that risk for infection increases with allogeneic transfusion; related to age of blood (>14 days) and volume of blood transfused (>6 units); effect of leukoreduction strategies on leuko­cytes (washing before transfusion thought to attenuate effect on leukocytes, but good data lacking); biggest concern release of inflammatory mediators, which leads to cytotoxic neutrophil activation syndrome and drives multiple or­gan failure; major impetus for development of blood substitutes

Blood substitutes: ideal resuscitation fluid  —  cost-effective, abundant, and safe (would not transmit disease or cause transfusion-related immunologic problems); universally compatible; easy to store and transport; allows for low-volume resuscitation during field use; carries oxygen; »50% of autologous and allogeneic blood currently used in preoperative, intraoperative, and postoperative settings could be replaced by blood substitute; obstacles to devel­oping blood substitutes  —  removing red blood cell (RBC) membrane removes environment for 2,3-diphospho­glyceric acid (2,3-DPG); shifts oxygen-hemoglobin (Hb) dissociation curve because release of oxygen from Hb slowed (undesirable in hemorrhagic shock); tetramer-dimer dissociation leads to rapid renal elimination and re­nal toxicity; chemical modifications of blood substitutes focus on maintaining or increasing half-life and P₅₀ (ox­ygen tension corresponding to 50% oxygen saturation)

Strategies of chemical modification: surface mounted  —currently in use; conjugated with larger molecule (eg, dex­tran); prolongs intravascular retention, increases oncotic pressure, and expands volume; intermolecular crosslinking  —  stabilizes peptide chain and prevents dissociation; led to concept of diacylated crosslinked Hb; oxygen-binding pocket can be modified through pyridoxilation; shifts P₅₀ back to normal range; attempts to re­store Hb activity lost in red cell dissociation; Hb polymerization  —  most effective in clinical trials; involves chemically creating crosslinks between adjacent molecules, which results in formation of Hb polymers; im­proves intravascular retention and oxygen-binding pocket modification, and increases P₅₀; encapsulation  —  currently under study in Japan; Hb encapsulated and placed in new RBC using liposomes; oxygen delivery ex­cellent; risk for splenic or hepatic dysfunction due to phagocytosis main drawback

Polymerized Hb: studied in clinical trials over last 10 yr; in 1999 trial, 112 trauma patients received £1 L diaspirin crosslinked Hb (DCLHb) or normal saline in emergency department; DCLHb associated with higher 28-day mortality, although patients who received DCLHb had more severe injuries (many deaths resulted from cardiac arrest); findings slowed field for next 5 to 6 yr; presence of free Hb in bloodstream allows scavenging of nitric oxide, with resulting increase in blood pressure; polymerization may prevent this process, therefore cited as fo­cus of research into development of blood substitutes

Products currently in clinical trials in United States: polymerized human Hb (PolyHeme) and bovine Hb gluta­mer-250 (Hemopure); 1 unit of normal RBCs has volume of 350 mL, P₅₀ of 26, half-life of 31 days, shelf life of 42 days, with modest vasoreactivity; substitutes have similar volume and oxygen-carrying capacity and better P₅₀; half-life “a problem, other than for acute use”; shelf life superior to that of blood; vasoreactivity potential problem; clinical trials with bovine Hb show products allowed high proportion of patients undergoing elective noncardiac or orthopedic surgery to avoid transfusion; suggests wide applicability of such products if available; adverse effects  —  incidence significant; included mild to moderate hypertension, moderately increased systemic vascular resistance, and mildly reduced cardiac output; occurred mostly in elderly or patients with preexisting heart disease; respiratory complications (mostly associated with cardiac effects); gastrointestinal effects included transient dysphagia, ab­dominal pain, and “modest amount” of renal failure

Prehospital clinical trial with polymerized human Hb:  rationale  —  earlier replacement of oxygen-carrying capac­ity would reduce mortality and inflammatory response; protocol  —  control group received crystalloid prehospital, followed by RBCs in hospital; experimental group received polymerized human Hb product prehospital, followed by RBCs in hospital; 590 patients treated according to protocol; results  —  no difference between groups in overall survival; adverse events included myocardial infarction, coagulopathy, and increased blood pressure; suggests high risk for adverse cardiovascular events associated with substitutes    

New Concepts in Transfusion Therapy in the Critically Injured Patient

John B. Holcomb, MD, Professor of Surgery, Chief, Division of Acute Care Surgery, and Director, Center for Translational Injury Research, University of Texas Health Science Center, Houston

Patients at risk of bleeding to death: arrive at trauma center in shock, bleeding rapidly, pale, diaphoretic, hypoten­sive, acidotic, and hypothermic; military data show deaths result primarily from truncal hemorrhage; mortality peaks at 1 to 6 hr (“all bleeding stops within 6 hr, one way or the other”)

Coagulopathy: shown in new data to be present on admission; therefore, all parts of lethal triad (hypothermia, acido­sis, and coagulopathy) present on admission; crystalloid exacerbates coagulopathy by diluting clotting factors; more plasma recommended as primary resuscitative fluid; massive transfusion indicated for 5% to 7% of military trauma patients and 1.7% to 2% of civilian patients; in study of 466 cases of massive transfusion, high ratio of plasma and platelets to RBCs associated with best survival (administration of coagulation-promoting factors pre­vents bleeding to death); no prospective, randomized studies of massive transfusion in trauma patients; current resuscitation practices based on 1976 paper recommending infusion of 2 L lactated Ringer’s solution over 45 min while preparing whole blood (translates today to 1:1:1 ratio of plasma to packed RBCs to platelets); in human studies, patients do better when given less crystalloid (one study showed less crystalloid associated with lower incidence of intra-abdominal hypertension, abdominal compartment syndrome, multiorgan system failure, and death); conclusion  —  “too much crystalloid is bad for your patient”; studies published >20 yr ago based on trans­fusion of whole blood; today, if administering packed RBCs, plasma administration necessary to provide clotting factors

Recent technology: shelf life of RBCs has increased to »45 days (may soon increase to 70 days); no data document clinical impact of extending RBC shelf life; as preservative solutions improved, plasma content of RBC products decreased; effects on efficacy and patient outcomes unknown

Iatrogenic resuscitation injury: when blood components (RBCs, plasma, platelets, and cryoprecipitate) combined in beaker, result described as “anemic, thrombocytopenic, and coagulopathic fluid”; addition of crystalloid or col­loid exacerbates drawbacks; in speaker’s opinion, administration of crystalloid to trauma patients creates iatro­genic resuscitation injury (dilutional coagulopathy)

Recommendations: return to whole blood or have immediate access to whole blood reconstituted in 1:1:1 ratio

Component therapy: no data showing benefit; RBC preservative fluids created to extend shelf life, not for clinical benefit; work well if patient not in shock; in speaker’s opinion, products less effective for patients in shock (now collecting data)

Diagnosing coagulopathy: some evidence that thromboelastography better than prothrombin time or partial throm­boplastin time; mechanism of early coagulopathy of trauma still not understood

Conclusions: noncrystalloid-based resuscitation should be studied; better resuscitation will permit longer, more de­finitive surgery, with less need for damage control; with good resuscitation, operating room “will no longer be a physiologically hostile environment”; risk of administering more plasma and platelets includes transfusion-associ­ated lung injury (TRALI); occurs in 1 in 10,000 to 60,000 transfusions; fatal in one-third of cases; in speaker’s opinion, benefits outweigh risks; use of prediction models recommended; move early to definitive hemostasis inter­vention; leading preventable cause of death truncal hemorrhage; use of more plasma and platelets requires advance coordination with blood bank and transfusion committee; “in general, giving more plasma and platelets to trauma patients improves their outcome”

Phony Blood: What’s the Problem?

Lynette A. Scherer, MD, Associate Professor of Surgery, Trauma and Emergency Surgery Services, Pro­gram Director, General Surgery Residency, University of California, Davis, School of Medicine, Sacra­mento

Blood substitutes: maleimide-polyethylene glycol-modified Hb solution (Hemospan, made by Sangart; currently un­available in United States); diaspirin crosslinked Hb (HemAssist, made by Baxter International; no ongoing reg­istered trials); polymerized human Hb (Hemolink, made by Hemosol. [phase II trials suspended]); polymerized bovine Hb (Hemopure, made by Biopure; clinical trials suspended); and polymerized human Hb (PolyHeme, made by Northfield Laboratories)

Safety profile: all products have demonstrated vasopressor effect thought to be mediated through nitric oxide; in earlier products, tetrameric Hb believed to extravasate through endoluminal surface, stay in abluminal position, and bind nitric oxide, leading to unopposed vasoconstriction; polymerized Hb molecules larger and less likely to extravasate through endothelium

Controversy: 2008 meta-analysis of 16 trials involving 5 products (including 2 already off market) reported in­creased risk for death and myocardial infarction associated with blood substitutes; authors criticized Food and Drug Administration for failure to anticipate risks and place moratorium on trials; lead author had several con­flicts of interest (eventually sued by Biopure); later editorial deemed findings of meta-analysis “confounded”

USA multicenter trial of human polymerized Hb for the treatment of hemorrhagic shock when blood unavailable: conducted at 29 urban, level 1 trauma centers; hypotensive patients (systolic blood pressure <90 mm Hg) ran­domized in field to receive  polymerized human Hb in field or blood on arrival at emergency department; 714 pa­tients enrolled; no mortality difference between groups at 30 days; rate of adverse events 93% among patients receiving  polymerized human Hb and 88% among those receiving blood (statistically significant); authors came to guarded conclusion that polymerized human Hb “should be considered an alternative when blood is unavail­able” (excludes most hospitals in United States, which usually have blood available)

Conclusions: “Hb-based oxygen carriers are not better than the real thing”; currently no blood substitute available for routine use in United States

Suggested Reading

Carrico CJ et al: Fluid resuscitation following injury: rationale for the use of balanced salt solutions. Crit Care Med 4:46, 1976; Hess JR: Blood and coagulation support in trauma care. Hematology Am Soc Hematol Educ Program 187, 2007; Hess JR et al: Giving plasma at a 1:1 ratio with red cells in resuscitation: who might benefit? Transfusion 48:1763, 2008; Ho AM et al: A mathematical model for fresh frozen plasma transfusion strategies during major trauma resuscitation with ongoing hemorrhage. Can J Surg 48:470, 2005; Holcomb JB et al: Damage control resus­citation: directly addressing the early coagulopathy of trauma. J Trauma 62:307, 2007; Holcomb JR et al: Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 248:447, 2008; Lu KJ et al: Hemodynamic patterns of blunt and penetrating injuries. J Am Coll Surg 203:899, 2006; Moore EE et al: Human polymerized hemoglobin for the treatment of hemorrhagic shock when blood is unavailable: the USA multicenter trial. J Am Coll Surg 208:1, 2009; Natanson C et al: Cell-free hemoglo­bin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis. JAMA 299:2304, 2008; Sloan EP et al: Diaspirin cross-linked hemoglobin (DCLHb) in the treatment of severe traumatic hemorrhagic shock: a randomized controlled efficacy trial. JAMA 282:1857, 1999; Sloan EP: The clinical trials of diaspirin cross-linked hemoglobin (DCLHb) in severe traumatic hemorrhagic shock: the tale of two continents. Intensive Care Med 29:347, 2003; Sloan EP et al: The informed consent process and the use of the exception to informed consent in the clinical trial of diaspirin cross-linked hemoglobin DCLHb) in severe traumatic hemorrhagic shock. DCLHb Traumatic Hem­orrhagic Shock study group. Acad Emerg Med 6:1203, 1999.