Bloodless Management of the Anemic Patient in the Emergency Department.

Anemia is a commonly encountered condition in emergency medicine; transfusion of packed red blood cells is commonly performed for anemic patients in the emergency department (ED), but some patients are unable to accept transfusion of blood products due to medical or religious concerns. The unique, acute, and time-sensitive nature of emergency medicine practice requires that physicians maintain an enhanced awareness of bloodless medicine treatment modalities. Identification of bloodless medicine patient preferences in the ED can help guide physicians in the recommendation of acceptable methods of treating anemia in this patient population. A focus on early hemostasis and resuscitation, instead of attempts to convince the patient to accept blood transfusion, can be lifesaving in patients with acute bleeding. Treatment strategies including the use of methods to reduce unnecessary blood loss, enhance red blood cell production, and increase the oxygen-carrying capacity of blood should also be considered early in patient presentation. Timely involvement of the Hospital Liaison Committee can help facilitate successful interpersonal communication and shared decisionmaking between emergency physicians and bloodless medicine patients. By embracing an understanding of bloodless medicine patient needs as well as available treatment strategies, ED physicians can contribute to optimal overall outcomes for anemic bloodless medicine patients.

PEGylated carboxyhemoglobin bovine (SANGUINATE) ameliorates myocardial infarction in a rat model.

Artificial oxygen (O2 ) carriers were reported to be protective in ischemia/reperfusion (I/R) in various organs including the heart. In the current study, 20 rats underwent ligation (MI) of the left anterior descending artery, were treated with 10 mL/kg of PEGylated carboxyhemoglobin bovine (SANGUINATE, S+, n = 10) or saline (S-, n = 10) 10 minutes after MI and daily thereafter for 3 days, and were followed by weekly echocardiography for 4 weeks, when they had left ventricular pressure volume relationship (PVR) analyses followed by necropsy. Echocardiography showed an increase in end-systolic dimension rather than end-diastolic dimension, preserved fractional shortening (36 vs. 26%, P < .01), and milder mitral regurgitation in S+ compared with S- rats. PVR revealed a milder increase in end-systolic volume, larger stroke volume (101 vs. 74 µL, P < .005) and cardiac output (33.4 vs. 23.8 mL/min, P = .004) in S+ rats in actual determination and under a wide range of standardized loading conditions 4 weeks after MI. Excised heart showed significantly limited area of MI (8.9 vs. 13.3%, P = .028). The results suggest that SANGUINATE in short-term repeated doses may accelerate weight recovery, preserving the myocardium, mitral competence, and cardiac function after MI. The mechanism of action and optimal treatment for MI remain to be studied.

Hemoglobin-Based Oxygen Carrier Rescues Double-Transplant Patient From Life-Threatening Anemia.

This case describes a 46-year-old male recipient of a kidney-pancreas transplant who is Jehovah's Witness. Early in the postoperative period, he was found to have splenic vein thrombosis requiring heparin infusion. Two days later, he developed severe symptomatic anemia (hemoglobin <6 g/dL). Standard medical therapy for bloodless surgical patients with severe anemia was instituted. Nevertheless, the patient's hemoglobin concentration continued to decline to critical levels (2 g/dL). Because he was Jehovah's Witness, transfusion of allogeneic blood products was not an option, prompting use of a hemoglobin-based oxygen carrier (HBOC). After approval by the U.S. Food and Drug Administration and the local institutional review board, 12 U of HBOC-201 were transfused over a period of 8 days. Two weeks later, the patient's hemoglobin levels had increased to 6.8 g/dL. The patient's overall clinical condition improved, and he was discharged home. This case describes the first use of HBOC transfusion in a double solid organ transplant patient. HBOC may represent a viable option in patients with severe symptomatic anemia when allogeneic blood transfusion is not an option.

High-Dose Polymerized Hemoglobin Fails to Alleviate Cardiac Ischemia/Reperfusion Injury due to Induction of Oxidative Damage in Coronary Artery.

Objective. Ischemia/reperfusion (I/R) injury is an unavoidable event for patients in cardiac surgery under cardiopulmonary bypass (CPB). This study was designed to investigate whether glutaraldehyde-polymerized human placenta hemoglobin (PolyPHb), a hemoglobin-based oxygen carrier (HBOC), can protect heart against CPB-induced I/R injury or not and to elucidate the underlying mechanism. Methods and Results. A standard dog CPB model with 2-hour cardiac arrest and 2-hour reperfusion was established. The results demonstrated that a low-dose PolyPHb (0.1%, w/v) provided a significant protection on the I/R heart, whereas the high-dose PolyPHb (3%, w/v) did not exhibit cardioprotective effect, as evidenced by the impaired cardiac function, decreased myocardial oxygen utilization, and elevated enzymes release and pathological changes. Further study indicated that exposure of isolated coronary arteries or human umbilical vein endothelial cells (HUVECs) to a high-dose PolyPHb caused impaired endothelium-dependent relaxation, which was companied with increased reactive oxygen species (ROS) production, reduced superoxide dismutase (SOD) activity, and elevated malonaldehyde (MDA) formation. Consistent with the increased oxidative stress, the NAD(P)H oxidase activity and subunits expression, including gp91(phox), p47(phox), p67(phox), and Nox1, were greatly upregulated. Conclusion. The high-dose PolyPHb fails to protect heart from CPB-induced I/R injury, which was due to overproduction of NAD(P)H oxidase-induced ROS and resultant endothelial dysfunction.

Hextend-perfluorocarbon cocktail inhibits mean arterial pressure response in a rabbit shock model.

BACKGROUND: Hextend (HEX) is standard of care resuscitation fluid for combat-related traumatic hemorrhage. Because HEX has limited oxygen-carrying capacity, combination therapy with oxygen therapeutics could improve oxygen delivery after hemodynamic shock. We hypothesized that addition of perfluorocarbon (PFC) to HEX would improve hemodynamics and oxygen delivery marker response in a rabbit model of hemorrhagic shock. METHODS: Anesthetized New Zealand rabbits (n = 23) were randomly allocated to resuscitation with fresh whole blood (FWB), HEX, or HEX plus PFC (HEX + PFC) after 60 min of hemorrhagic hypotension. Mean arterial pressure (MAP) was sampled every 2-3 min for 120 min postinfusion; MAP profiles were modeled by a one-compartment pharmacokinetic model to determine peak MAP (Pmax), time to peak MAP (tmax), and postinfusion MAP persistence. Arterial blood was sampled every 15 min to examine pH, blood gases PO2 and pCO2, metabolites lactate and glucose, methemoglobin (metHb), and electrolytes. RESULTS: Compared with FWB and HEX, HEX + PFC administration resulted in delayed peak MAP and less persistent (P < 0.0001) MAP elevation; metHb was significantly elevated (P < 0.0001) compared with FWB and HEX. There were no significant differences in PO2, pCO2, or pH. Glucose, hematocrit, and hemoglobin of both HEX and HEX + PFC were significantly lower relative to FWB. Lactate clearance was modest and transient for all treatments; base deficit was significantly more negative for HEX + PFC. CONCLUSIONS: Addition of PFC to HEX did not improve hemodynamics or acidosis. Further dose- and volume-range studies are required to test efficacy of PFC in combination with HEX for hemorrhagic shock.

How do we treat life-threatening anemia in a Jehovah's Witness patient?

The refusal of allogeneic human blood and blood products by Jehovah's Witness (JW) patients complicates the treatment of life-threatening anemia. For JW patients, when hemoglobin (Hb) levels decrease beyond traditional transfusion thresholds (<7 g/dL), alternative methods to allogeneic blood transfusion can be utilized to augment erythropoiesis and restore endogenous Hb levels. The use of erythropoietin-stimulating agents and intravenous iron has been shown to restore red blood cell and Hb levels in JW patients, although these effects may be significantly delayed. When JW patients have evidence of life-threatening anemia (Hb <5 g/dL), oxygen-carrying capacity can be supplemented with the administration of Hb-based oxygen carriers (HBOCs). Although HBOCs are not Food and Drug Administration (FDA) approved, they may be obtained and administered with FDA, institutional review board, and patient approval. We describe a protocol-based algorithm to the management of life-threatening anemia in JW patients and review time to anemia reversal and patient outcomes using this approach.

[Impact of a combined application of ozonized perftoran and glutoxim on the immune status of the patients and the cytokines profile in extended peritonitis].

The immune status was studied while surgical treatment of 74 patients, suffering extended peritonitis (EP). In 38 patients (group of comparison) a complex routine therapy was conducted, in 36 (the main group)--along with routine complex measures of treatment a local and systemic ozonotherapy, using ozonized perftoran (OP) and glutoxim (for immunocorrection), were applied. The patients severity state was estimated in accordance to the Mahnheim's peritoneal index. In all the patients while hospitalization there were revealed changes in T--and B--links of immunity, in phagocytosis and the cytokins profile, significant of which have depended upon the EP severity. The combined local and systemic application of OP and glutoxim in complex of conservative treatment is pathogenetically substantiated, it permits more rapidly to eliminate the immunity disorders and the cytokines balance, as well as inflammatory process in abdominal cavity and to improve the results of surgical treatment significantly.

Impact of acellular hemoglobin-based oxygen carriers on brain apoptosis in rats.

BACKGROUND: Extracellular hemoglobin (Hb)-based oxygen carriers (HBOCs) are under extensive consideration as oxygen therapeutics. Their effects on cellular mechanisms related to apoptosis are of particular interest, because the onset of proapoptotic pathways may give rise to tissue damage. STUDY DESIGN AND METHODS: The objective was to assess whether the properties of the Hb that replaces blood during an isovolemic hemodilution would modulate apoptotic-response mechanisms in rat brain and whether such signaling favors cytoprotection or damage. We exposed rats to exchange transfusion (ET; 50% blood volume and isovolemic replacement with Hextend [negative colloid control], MP4OX [PEGylated HBOC with high oxygen affinity], and ααHb [αα-cross-linked HBOC with low oxygen affinity; n=4-6/group]). Sham rats acted as control. Animals were euthanized at 2, 6, and 12 hours after ET; brain tissue was harvested and processed for analysis. RESULTS: In MP4OX animals, the number of neurons that overexpressed the hypoxia-inducible factor (HIF)-1α was higher than in ααHb, particularly at the early time points. In addition, MP4OX was associated with greater phosphorylation of protein kinase B (Akt), a well-known cytoprotective factor. Indeed, the degree of apoptosis, measured as terminal deoxynucleotidyl transferase-positive neurons and caspase-3 cleavage, ranked in order of MP4OX < Hextend < ααHb. CONCLUSION: Even though both HBOCs showed increased levels of HIF-1α compared to shams or Hextend-treated animals, differences in signaling events resulted in very different outcomes for the two HBOCs. ααHb-treated brain tissue showed significant neuronal damage, measured as apoptosis. This was in stark contrast to the protection seen with MP4OX, apparently due to recruitment of Akt and neuronal specific HIF-1α pathways.

2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Actualización del Documento Sevilla / The 2013 Seville Consensus Document on alternatives to allogenic blood transfusion. An update on the Seville Document

La transfusión de sangre alogénica (TSA) no es inocua, y como consecuencia han surgido múltiples alternativas a la misma (ATSA). Existe variabilidad respecto a las indicaciones y buen uso de las ATSA. Dependiendo de la especialidad de los médicos que tratan a los pacientes, el grado de anemia, la política transfusional, la disponibilidad de las ATSA y el criterio personal, estas se usan de forma variable. Puesto que las ATSA tampoco son inocuas y pueden no cumplir criterios de coste-efectividad, la variabilidad en su uso es inaceptable. Las sociedades españolas de Anestesiología y Reanimación (SEDAR), Hematología y Hemoterapia(SEHH), Farmacia Hospitalaria (SEFH), Medicina Intensiva y Unidades Coronarias(SEMICYUC), Trombosis y Hemostasia (SETH) y Transfusiones Sanguíneas (SETS) han elaborado un documento de consenso para el buen uso de la ATSA. Un panel de expertos de las 6sociedades ha llevado a cabo una revisión sistemática de la literatura médica y elaborado el 2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Solo se contempla las ATSA dirigidas a disminuir la transfusión de concentrado de hematíes. Se definen las ATSA como toda medida farmacológica y no farmacológica encaminada a disminuir la transfusión de concentrado de hematíes, preservando siempre la seguridad del paciente. La cuestión principal que se plantea en cada ítem se formula, en forma positiva o negativa, como: “La ATSA en cuestión reduce/no reduce la tasa transfusional». Para formular el grado de recomendación se ha usado la metodología Grades of Recommendation Assessment, Development and Evaluation (GRADE) (AU)

Since allogeneic blood transfusion (ABT) is not harmless, multiple alternatives to ABT (AABT) have emerged, though there is great variability in their indications and appropriate use. This variability results from the interaction of a number of factors, including the specialty of the physician, knowledge and preferences, the degree of anemia, transfusion policy, and AABT availability. Since AABTs are not harmless and may not meet cost-effectiveness criteria, such variability is unacceptable. The Spanish Societies of Anesthesiology (SEDAR), Hematology and Hemotherapy (SEHH), Hospital Pharmacy (SEFH), Critical Care Medicine (SEMICYUC), Thrombosis and Hemostasis (SETH)and Blood Transfusion (SETS) have developed a Consensus Document for the proper use of AABTs. A panel of experts convened by these 6 Societies have conducted a systematic review of the medical literature and have developed the 2013 Seville Consensus Document on Alternatives to Allogeneic Blood Transfusion, which only considers those AABT aimed at decreasing the transfusion of packed red cells. AABTs are defined as any pharmacological or non-pharmacological measure aimed at decreasing the transfusion of red blood cell concentrates, while preserving patient safety. For each AABT, the main question formulated, positively or negatively, is: “Does this particular AABT reduce the transfusion rate or not? “All the recommendations on the use of AABTs were formulated according to the Grades of Recommendation Assessment, Development and Evaluation(GRADE) methodology (AU)

Current status of pharmacologic therapies in patient blood management.

Patient blood management(1,2) incorporates patient-centered, evidence-based medical and surgical approaches to improve patient outcomes by relying on the patient's own (autologous) blood rather than allogeneic blood. Particular attention is paid to preemptive measures such as anemia management. The emphasis on the approaches being "patient-centered" is to distinguish them from previous approaches in transfusion medicine, which have been "product-centered" and focused on blood risks, costs, and inventory concerns rather than on patient outcomes. Patient blood management(3) structures its goals by avoiding blood transfusion(4) with effective use of alternatives to allogeneic blood transfusion.(5) These alternatives include autologous blood procurement, preoperative autologous blood donation, acute normovolemic hemodilution, and intra/postoperative red blood cell (RBC) salvage and reinfusion. Reviewed here are the available pharmacologic tools for anemia and blood management: erythropoiesis-stimulating agents (ESAs), iron therapy, hemostatic agents, and potentially, artificial oxygen carriers.

Administration of bovine polymerized haemoglobin before and during coronary occlusion reduces infarct size in rabbits.

BACKGROUND: Haemoglobin-based oxygen carriers (HBOC) seem to increase the risk of mortality and myocardial infarction in clinical trials. Therefore, we designed this randomized placebo-controlled animal study to evaluate the effects of prophylactic and therapeutic administration of HBOC in a myocardial ischaemia-reperfusion model with respect to infarct size and areas of impaired perfusion (no reflow, NR). METHODS: Thirty-two anaesthetized, mechanically ventilated rabbits were randomized to one of the four groups. Group G1 received 0.4 g kg(-1) i.v. HBOC-200 25 min before coronary artery occlusion, G2 received the same dose i.v. 10 min after occlusion, and G3 and 4 received i.v. saline. G1, 2, and 3 were subjected to 30 min occlusion of left coronary artery followed by 240 min of reperfusion. G4 was treated without ischaemia-reperfusion. Measurement included assessment of the area at risk and infarct size using triphenyltetrazolium chloride stain and areas of NR using thioflavin stain. Ischaemia-reperfusion was confirmed by microspheres technique. RESULTS: Infarct size as a percentage of the area at risk was significantly reduced in G1 [25 (sd 13)%, P=0.026] and G2 [22 (20)%, P=0.009] compared with G3 [48 (17)%]. The areas of NR in percentage of the area at risk [G1, 26 (15)%; G2, 34 (22)%; G3, 36 (12)%; G4, 5 (3)%] did not differ between the groups of animals undergoing coronary occlusion and reperfusion. CONCLUSIONS: Prophylactic and therapeutic administration of HBOC-200 reduces infarct size in myocardial ischaemia and reperfusion in rabbits. This reduction of infarct size is not accompanied by an improvement of areas of NR.

Predictors of blood loss in fronto-orbital advancement and remodeling.

Fronto-orbital advancement and remodeling for craniosynostosis is extensive surgery and is associated with potential risks; the most significant of these is blood loss. We prospectively studied 116 consecutive patients undergoing fronto-orbital advancement by the same surgical team for a 5-year 6-month period to determine what factors are associated with blood loss and transfusion of blood products. The data collected on the calvarial sutures involved were whether the patient had a diagnosed syndrome, the age at operation, the length of the operation, the estimated blood volume lost during the perioperative course, the number of units of packed cells transfused (donor exposures), and the use of other blood products. The mean (SD) total blood volume lost was 116% (5.4) of the estimated preoperative volume. The median number of whole units of packed cells transfused was 2 units. Other blood products were given in 28% of the cases. There was significantly greater blood loss in those patients with recognized craniofacial syndromes, pansynostosis, an operating time longer than 5 hours, and an age of 18 months or younger at operation. The use of other blood products was associated with those patients losing a blood volume higher than the mean.

Recombinant human erythropoietin therapy in critically ill Jehovah's Witnesses.

Blood transfusions and blood products are often given as a life-saving measure in patients with critical illness. However, some patients, such as Jehovah's Witnesses, may refuse their administration due to religious beliefs. Jehovah's Witnesses accept most available medical treatments, but not blood transfusions or blood products due to their religion's interpretation of several passages from the Bible. Since recombinant human erythropoietin (rHuEPO) became available, several cases have been reported in which rHuEPO was successfully administered to critically ill Jehovah's Witnesses. Administration of rHuEPO in combination with other blood conservation techniques has been shown to increase hemoglobin levels and survival in patients who experienced trauma, burns, general surgery, or gastrointestinal hemorrhage. We performed a literature search of the MEDLINE and International Pharmaceutical Abstracts databases of rHuEPO therapy in the Jehovah's Witness population. Fourteen cases were identified in which rHuEPO was administered to Jehovah's Witnesses who required the drug for critical care resuscitation as an alternative to blood products. In each clinical situation, rHuEPO enhanced erythropoiesis; however, time to the start of treatment, dosages, route of administration, and treatment duration varied widely. Supplementation with adjunctive agents, such as iron, folic acid, and vitamin B12, was also beneficial. Use of rHuEPO in Jehovah's Witnesses may provide an alternative to blood transfusions or blood products. Other alternatives, such as hemoglobin-based oxygen carriers and perfluorocarbons, are also being explored.

Inhaled nitric oxide enables artificial blood transfusion without hypertension.

BACKGROUND: One of the major obstacles hindering the clinical development of a cell-free, hemoglobin-based oxygen carrier (HBOC) is systemic vasoconstriction. METHODS AND RESULTS: Experiments were performed in healthy mice and lambs by infusion of either murine tetrameric hemoglobin (0.48 g/kg) or glutaraldehyde-polymerized bovine hemoglobin (HBOC-201, 1.44 g/kg). We observed that intravenous infusion of either murine tetrameric hemoglobin or HBOC-201 induced prolonged systemic vasoconstriction in wild-type mice but not in mice congenitally deficient in endothelial nitric oxide (NO) synthase (NOS3). Treatment of wild-type mice by breathing NO at 80 ppm in air for 15 or 60 minutes or with 200 ppm NO for 7 minutes prevented the systemic hypertension induced by subsequent intravenous administration of murine tetrameric hemoglobin or HBOC-201 and did not result in conversion of plasma hemoglobin to methemoglobin. Intravenous administration of sodium nitrite (48 nmol) 5 minutes before infusion of murine tetrameric hemoglobin also prevented the development of systemic hypertension. In awake lambs, breathing NO at 80 ppm for 1 hour prevented the systemic hypertension caused by subsequent infusion of HBOC-201. CONCLUSIONS: These findings demonstrate that HBOC can cause systemic vasoconstriction by scavenging NO produced by NOS3. Moreover, in 2 species, inhaled NO administered before the intravenous infusion of HBOC can prevent systemic vasoconstriction without causing methemoglobinemia.

Bloodless cardiac surgery: not just possible, but preferable.

Blood transfusions after cardiac surgery are very common, and the rates are highly variable among institutions. Transfusion carries the risk of infectious and noninfectious hazards and is often clinically unnecessary. This article discusses the history of bloodless cardiac surgery, the hazards of transfusion, the benefits of reducing or eliminating transfusion, and strategies to conserve blood. It also provides a list of resources for those who are interested in learning more about bloodless care.

Vasoactivity of bovine polymerized hemoglobin (HBOC-201) in swine with traumatic hemorrhagic shock with and without brain injury.

BACKGROUND: We previously reported that bovine polymerized hemoglobin (HBOC- 201) improved outcome in swine with hemorrhagic shock (HS) with and without traumatic brain injury (TBI). Herein, we add analyses of blood pressure (BP) responses, associated physiologic data, and HS fluid infusion guidelines. METHODS: HBOC-201 versus standard fluid resuscitation was compared in four anesthetized invasively monitored swine models: moderate controlled HS, severe controlled HS, severe uncontrolled HS (liver injury), and severe uncontrolled HS/TBI (liver/parietal brain injuries). Pigs received fluid for hypotension and tachycardia, and were followed up to 6 (HS alone) or 72 hours (HS/TBI). The change in mean arterial pressure (DeltaMAP) response severity was stratified and analyzed based on infusion number and HS severity, using Student's t and Fisher's exact tests. RESULTS: HBOC-201 vasoactivity resulted in higher MAP in all studies. Among HBOC-201 pigs, DeltaMAP responses were significant for the first two infusions and inversely related to HS severity. Among controls, DeltaMAP responses remained significant through the fourth infusion in controlled HS models, and through the first in severe uncontrolled HS/TBI; none were significant in severe uncontrolled HS. DeltaMAP was higher with HBOC-201 through the first infusion in moderate controlled HS, the fifth in severe uncontrolled HS, and the second in severe uncontrolled HS/TBI; there were no group differences in severe controlled HS. No severe MAP responses occurred. Higher DeltaMAP severity did not impact outcome. Hypotension satisfied fluid reinfusion criteria less consistently than tachycardia. Overall, HBOC-201 improved physiologic parameters and survival without causing hypoperfusion; in severe HS, perfusion improved. CONCLUSIONS: In swine with HS +/- TBI, HBOC-201 had mild to moderate vasoactivity, resulting in significant DeltaMAP responses mainly after initial infusions, no severe/adverse responses, and improved outcome. Our data suggest that use of physiologic parameters (e.g., tachycardia), in addition to hypotension to guide fluid reinfusion during HS resuscitation with HBOC-201, will minimize hypoperfusion risk and maximize potential benefit.