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Objectives: Linezolid is an oxazolidin commonly related to the development of haematological toxicity, being renal clearance the major factor involved in the drug clearance. The aim of this study is to evaluate the influence of increased filtration rates in the incidence of linezolid-induced haematological toxicity by comparing augmented renal clearance (ARC) patients versus normal renal function patients., Material and Methods: A retrospective, observational study was conducted on hospitalized patients treated with linezolid for 5 days or more during 2014-2019 period. Patients with a filtration rate of ≥130 mL/min versus reference patients (60-90 mL/min) were compared. Haematological toxicity was defined as a decrease of 25% in platelets, of 25% in haemoglobin, and/or 50% in neutrophils from baseline. Toxicity relevance was classified according to Common Terminology Criteria for Adverse Events v5. Incidence of haematological toxicity between groups was studied by chi-square and Fisher test. Furthermore, percentage diminution of all 3 parameters was calculated and compared by Mann-Whitney test and treatment interruption and transfusion requirements were registered., Results: 30 ARC patients and 38 reference patients were included. Haematological toxicity was observed in 16.66% of ARC patients vs 44.74% of reference patients (P=.014); thrombocytopenia in 13.33% vs 36.84% (P=.051), anaemia in 3.3% vs 10.52% (P=.374) and neutropenia in 10% vs 23.68% (P=.204). Median percentage of platelets decrease in ARC patients was -10.36 (-193.33-62.03) vs 2.68 (-163.16-82.71) in reference patients (P=.333), while haemoglobin decrease was 2.50 (-12.12-25.93) vs 9.09 (-17.72-30.63) (P=.047) and neutrophils decrease was 9.14 (-73.91-76.47) vs 27.33 (-86.66-90.90) (P=.093). 10.5% of normal renal function patients reported at least 1 adverse event grade 3 or superior while 2.6% of them interrupted treatment and 5.2% had transfusion requirements. No major events or interruptions were reported in ARC patients., Conclusion: Our findings suggest a lower incidence and clinical relevance of haematological toxicity in augmented renal clearance patients. Thrombocytopenia was the major event in both populations. This might be related to a lower exposure to the drug due to the higher clearance and likely lower therapeutic efficiency. These results suggest a potential benefit of therapeutic drug monitoring on high risk patients., Competing Interests: Conflicts of interest None declared., (Copyright © 2023 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Publicado por Elsevier España, S.L.U. All rights reserved.)

Objectives: Linezolid is an oxazolidin commonly related to the development of hematological toxicity, being renal clearance the major factor involved in the drug clearance. The aim of this study is to evaluate the influence of increased filtration rates in the incidence of linezolid-induced hematological toxicity by comparing augmented renal clearance (ARC) patients versus normal renal function patients., Material and Methods: A retrospective, observational study was conducted on hospitalized patients treated with linezolid for 5 days or more during 2014-2019 period. Patients with a filtration rate of ≥130 mL/min versus reference patients (60-90 mL/min) were compared. Hematological toxicity was defined as a decrease of 25% in platelets, of 25% in hemoglobin and/or 50% in neutrophils from baseline. Toxicity relevance was classified according to Common Terminology Criteria for Adverse Events v5. Incidence of hematological toxicity between groups was studied by chi-square and Fisher test. Furthermore, percentaje disminution of all three parameters was calculated and compared by Mann-Whitney test and treatment interruption and tranfusion requirements were registered., Results: 30 ARC patients and 38 reference patients were included. Hematological toxicity was observed in 16.66% of ARC patients vs 44.74% of reference patients (p = 0.014); thrombocytopenia in 13.33% vs 36.84% (p = 0.051), anemia in 3.3% vs 10.52% (p = 0.374) and neutropenia in 10% vs 23.68% (p = 0.204). Median percentaje of platelets decrease in ARC patients was -10.36 (-193.33-62.03) vs 2.68 (-163.16-82.71) in reference patients (p = 0.333), while hemoglobin decrease was 2.50 (-12.12-25.93) vs 9.09 (-17.72-30.63) (p = 0.047) and neutrophils decrease was 9.14 (-73.91-76.47) vs 27.33 (-86.66-90.90) (p = 0.093). 10.5% of normal renal function patients reported at least one adverse event grade 3 or superior while 2.6% of them interrupted treatment and 5.2% had tranfusion requirements. No major events or interruptions were reported in ARC patients., Conclusion: Our findings suggest a lower incidence and clinical relevance of hematological toxicity in augmented renal clearance patients. Thrombocytopenia was the major event in both populations. This might be related to a lower exposure to the drug due to the higher clearance and likely lower therapeutic efficiency. These results suggest a potential benefit of therapeutic drug monitoring on high risk patients., (Copyright © 2023 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Publicado por Elsevier España, S.L.U. All rights reserved.)

Heme proteins, the stuff of life, represent an ingenious biologic strategy that capitalizes on the biochemical versatility of heme, and yet is one that avoids the inherent risks to cellular vitality posed by unfettered and promiscuously reactive heme. Heme proteins, however, may be a double-edged sword because they can damage the kidney in certain settings. Although such injury is often viewed mainly within the context of rhabdomyolysis and the nephrotoxicity of myoglobin, an increasing literature now attests to the fact that involvement of heme proteins in renal injury ranges well beyond the confines of this single disease (and its analog, hemolysis); indeed, through the release of the defining heme motif, destabilization of intracellular heme proteins may be a common pathway for acute kidney injury, in general, and irrespective of the underlying insult. This brief review outlines current understanding regarding processes underlying such heme protein-induced acute kidney injury (AKI) and chronic kidney disease (CKD). Topics covered include, among others, the basis for renal injury after the exposure of the kidney to and its incorporation of myoglobin and hemoglobin; auto-oxidation of myoglobin and hemoglobin; destabilization of heme proteins and the release of heme; heme/iron/oxidant pathways of renal injury; generation of reactive oxygen species and reactive nitrogen species by NOX, iNOS, and myeloperoxidase; and the role of circulating cell-free hemoglobin in AKI and CKD. Also covered are the characteristics of the kidney that render this organ uniquely vulnerable to injury after myolysis and hemolysis, and pathobiologic effects emanating from free, labile heme. Mechanisms that defend against the toxicity of heme proteins are discussed, and the review concludes by outlining the therapeutic strategies that have arisen from current understanding of mechanisms of renal injury caused by heme proteins and how such mechanisms may be interrupted., Competing Interests: C.M. Adams reports ownership interest in Emmyon, Inc.; research funding from Emmyon, Inc.; patents or royalties from Emmyon, Inc.; and an advisory or leadership role for Emmyon, Inc. K.A. Nath reports an advisory or leadership role for the Journal of the American Society of Nephrology and Mayo Clinic Proceedings. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Background: Hemoglobin (Hb)-based oxygen (O 2 ) carriers (HBOCs) are being developed as alternatives to red blood cells and blood when these products are unavailable. Clinical trials of previous HBOC generations revealed side effects, including hypertension and vasoconstriction, that were not observed in preclinical studies. Large molecular weight (MW) polymerized bovine Hb (PolybHb) represents a new class of HBOC with promising results. We evaluated the safety profile of PolybHb after an exchange transfusion (ET) in guinea pigs (GPs). This study compares changes in indices of cardiac, inflammatory, and organ function after ET with high (R-state) and low (T-state) O 2 affinity PolybHb with high MW., Study Design and Methods: Guinea pigs underwent a 20% ET with PolybHb. To assess the implication of PolybHb ET on the microcirculation, hamsters instrumented with a dorsal window chamber were subjected to a similar volume ET., Results: T and R-state PolybHb did not induce significant alterations in cardiac function. T-state PolybHb induced mild vasoconstriction shortly after transfusion, while R-state did not have acute effects on microvascular tone., Conclusion: Large MW PolybHbs were found to be safe and efficacious in increasing O 2 carrying capacity and the O 2 affinity of the PolybHb did not affect O 2 delivery or extraction by tissues in relevant preclinical models. In conclusion, these results suggest that both T-state and R-state PolybHb are safe and do not impair O 2 delivery. The results are encouraging and support further evaluation of high MW PolybHbs and their future feasibility compared to allogenic blood in a trauma model., (© 2020 AABB.)

Background: Hemoglobin-Based Oxygen Carriers (HBOCs) can act as an "oxygen bridge" in acute severe anemia when transfusion is indicated, but not possible. We present data on 10 Expanded Access (EA) patients treated with high cumulative doses of Hemopure (HBOC-201), to assess the ability of HBOC-201 to safely treat life threatening anemia in situations where high volumes of product were administered over an extended period of time., Study Design and Methods: Inclusion in this study required that the patient receive at least 10 units of HBOC-201 between 2014 and 2017 under the FDA-sanctioned EA program. Depending on a patient's geographical location, treatment with HBOC-201 was obtained through either a single patient emergency Investigational New Drug (IND) application, or an intermediate size population IND. Of the 41 patients who were treated during this period, 10 patients received 10 or more units of the product. Data were obtained from medical records., Results: Treatments with HBOC-201 started within 24 hours of signing consent and were administered at an average rate of 1.99 (SD 0.17) units per day over a mean of 8.2 days (SD 2.9), during which patients received on average 16.2 units (SD 5.7 units) of HBOC-201. The median pre-treatment nadir corpuscular hemoglobin (Hb) concentration was 3.3 (SD 0.9) g/dL and post-treatment Hemoglobin was 7.3 (SD 1.7) g/dL. Common side effects included methemoglobinemia, gastrointestinal symptoms, and hypertension. However, no product-related serious adverse events (SAEs) were noted. All patients survived., Conclusions: Administration of HBOC-201 over an extended period is a feasible and safe oxygen bridge for severely anemic patients who cannot be transfused with RBC., (© 2020 AABB.)

The incidence of investigator diagnosed myocardial infarction (MI) is greater in patients treated with haemoglobin-based oxygen carriers (HBOCs) than controls. Clinical trials and literature pertaining to possible HBOC toxicity mechanisms have been analyzed in order to identify possible reasons for this imbalance. MI diagnosis is hampered by potential interference of troponin assays by haemoglobin, haemolysis and bilirubin. Nevertheless, insofar as the reported incidence correlates with actual occurrence, there is a positive relationship between MI and HBOC dose and size. Preclinical and clinical data suggest that direct cardiac toxicity and coronary vasoconstriction are unlikely. More probable are detrimental intravascular interactions between HBOCs and components of the coagulation cascade, particularly dysfunctional endothelium. Elucidation of mechanisms is impeded by a lack of clinical data. Measurement of relevant biomarkers would be extremely useful in this regard and in improving patient selection criteria. Conduct of clinical trials in carefully selected patient populations after the development of improved protocols for MI diagnosis, along with concomitant biomarker data collection, is recommended.

Background: Delayed hemolytic transfusion reaction (DHTR) with hyperhemolysis is a potentially fatal complication resulting from alloimmunization that can cause severe hemolysis of both transfused and intrinsic red blood cells (RBCs). Patients with sickle cell disease often receive multiple RBC units during their lifetime and thus are likely to develop alloantibodies that increase the risk for DHTR. Treatment to decrease hemolysis includes intravenous immunoglobulin (IVIG), steroids, eculizumab, rituximab, and plasmapheresis in addition to erythropoietin (EPO), intravenous (IV) iron, vitamin B12, and folate to support erythropoiesis. RBC transfusion is preferably avoided in DHTR due to an increased risk of exacerbating the hemolysis., Case Report: We report a rare case of anti-N and anti-Do a immunoglobulin (Ig)G alloantibody-mediated life-threatening DHTR with hyperhemolysis in a patient with hemoglobin SS after RBC transfusion for acute chest syndrome who was successfully treated with eculizumab and HBOC-201 (Hemopure) in addition to steroids, IVIG, EPO, IV iron, and vitamin B12. HBOC-201 (Hemopure) was successfully used as a RBC alternative in this patient., Conclusion: Anti-N and anti-Do a IgG alloantibodies can rarely cause severe life-threatening DHTR with hyperhemolysis. HBOC-201 (Hemopure) can be a lifesaving alternative in this scenario. Our report also supports the use of eculizumab in DHTR; however, prospective studies are needed to determine the appropriate dose and sequence of eculizumab administration., (© 2019 AABB.)

Objective: Ischaemia is one of the biggest problems in wound healing. It causes chronic wounds and also prevents normal wound healing because the tissue is oxygen deprived. Most oxygen-supplying therapies are only feasible in a clinical setting, but topical haemoglobin applications, such as Granulox, can be used in a non-clinical setting. For home application, the haemoglobin solution is sprayed topically onto the wound using a pressurised ready-to-use device with a bag-on-valve system. Although this system does not mix product and propellant, the risk of product inhalation by the patient, user or bystanders has to be minimised. This safety study aimed to determine particle size and product concentration in the surroundings after application to determine if there is a risk that product particles enter the respiratory tract., Methods: Measurements were performed using a laser scattered light photometer and a Scanning Mobility Particle Sizer (SMPS)-Spectrometer at different distances from the measuring devices to determine the inhalation risk for a possible user, patient and bystander. At all measuring points the amount of particles, their size and the formation of dust were measured., Results: No nanoparticles or dust were created during the application of the haemoglobin spray. The concentrations of the measured particles are below the allowed limits defined by Austrian law., Conclusion: There is no risk of inhaling nanoparticles or being exposed to harmful concentrations of larger particles of the tested product. All the product's ingredients can be degraded and excreted by the human body through natural pathways.

The development of hemoglobin (Hb)-based oxygen carriers (HBOCs) has been hampered because of safety concerns in humans. Chemical and/or genetic modifications of the Hb introduce varied structural and conformational constraint on the molecule that resulted in proteins with diverse allosteric responses, nitrosative and oxidative side reactions. Here, we present for the first time a comprehensive biochemical and biophysical comparison of human, bovine, and genetically engineered HBOCs that have been tested in humans. We evaluate oxygen equilibrium and ligand binding kinetics under different experimental conditions as well as their autoxidation kinetics, redox reactions, and heme release. We determined the effects of HBOCs on cellular redox states and mitochondrial respiration. Taken together, these experiments provide a better understanding of the relationship between the structure-function and oxidative reactivity of these proteins. One can therefore select independently among these diverse properties to engineer a safe and effective HBOC with improved biochemical/biophysical characteristics.

Hemoglobin-based oxygen carriers (HBOCs) are being developed as oxygen and plasma volume-expanding therapeutics though their potential to promote oxidative tissue injury and nitric oxide (NO) scavenging combined with vasoconstriction has raised safety concerns. Therefore, we focused on these aspects during preclinical studies performed with the recently introduced hemoglobin microparticles (HbMP-700). Besides oxidative stress, we investigated possible vasoconstrictory influence of HBOCs as well as genetic toxicity. The novel developed HbMP-700 presented here provides a high oxygen affinity which prevents premature oxygen oversupply and avoids vasoconstriction of small blood vessels in vitro. The size of these particles is 700 nm (larger than 100 nm and smaller than 1000 nm) in order to prevent penetration through the blood vessel's endothelial gaps, NO-scavenging, and to avoid phagocytosis of large particles. We expect that the HbMP-700 meets the sophisticated requirements as a universal blood substitute., (© 2018 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Objective: To assess the safety of a restrictive threshold for the transfusion of red blood cells (RBCs) compared to a liberal threshold in high-risk patients undergoing brain tumor surgery., Patients and Methods: We reviewed patients who were 50 years of age or older with a preoperative American Society of Anesthesiologists physical status class II to V who underwent open craniotomy for tumor resection and were transfused packed RBCs during or after surgery. We retrospectively assigned patients to a restrictive-threshold (a pretransfusion hemoglobin level <8g/dL) or a liberal-threshold group (a pretransfusion hemoglobin level of 8-10/dL). The primary outcome was in-hospital mortality rate. Secondary outcomes were in-hospital complication rates, length of stay, and discharge disposition., Results: Twenty-five patients were included in the study, of which 17 were assigned to a restrictive-threshold group and 8 patients to a liberal-threshold group. The in-hospital mortality rates were 12% for the restrictive-threshold group (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.07-12.11) and 13% for the liberal-threshold group. The in-hospital complication rates were 52.9% for the restrictive-threshold group (OR 1.13, 95% CI 0.21-6.05) and 50% for the liberal-threshold group. The average number of days in the intensive care unit and hospital were 8.6 and 22.4 days in the restrictive-threshold group and 6 and 15 days in the liberal-threshold group, respectively (P=0.69 and P=0.20). The rates of non-routine discharge were 71% in the restrictive-threshold group (OR 2.40, 95% CI 0.42-13.60) and 50% in the liberal-threshold group., Conclusions: A restrictive transfusion threshold did not significantly influence in-hospital mortality or complication rates, length of stay, or discharge disposition in patients at high operative risk., (Copyright © 2017. Published by Elsevier B.V.)

Background: Hyperfibrinolysis plays an integral role in the genesis of trauma-induced coagulopathy. Recent data demonstrate that red blood cell lysis promotes fibrinolysis; however, the mechanism is unclear. Hemoglobin-based oxygen carriers (HBOCs) have been developed for resuscitation and have been associated with coagulopathy. We hypothesize that replacement of whole blood (WB) using an HBOC results in a coagulopathy because of the presence of free hemoglobin., Materials and Methods: WB was sampled from healthy donors (n = 6). The clotting profile of each citrated sample was evaluated using native thromboelastography. Serial titrations were performed using both HBOC (PolyHeme) and normal saline (NS; 5%, 25%, and 50%) and evaluated both with and without a 75-ng/mL tissue plasminogen activator (tPA) challenge. Tranexamic acid (TXA) was added to inhibit plasmin-dependent fibrinolysis. Fibrinolysis was measured and recorded as lysis at 30 min (LY30), the percentage of clot LY30 after maximal clot strength. Dilution of WB with NS or HBOC was correlated using LY30 via Spearman rho coefficients. Groups were also compared using a Friedman test and post hoc analysis with a Bonferroni adjustment., Results: tPA-provoked fibrinolysis was enhanced by both HBOC (median LY30 at 5%, 25%, and 50% titrations: 11%, 21%, and 44%, respectively; Spearman = 0.94; P < 0.001) and NS (11%, 28%, and 58%, respectively; Spearman = 0.790; P < 0.001). However, HBOC also enhanced fibrinolysis without the addition of tPA (1%, 4%, 5%; Spearman = 0.735; P = 0.001) and NS did not (1%, 2%, 1%; r = 0.300; P = 0.186. Moreover, addition of TXA did not alter or inhibit this fibrinolysis (WB versus 50% HBOC: 1.8% versus 5.7%, P = 0.04). There was no significant difference in fibrinolysis of HBOC with or without TXA (50% HBOC versus 50% HBOC + TXA: 5.6% versus 5.7%, P = 0.92). In addition, the increased fibrinolysis seen with NS was reversed when TXA was present (WB versus 50% NS: 1.8% versus 1.7%, P = 1.0)., Conclusions: HBOCs enhance fibrinolysis both with and without addition of tPA; moreover, this mechanism is independent of plasmin as the phenomenon persists in the presence of TXA. Our findings indicate the hemoglobin molecule or its components stimulate fibrinolysis by both tPA-dependent and innate mechanisms., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Significance: Worldwide demand has driven the development of hemoglobin (Hb)-based oxygen carriers (HBOCs) as potential acellular oxygen therapeutics. HBOCs have the potential to provide an oxygen bridge to patients and minimize current problems associated with supply and storage of donated blood. However, to date, safety and efficacy issues have hampered the approval of viable HBOCs in the United States. These previous efforts have underscored the need for a better molecular understanding of toxicity to design safe and oxidatively stable HBOCs. Recent Advances: High-resolution accurate mass (HRAM) mass spectrometry (MS) has recently become a versatile tool in characterizing oxidative post-translational modifications that occur in Hb. When integrated with other analytical techniques, HRAM data have been invaluable in providing mechanistic insight into the extent of oxidative modification by quantifying oxidation in amino acids near the reactive heme or at specific "oxidative hotspots.", Critical Issues: In addition to providing a deeper understanding of Hb oxidative toxicity, HRAM MS studies are currently being used toward developing suitable HBOCs using a "two-prong" strategy that involves (i) understanding the mechanism of Hb toxicity by evaluating mutant Hbs identified in patients with hemoglobinopathies and (ii) utilizing this information toward designing against (or for) these reactions in acellular oxygen therapeutics that will result in oxidatively stable protein., Future Directions: Future HRAM studies are aimed at fully characterizing engineered candidate HBOCs to determine the most oxidatively stable protein while retaining oxygen carrying function in vivo. Antioxid. Redox Signal. 26, 777-793.

Oxidative side reaction is one of the major factors hindering the development of hemoglobin-based oxygen carriers (HBOCs). To avoid the oxidative toxicity, we designed and synthesized polydopamine-coated hemoglobin (Hb-PDA) nanoparticles via simple one-step assemblage without any toxic reagent. Hb-PDA nanoparticles showed oxidative protection of Hb by inhibiting the generation of methemoglobin (MetHb) and ferryl (Fe IV) Hb, as well as excellent antioxidant properties by scavenging free radicals and reactive oxygen species (ROS). Interestingly, the scavenging rate of Hb-PDA nanoparticles for ABTS + radical is at most 89%, while for DPPH radical it reaches 49%. In addition, Hb-PDA efficiently reduced the intracellular H 2 O 2 -induced ROS generation. Moreover, Hb-PDA nanoparticles exhibited high oxygen affinity, low effect on blood constituents, and low cytotoxicity. The results indicate that polydopamine-coated hemoglobin might be a promising approach for constructing novel oxygen carriers with the capacity to reduce oxidative side reaction.

There is a 0.138% incidence of adverse reactions related to blood transfusion. Transfusion-related acute lung injury, immunosuppression, fever, pathogen transmission, and hemolytic transfusion reactions are the most common ones. Synthetic oxygen carriers have been developed to deal with blood shortages and for use in the field where stored blood was not available. They were also designed to be pathogen free, including unknown viruses. In this study, we used Male Golden Syrian Hamsters implemented with a dorsal window chamber to determine how infusion of three different, genetically crosslinked recombinant acellular hemoglobin (rHb) solutions with different oxygen affinities and nitric oxide kinetics affect mean arterial pressure (MAP), heart rate (HR), kidney function, and kidney structure. We found that the administration of all three rHb solutions caused mild hypertension and bradycardia 30 minutes after infusion. However, acute changes in glomerular filtration rate (GFR) were not detected, even though histological analysis was performed 72 hours after treatment revealed some structural changes. All the rHb solutions resulted in hypertension 30 minutes after a 10% topload administration. Regardless of their properties, the presence of acellular Hb causes significant alterations to kidney tissue.

Previous studies have shown that intraparenchymal transplantation of neural stem cells ameliorates neurological deficits in animals with intracerebral hemorrhage. However, hemoglobin in the host brain environment causes massive grafted cell death and reduces the effectiveness of this approach. Several studies have shown that preconditioning induced by sublethal hypoxia can markedly improve the tolerance of treated subjects to more severe insults. Therefore, we investigated whether hypoxic preconditioning enhances neural stem cell resilience to the hemorrhagic stroke environment and improves therapeutic effects in mice. To assess whether hypoxic preconditioning enhances neural stem cell survival when exposed to hemoglobin, neural stem cells were exposed to 5% hypoxia for 24 hours before exposure to hemoglobin. To study the effectiveness of hypoxic preconditioning on grafted-neural stem cell recovery, neural stem cells subjected to hypoxic preconditioning were grafted into the parenchyma 3 days after intracerebral hemorrhage. Hypoxic preconditioning significantly enhanced viability of the neural stem cells exposed to hemoglobin and increased grafted-cell survival in the intracerebral hemorrhage brain. Hypoxic preconditioning also increased neural stem cell secretion of vascular endothelial growth factor. Finally, transplanted neural stem cells with hypoxic preconditioning exhibited enhanced tissue-protective capability that accelerated behavioral recovery. Our results suggest that hypoxic preconditioning in neural stem cells improves efficacy of stem cell therapy for intracerebral hemorrhage., (© The Author(s) 2015.)

A series of hemoglobin-based oxygen carrier candidates (HBOC), previously noted for their differences in prooxidative and physiological reactivity, were compared in terms of the negative effects displayed upon injection in Wistar rats. At the concentrations tested, antioxidant strategies based on albumin as well as based on rubrerythrin appear to offer observable physiological advantages.

MP4CO, developed by Sangart Inc. (San Diego, CA), is a pegylated human hemoglobin-based carbon monoxide (CO) delivery agent and oxygen therapeutic that has shown potential to prevent and reverse red cell sickling. A double blind, comparator controlled, dose-escalation, Phase 1b study was conducted to assess the safety of MP4CO. Adult sickle cell patients with HbSS or S/β(0) Thal genotype who were not experiencing a painful crisis were randomized to receive either MP4CO or normal saline (NS) in a sequential series of six escalating dose cohorts (A-F). In each cohort, three patients received MP4CO (Treatment group) and one patient received NS (Controls). Single IV doses ranged from 15 mg/kg/dose (0.35 mL/kg infusion) to 172 mg/kg/dose (4 mL/kg infusion). Two cohorts received fractionated doses of 172 or 344 mg/kg (4-8 mL/kg, given as two IV infusions, 24 h apart). Overall, 16/24 patients (66.7 %) reported mild to moderate adverse events (AEs); with 13/18 (72 %) in MP4CO group vs. 3/6 (50 %) in NS Controls. No serious adverse events (SAEs) were experienced and no deaths occurred. Most common AEs (reported by >2 patients) included headaches (mild and transient), fatigue and rash at the application site of the Holter electrodes. No treatment-emergent abnormalities in clinical lab values were noted. Vital signs, ECG readings, and pulmonary pressures remained within normal limits. The maximum increase in blood CO-Hb level was ~2 %, which returned to pre-dosing levels within 8 h after dosing. The mean increase in free plasma Hb (an index of MP4CO dose) ranged from 0.20 to 0.35 g/dL in the two highest dose cohorts, with no significant change in total whole blood hemoglobin level. There was no symptomatic or clinical evidence of renal dysfunction in either group based on serum creatinine and urinary albumin results. Two patients had elevated renal biomarkers (β2M and NAG) at Hour 72, which normalized at follow-up visits. Both patients had documented intercurrent illnesses during the study. Further testing of stored urine samples were within normal limits, which suggested the changes were reflective of a generalized inflammatory state rather than direct tubular injury.

Polymerized porcine hemoglobin (pPolyHb), which was synthesized from chemically modified porcine hemoglobin, can carry and deliver oxygen to tissues in addition to restoring intravascular volume. Assessment of the inflammatory response generated in the host is a part of the overall safety evaluation of pPolyHb. In this study, we measured the levels of IL-1β, IL-10, and CD11b/CD18 in response to pPolyHb stimulation, both in vivo (in rats) and in vitro. Our results suggest that the levels of these indicators are not statistically changed by pPolyHb, indicating that pPolyHb is not immunotoxic to cells and animals in this respect.

Background: We present the results of a previously unpublished hemoglobin-based oxygen carrier (HBOC) study conducted in 1998-1999., Methods: In a multicenter, randomized, single-blind, comparative study of HBOC-201 versus allogeneic red blood cell (RBC) transfusions, no-cardiac surgery patients received HBOC-201 to a maximum of 7 units (n = 83) or RBCs (n = 77). Patients could be switched to RBCs for safety or any other reason. The efficacy end points were elimination and/or reduction of allogeneic RBC transfusions for 28 days., Results: The proportion of patients in the HBOC-201 group that avoided RBC transfusion was 0.427 (95% confidence interval, 0.321-0.533). Subjects in the HBOC-201 group received on average 3.2 units of RBCs versus 4.4 units in the control arm (P = 0.004). Seventy-nine (95.2%) subjects in the HBOC-201 group and 72 (93.5%) in the RBC group experienced adverse events (AEs), judged to be associated with study treatment in 59 (71.1%) and 18 (23.4%) subjects, respectively. Thirty-day mortality, 5 (6.0%) vs 4 (5.2%) patients (P = 1.00), incidence of serious AEs, 24 (28.9%) vs 20 (26.0%) (P = 0.73), or time to intensive care unit (log-rank P = 0.15) or hospital discharge (log-rank P = 0.53) were similar for the HBOC-201 and RBC groups, respectively., Conclusions: Up to 7 units of HBOC-201 infused over the course of 6 days resulted in RBC transfusion avoidance in 43% of patients. There were no notable differences in mortality and serious AEs incidence. The use of HBOC-201 was associated with a notable excess of nonserious AEs.

The cannabinoid system has been demonstrated to modulate the acute and chronic pain of multiple origins. Mouse VD-hemopressin(α) [(m)VD-Hpα], an 11-residue α-hemoglobin-derived peptide, was recently reported to function as a selective agonist of the cannabinoid receptor type 1 (CB₁) in vitro. To characterize its behavioral and physiological properties, we investigated the in vivo effects of (m)VD-Hpα in mice. In the mouse tail-flick test, (m)VD-Hpα dose-dependently induced antinociception after supraspinal (EC₅₀ = 6.69 nmol) and spinal (EC₅₀ = 2.88 nmol) administration. The antinociceptive effects of (m)VD-Hpα (intracerebroventricularly and intrathecally) were completely blocked by N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3- carboxamide (AM251; CB₁ antagonist), but not by 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl(4-methoxyphenyl)-methanone (AM630; CB₂ antagonist) or naloxone (opioid antagonist), showing its selectivity to the CB₁ receptor. Furthermore, the central nervous system (CNS) effects of (m)VD-Hpα were evaluated in body temperature, locomotor activity, tolerance development, reward, and food intake assays. At the highly antinociceptive dose (3 × EC₅₀), (m)VD-Hpα markedly exerted hypothermia and hypoactivity after supraspinal administration. Repeated intracerebroventricular injection of (m)VD-Hpα resulted in both development of tolerance to antinociception and conditioned place aversion. In addition, central injection of (m)VD-Hpα dose-dependently stimulated food consumption. These findings demonstrate that this novel cannabinoid peptide agonist induces CB₁-mediated central antinociception with some CNS effects, which further supports a CB₁ agonist character of (m)VD-Hpα. Moreover, the current study will be helpful to understand the in vivo properties of the endogenous peptide agonist of the cannabinoid CB₁ receptor.

Hemopressin is the first peptide ligand to be described for the CB₁ cannabinoid receptor. Hemopressin acts as an inverse agonist in vivo and can cross the blood-brain barrier to both inhibit appetite and induce antinociception. Despite being highly effective, synthetic CB₁ inverse agonists are limited therapeutically due to unwanted, over dampening of central reward pathways. However, hemopressin appears to have its effect on appetite by affecting satiety rather than reward, suggesting an alternative mode of action which might avoid adverse side effects. Here, to resolve the neuronal circuitry mediating hemopressin's actions, we have combined blood-oxygen-level-dependent, pharmacological-challenge magnetic resonance imaging with c-Fos functional activity mapping to compare brain regions responsive to systemic administration of hemopressin and the synthetic CB₁ inverse agonist, AM251. Using these complementary methods, we demonstrate that hemopressin activates distinct neuronal substrates within the brain, focused mainly on the feeding-related circuits of the mediobasal hypothalamus and in nociceptive regions of the periaqueductal grey (PAG) and dorsal raphe (DR). In contrast to AM251, there is a distinct lack of activation of the brain reward centres, such as the ventral tegmental area, nucleus accumbens and orbitofrontal cortex, which normally form a functional activity signature for the central action of synthetic CB₁ receptor inverse agonists. Thus, hemopressin modulates the function of key feeding-related brain nuclei of the mediobasal hypothalamus, and descending pain pathways of the PAG and DR, and not higher limbic structures. Thus, hemopressin may offer behaviourally selective effects on nociception and appetite, without engaging reward pathways., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Hemoglobin-based oxygen carriers (HBOC) and hypertonic saline solutions (HSS) are used for resuscitation of trauma patients with hemorrhagic shock. In this review, the clinical application, dosing, administration, and side effects of these solutions are discussed. Although HBOC and HSS are not ideal resuscitation fluids, until rapidly thawed universal donor frozen blood and blood component therapy becomes widely available in North America, these fluids should to be considered immediately after injury and throughout the spectrum of care for patients with hemorrhagic shock, until blood and blood components become available., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Cell-free hemoglobin (Hb) has been blamed for a spectrum of problems, including vasoconstriction pancreatitis, myocardial infarction, and pulmonary hypertension in hemolytic anemia, malaria, and sickle cell anemia, and from Hb-based oxygen carriers (HBOCs). Toxicities have been attributed to scavenging of nitric oxide (NO). However, while NO scavenging may explain many in vitro effects, and some effects in animal models and clinical trials with HBOCs, key inconsistencies in the theory require alternative explanations. This review considers the hypothesis that cell-free Hb oversupplies oxygen to tissues, leading to oxygen-related toxicity, possibly through formation of reactive oxygen species and local destruction of NO. Evidence for this hypothesis comes from various sources, establishing that tissue oxygen levels are maintained over very narrow (and low) levels, even at high oxygen consumption. Tissue is normally protected from excessive oxygen by its extremely low solubility in plasma, but introduction of cell-free Hb, even at low concentration, greatly augments oxygen supply, engaging protective mechanisms that include vasoconstriction and ischemia. The requirement to limit oxygen supply by cell-free Hb suggests novel ways to modify it to overcome vasoconstriction, independent of the intrinsic reaction of Hb with NO. This control is essential to the design of a safe and effective cell-free HBOC., (© 2012 American Association of Blood Banks.)

Age increases the risk for ischemic acute kidney injury (AKI). We questioned whether a similar age-dependent injury occurs following exposure to hemoglobin, a known nephrotoxin. Old mice (~16 mo old), but not young mice (~6 mo old), when administered hemoglobin, exhibited marked elevation in blood urea nitrogen (BUN) and serum creatinine, and acute tubular necrosis with prominent tubular cast formation. The aged kidney exhibited induction of heme oxygenase-1 (HO-1) and other genes/proteins that may protect against heme-mediated renal injury, including ferritin, ferroportin, haptoglobin, and hemopexin. Old mice did not evince induction of HO-2 mRNA by hemoglobin, whereas a modest induction of HO-2 mRNA was observed in young mice. To determine the functional significance of HO-2 in heme protein-induced AKI, we administered hemoglobin to relatively young HO-2(+/+) and HO-2(-/-) mice: HO-2(-/-) mice, compared with HO-2(+/+) mice, exhibited greater renal dysfunction and histologic injury when administered hemoglobin. In addition to failing to elicit a protective system such as HO-2 in response to hemoglobin, old mice exhibited an exaggerated maladaptive response typified by markedly greater induction of the nephrotoxic cytokine IL-6 (130-fold increase vs. 10-fold increase in mRNA in young mice). We conclude that aged mice, unlike relatively younger mice, are exquisitely sensitive to the nephrotoxicity of hemoglobin, an effect attended by a failure to induce HO-2 mRNA and a fulminant upregulation of IL-6. Age thus markedly augments the sensitivity of the kidney to heme proteins, and HO-2 confers resistance to such insults.

Cell-free hemoglobin (Hb) exposure may be a pathogenic mediator in the development of pulmonary arterial hypertension (PAH), and when combined with chronic hypoxia the potential for exacerbation of PAH and vascular remodeling is likely more pronounced. We hypothesized that Hb may contribute to hypoxia-driven PAH collectively as a prooxidant, inflammatory, and nitric oxide (NO) scavenger. Using programmable micropump technology, we exposed male Sprague-Dawley rats housed under room air or hypoxia to 12 or 30 mg per day Hb for 3, 5, and 7 wk. Blood pressure, cardiac output, right ventricular hypertrophy, and indexes of pulmonary vascular remodeling were evaluated. Additionally, markers of oxidative stress, NO bioavailability and inflammation were determined. Hb increased pulmonary arterial (PA) pressure, pulmonary vessel wall stiffening, and right heart hypertrophy with temporal and dose dependence in both room air and hypoxic cohorts. Hb induced a modest increase in plasma oxidative stress markers (malondialdehyde and 4-hydroxynonenal), no change in NO bioavailability, and increased lung ICAM protein expression. Treatment with the antioxidant Tempol attenuated Hb-induced pulmonary arterial wall thickening, but not PA pressures or ICAM expression. Chronic exposure to low plasma Hb concentrations (range = 3-10 μM) lasting up to 7 wk in rodents induces pulmonary vascular disease via inflammation and to a lesser extent by Hb-mediated oxidation. Tempol demonstrated a modest effect on the attenuation of Hb-induced pulmonary vascular disease. NO bioavailability was found to be of minimal importance in this model.

Background: Development of Haemoglobin-based oxygen carriers (HBOCs) as blood substitutes has reached an impasse due to clinically adverse outcomes attributed to vasoconstriction secondary to nitric oxide (NO) scavenging. Studies suggest haemoglobin exhibits nitrite reductase activity that generates NO and N(2)O(3); harnessing this property may offset NO scavenging. Therefore, the effects of concomitantly infusing sodium nitrite (NaNO(2)) with HBOC-201 were investigated., Methods: Swine underwent uncontrolled liver haemorrhage before receiving up to three 10min 10ml/kg infusions of HBOC-201 (HBOC) with or without concurrent NaNO(2) (5.4μmol/kg [LD NaNO(2)] or 10.8μmol/kg [HD NaNO(2)]) or 6% Hetastarch (HEX) with or without HD NaNO(2) during "prehospital" resuscitation (15, 30 and 45min after injury). Definitive surgical care occurred at 75min; anaesthetic recovery at 120min. Animals were euthanised at 72h., Results: NaNO(2) temporarily reduced systemic and pulmonary blood pressure increases from HBOC in a dose-dependent fashion. There was no significant effect between groups in indices of tissue oxygenation or survival. Adverse clinical signs requiring humane euthanasia occurred with highest frequency after HBOC+HD NaNO(2) (3 of 4 pigs) and HBOC+LD NaNO(2) (2 of 4 pigs). Gross evidence of pulmonary congestion was observed in 5 of 8 swine receiving a HBOC and NaNO(2) combination compared to 1 of 16 swine receiving HBOC alone, HEX alone, or HEX+NaNO(2). Gross lesions correlated with histological evidence of pulmonary oedema and congestion, and in 2 of 4 HBOC+HD NaNO(2) pigs, pulmonary fibrin thrombi also were found. No other pig had similar evidence of thrombi. Asymmetric pre-resuscitation cardiac index was a potential confounder., Conclusions: A significant interaction between NaNO(2) and HBOC-201 ameliorated HBOC-201 vasoconstrictive effects, consistent with HBOC possessing a nitrite reductase activity that generates vasodilator NO equivalents. Results were relatively equivalent in survival and markers of tissue oxygenation. The highest dose of NaNO(2) was the most effective in reducing HBOC-associated pulmonary and systemic vasoactivity but also with the highest incidence of adverse events. In this model, the transient nature of NaNO(2) in off-setting HBOC-201 vasoconstriction makes it less clinically promising than anticipated and the combination of NaNO(2) and HBOC appear to increase the risk of pulmonary complications in a dose-dependent fashion independently of haemodilutional effects on haemostatic components., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Introduction: Patients presenting with peritonitis require rapid treatment initiation including laparotomy. In the older population, this often leads to Hartmann's procedure being performed. The decision to perform surgery may be a difficult, multidisciplinary decision balancing premorbid comorbidity and quality of life with knowledge of the postoperative outcome. However, the evidence for survival outcome of emergency surgery based on age is lacking. The aim of this study was therefore to assess the survival implication of age and other prognostic factors on the outcome after Hartmann's procedure., Methods: A retrospective review of prospectively collected data of all patients undergoing emergency (National Confidential Enquiry into Patient Outcome and Death category 1-3) Hartmann's procedure in one NHS Health Board over a 5-year period., Results: 129 patients underwent Hartmann's procedure between November 2004 and November 2009. The largest group, 61 patients (47.3%) had the procedure performed for perforated sigmoid diverticular disease. When examined at 5-year stratifications around the median, the most significant survival difference was seen at the age of 75 years (log rank χ(2) 11.246, p=0.001). Patients over 75 years had median survival significantly lower than those aged <75 years (p<0.001). However, Cox regression analysis showed that preoperative American Society of Anesthesiologists (ASA) status and haemoglobin were more significant independent predictors of mortality than this age strata (p=0.001 and 0.045 vs 0.660, respectively), adjusting for diagnosis., Discussion: ASA grade and common blood abnormalities were more predictive of mortality after Hartmann's procedure than the most significant age stratification. Furthermore, age was not independently associated with survival. It would therefore be unreasonable to refuse Hartmann's procedure based on an age alone.

Blood transfusion represents the first and most prescribed cell-based therapy; however, clinical safety and efficacy trials are lacking. Clinical cohort studies have suggested that massive transfusion and/or transfusion of aged stored blood may contribute to multiorgan dysfunction in susceptible patients. In this issue of the JCI, Baek and colleagues report that aged stored blood hemolyzes after massive transfusion in a guinea pig model. Hemolysis led to vascular and kidney injury that was mediated by cell-free plasma hemoglobin and prevented by coinfusion of the specific hemoglobin scavenger protein, haptoglobin. These studies support an expanding body of research indicating that intravascular hemolysis is a pathological mechanism in several human diseases, including multiorgan dysfunction after either massive red blood cell transfusion or hemoglobin-based blood substitute therapy, the hemoglobinopathies, malaria, and other acquired and genetic hemolytic conditions.

Massive transfusion of blood can lead to clinical complications, including multiorgan dysfunction and even death. Such severe clinical outcomes have been associated with longer red blood cell (rbc) storage times. Collectively referred to as the rbc storage lesion, rbc storage results in multiple biochemical changes that impact intracellular processes as well as membrane and cytoskeletal properties, resulting in cellular injury in vitro. However, how the rbc storage lesion triggers pathophysiology in vivo remains poorly defined. In this study, we developed a guinea pig transfusion model with blood stored under standard blood banking conditions for 2 (new), 21 (intermediate), or 28 days (old blood). Transfusion with old but not new blood led to intravascular hemolysis, acute hypertension, vascular injury, and kidney dysfunction associated with pathophysiology driven by hemoglobin (Hb). These adverse effects were dramatically attenuated when the high-affinity Hb scavenger haptoglobin (Hp) was administered at the time of transfusion with old blood. Pathologies observed after transfusion with old blood, together with the favorable response to Hp supplementation, allowed us to define the in vivo consequences of the rbc storage lesion as storage-related posttransfusion hemolysis producing Hb-driven pathophysiology. Hb sequestration by Hp might therefore be a therapeutic modality for enhancing transfusion safety in severely ill or massively transfused patients.

Polymerized Porcine Hemoglobin (pPolyHb), a hemoglobin-based oxygen carrier (HBOC), was developed as a potential red blood substitute for clinical applications. Assessment of its effects on the immune system is an important component of the overall safety evaluation of HBOC. For this purpose, we assessed three inflammation indicators, including complement C3a, IL-6, and TNF-? in cultured cells and in a rat model when pPolyHb was incubated or administrated with the cells/animals. Our results suggested that the levels of these three indicators were not statistically changed upon pPolyHb stimulation, indicating that pPolyHb is not immunotoxic to cells and animals in this aspect.

Background: MP4OX (oxygenated polyethylene glycol-modified hemoglobin) is an oxygen therapeutic agent with potential applications in clinical settings where targeted delivery of oxygen to ischemic tissues is required. The primary goal of this study was to investigate MP4OX for preventing hypotensive episodes. An additional goal was to establish the safety profile of MP4OX in a large surgical population., Methods: Patients (n = 367) from 18 active study sites in six countries, undergoing elective primary hip arthroplasty with spinal anesthesia, were randomized to receive MP4OX or hydroxyethyl starch 130/0.4. Patients received a 250-ml dose at induction of spinal anesthesia and a second 250-ml dose if the protocol-specified trigger (predefined decrease in systolic blood pressure) was reached. The primary end point was the proportion of patients who developed one or more hypotensive episodes., Results: The proportion of patients with one or more hypotensive episodes was significantly lower (P < 0.0001) in the MP4OX group (66.1%) versus controls receiving hydroxyethyl starch 130/0.4 (90.2%). More MP4OX-treated patients experienced adverse events compared with controls (72.7% vs. 61.4%; P = 0.026). Transient elevations in laboratory values (e.g., alanine aminotransferase, aspartate aminotransferase, lipase, and troponin concentrations) occurred more frequently in the MP4OX group. There were no significant differences in the incidence of serious adverse events or in the composite morbidity and ischemia outcome end points, but nausea and hypertension were reported more often in MP4OX-treated patients., Conclusion: MP4OX significantly reduced the incidence of hypotensive episodes in patients undergoing hip arthroplasty, but the adverse event profile does not support use in routine low-risk surgical patients for the indication evaluated in this study.

Objective: To determine effects of bovine hemoglobin glutamer-200 (Hb-200) solution on systolic arterial blood pressure (SAP) in hypotensive cats and describe potential adverse effects associated with this treatment., Design: Retrospective case series., Animals: 44 cats., Procedures: Medical records of hypotensive (Doppler SAP ≤ 80 mm Hg) cats that received Hb-200 treatment were reviewed. Volume and rate of Hb-200 administration, treatments for hypotension given prior to Hb-200 administration, changes in SAP, potential adverse effects, and short-term outcome were evaluated., Results: 44 cats were included in the study. Mean ± SD SAP prior to Hb-200 administration was 52 ± 11 mm Hg, despite other treatments. Forty-three cats received Hb-200 via IV bolus administration (mean ± SD volume, 3.1 ± 2.2 mL/kg [1.41 ± 1.0 mL/lb] over 25.17 ± 17.51 minutes); 1 cat received a continuous rate infusion (CRI) only. The SAP increased to > 80 mm Hg in 33 of 44 (75%) cats. The SAP increased > 20 mm Hg above baseline value in 29 of these 33 cats and in 4 cats in which SAP did not exceed 80 mm Hg. A CRI (mean ± SD rate, 0.8 ± 0.5 mL/kg/h [0.36 ± 0.23 mL/lb/h]) of Hb-200 was administered to 37 cats (after bolus infusion in 36). Mean SAP during the CRI was 92 ± 18 mm Hg. Adverse effects included respiratory changes (n = 8 cats), vomiting (2), and pigmented serum (30). Seventeen (39%) cats survived to discharge from the hospital, 6 died, and 21 were euthanized., Conclusions and Clinical Relevance: Hb-200 effectively increased SAP in hypotensive cats with few adverse effects.

History and Admission Findings: A 50-year-old patient with alcoholic liver cirrhosis was admitted due to hematemesis and melaena., Diagnosis: Endoscopy showed esophageal variceal hemorrhage. A dose of erythromycin was administered before endoscopy for optimal endoscopic view., Treatment and Course: After conservative treatment with hemopressin, ciprofloxacin, and substitution with blood and fresh frozen plasma, the patient had an episode of atrial fibrillation with rapid ventricular response. The episode was terminated by intravenous administration of amiodarone, with subsequent conversion to sinus rhythm. Later on, the patient suffered from torsades de pointes tachycardia., Conclusion: Secondary torsades de pointes tachycardias have a low incidence, but often fatal outcome. Torsades de pointes tachycardias mostly are the result of administration of QT-active drugs, and other cofactors. Emergency treatment addresses the reestablishment, and stabilization of sinus rhythm. Preferably, drug-induced torsades de pointes tachycardias are prevented by permanent critical review of administered drugs with respect to indications, interactions, and adverse reactions.

Hemoglobin-based oxygen carriers (HBOC) are being developed to provide the oxygen necessary in clinical situations when whole blood is not available. The safety and effectiveness of each HBOC must be determined before clinical approval. In the past several years animal studies have been conducted with zero-linked polymers to evaluate their effectiveness at delivering oxygen in vivo. Studies have addressed issues associated with interstitial extravasation, cerebral ischemia and blood flow, resuscitation, and coagulation interactions. Several of the investigations reviewed are based on early preparations of zero-linked polymerized bovine hemoglobins (ZL-HbBv), which contained a wide range of high-molecular-weight polymers. Recent studies using the Oxyvita product OxyVita Hb, which contains a more homogenous population (97%) of large-molecular-weight species (~17 MDa), are also included in this review.

The hemoglobin vesicle (HbV) is an artificial oxygen carrier in which a concentrated Hb solution is encapsulated in lipid vesicles. Our previous studies demonstrated that HbV is metabolized by the mononuclear phagocyte system, and the lipid components are excreted from the liver. It is well-known that many hepatically-metabolized and -excreted drugs show altered pharmaceutics under conditions of liver impairment, which results in adverse effects. The aim of this study was to determine whether the administration of HbV causes toxicity in rats with carbon tetrachloride induced liver cirrhosis. Changes in plasma biochemical parameters, histological staining and the pharmacokinetic distribution of HbV were evaluated after an HbV injection of the above model rats at a putative clinical dose (1400 mgHb/kg). Plasma biochemical parameters were not significantly affected, except for a transient elevation of lipase, lipid components and bilirubin, which recovered within 14 days after an HbV infusion. Negligible morphological changes were observed in the kidney, liver, spleen, lung and heart. Hemosiderin, a marker of iron accumulation in organs, was observed in the liver and spleen up to 14 days after HbV treatment, but no evidence of oxidative stress in the plasma and liver were observed. HbV is mainly distributed in the liver and spleen, and the lipid components are excreted into feces within 7 days. In conclusion, even under conditions of hepatic cirrhosis, HbV and its components exhibit the favorable metabolic and excretion profile at the putative clinical dose. These findings provide further support for the safety and effectiveness of HbV in clinical settings., (Crown Copyright © 2010. Published by Elsevier Inc. All rights reserved.)

At the time of this writing, a widely publicized, waived-consent trial is underway. Sponsored by Northfield Laboratories, Inc. (Evanston, IL) the trial is intended to evaluate the emergency use of PolyHeme®, an oxygen-carrying resuscitative fluid that might prevent deaths from uncontrolled bleeding. The protocol allows patients in hemorrhagic shock to be randomized between PolyHeme® and saline in the field and, still without consent, randomized between PolyHeme® and blood after arrival at an emergency department. The Federal regulations that govern the waiver of consent restrict its applicability to circumstances where proven, satisfactory treatments are unavailable. Blood-the standard treatment for hemorrhagic shock-is not available in ambulances but is available in hospitals. The authors argue that the in-hospital stage of the study fails to meet ethical and regulatory standards.

Background: It is unclear whether blood pressure (BP) should be altered actively during the acute phase of stroke., Objectives: To assess the effect of lowering or elevating BP in people with acute stroke, and the effect of different vasoactive drugs on BP in acute stroke., Search Strategy: We searched the Cochrane Stroke Group Trials Register (last searched June 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2009), MEDLINE (1966 to October 2009), EMBASE (1980 to October 2009), and Science Citation Index (1981 to October 2009)., Selection Criteria: Randomised trials of interventions that would be expected, on pharmacological grounds, to alter BP in patients within one week of the onset of acute stroke., Data Collection and Analysis: Two review authors independently applied the trial inclusion criteria, assessed trial quality, and extracted data., Main Results: We identified 131 trials involving in excess of 18,000 patients; a further 13 trials are ongoing. We obtained data for 43 trials (7649 patients). Among BP-lowering trials, beta receptor antagonists lowered BP (early systolic BP (SBP) mean difference (MD) -6.1 mmHg, 95% CI -11.4 to -0.9; late SBP MD -4.9 mmHg, 95% CI -10.2 to 0.4; late diastolic BP (DBP) MD -4.5 mmHg, 95% CI -7.8 to -1.2). Oral calcium channel blockers (CCB) lowered BP (late SBP MD -3.2 mmHg, 95% CI -5.4 to -1.1; early DBP MD -2.5, 95% CI -5.6 to 0.7; late DBP MD -2.1, 95% CI -3.5 to -0.7). Nitric oxide donors lowered BP (early SBP MD -10.3 mmHg, 95% CI -17.6 to -3.0). Prostacyclin lowered BP (late SBP MD, -7.7 mmHg, 95% CI -15.6 to 0.2; late DBP MD -3.9 mmHg, 95% CI -8.1 to 0.4). Among BP-increasing trials, diaspirin cross-linked haemoglobin (DCLHb) increased BP (early SBP MD 15.3 mmHg, 95% CI 4.0 to 26.6; late SBP MD 15.9 mmHg, 95% CI 1.8 to 30.0). None of the drug classes significantly altered outcome apart from DCLHb which increased combined death or dependency (odds ratio (OR) 5.41, 95% CI 1.87 to 15.64)., Authors' Conclusions: There is not enough evidence to evaluate reliably the effect of altering BP on outcome after acute stroke. However, treatment with DCLHb was associated with poor clinical outcomes. Beta receptor antagonists, CCBs, nitric oxide, and prostacyclin each lowered BP during the acute phase of stroke. In contrast, DCLHb increased BP.

Vasoconstriction is a major adverse effect of first and second generation hemoglobin-based oxygen carriers (HBOCs) that hinders their development as blood substitute. However, intravenous infusion of HBOC-201 (second generation) to patients induces significant pulmonary hypertension without significant coronary vasoconstriction. We compared contractile responses of isolated bovine pulmonary and coronary arterial strips to HBOC-201 and HBOC-205LL.LT.MW600 (third generation), polymerized bovine hemoglobins of different molecular weight, and their attenuation by nitroglycerin, sodium nitroprusside (SNP), and sodium nitrite. Pulmonary arteries developed negligible basal tone, but exhibited HBOC-dependent amplification of phenylephrine-induced contractions. In contrast, coronary arteries developed significant basal tone, and exhibited HBOC-dependent constant force increment to serotonin-induced contractions. Therefore, relative to basal tone, HBOC-induced contractions were greater in pulmonary than coronary arteries. Furthermore, HBOC-205LL.LT.MW600 appeared to be less vasoactive than HBOC-201. Unexpectedly, pulmonary and coronary arteries exhibited differential sensitivities to nitrovasodilators in parallel with their differential sensitivities to HBOC. However, SNP and sodium nitrite induced significant methemoglobin formation from HBOC, whereas nitroglycerin did not. These results suggest that phenotypic differences between pulmonary and coronary vascular smooth muscle cells could explain the differential hypertensive effects of HBOC on pulmonary and coronary circulation in patients. Among the three nitrovasodilators investigated, nitroglycerin appears to be the most promising candidate for attenuating HBOC-induced pulmonary hypertension in older HBOCs.

Background: Diaspirin cross-linked hemoglobin (DCLHb) has demonstrated a pressor effect that could adversely affect traumatic hemorrhagic shock patients through diminished perfusion to vital organs, causing base deficit (BD) and lactate abnormalities., Methods: Data from two parallel, multicenter traumatic hemorrhagic shock clinical trials from 17 US Emergency Departments and 27 European Union prehospital services using DCLHb, a hemoglobin-based resuscitation fluid., Results: In the 219 patients, the mean age was 37.3 years, 64% of the patients sustained a blunt injury, 48% received DCLHb resuscitation, and the overall 28-day mortality rate was 36.5%. BD data did not differ by treatment group (DCLHb vs. normal saline [NS]) at any time point. Study entry BD was higher in patients who died when compared with survivors in both studies (US: -14.7 vs. -9.3 and European Union: -11.1 vs. -4.1 mEq/L, p < 0.003) and at the first three time points after resuscitation. No differences in BD based on treatment group were observed in either those who survived or those who died from the hemorrhagic shock. US lactate data did not differ by treatment group (DCLHb vs. NS) at any time point. Study entry lactates were higher in US patients who ultimately died when compared with survivors (82.4 vs. 56.1 mmol/L, p < 0.003) and at all five postresuscitation time points. No lactate differences were observed between DCLHb and NS survivors or in those who died based on treatment group., Conclusions: Although patients who died had more greatly altered perfusion than those who survived, DCLHb treatment of traumatic hemorrhagic shock patients was not associated with BD or lactate abnormalities that would indicate poor perfusion.