Pulmonary Hypertension and Systemic Vasoconstriction May Offset the Benefits of Acellular Hemoglobin Blood Substitutes

Figueiredo, Luiz Francisco Poli de; Mathru, M.; Solanki, Daneshvari R.; Macdonald, Victor W.; Hess, John R.; Kramer, George C.

doi:10.1097/00005373-199705000-00015

Cited by 54 publications

(48 citation statements)

References 31 publications

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“…21 A major limitation to the clinical application of artificial blood transfusion has been the concern that some HBOC have caused coronary vasoconstriction that would reduce coronary perfusion and result in myocardial ischemia. [22][23][24][25] Several hemoglobin modifications have been attempted to limit vasoconstriction after HBOC administration. One strategy has been to genetically engineer the heme pocket of hemoglobin to reduce its NO affinity.…”

Section: Discussionmentioning

confidence: 99%

Inhaled Nitric Oxide Enables Artificial Blood Transfusion Without Hypertension

et al. 2008

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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.

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Section: Discussionmentioning

confidence: 99%

Inhaled Nitric Oxide Enables Artificial Blood Transfusion Without Hypertension

et al. 2008

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“…Acute hypoxia stimulates the expression of HIF-1α and p38 mitogen-activated protein kinase (MAPK), particularly in the lung, which are linked to the proliferation of pulmonary artery fibroblasts and remodeling (30). Pulmonary and systemic vasoconstriction and low peripheral perfusion are associated with use of a modified Hb tetrametric solution (11,22), which causes scavenging of nitric oxide (NO) and enhanced endothelin release (10). NO scavenging enhances hypoxic pulmonary vasoconstriction (1), worsens pulmonary hypertension and reduces cardiac output after hemorrhagic shock.…”

Section: Discussionmentioning

confidence: 99%

Fluid resuscitation with hemoglobin-vesicle solution does not increase hypoxia or inflammatory responses in moderate hemorrhagic shock

et al. 2006

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The aim of the present study was to compare the hypoxic and inflammatory effects of transfusing hemoglobin-vesicles (HbV) or lactated Ringer's (LR) solution on several organs in a hemorrhagic shock model. Hemorrhagic shock was induced in 48 anesthetized rats by withdrawing 28 mL/kg blood. The animals were resuscitated by replacing the blood with an equal volume of HbV solution or three times the volume of LR solution. The heart, lung, liver, kidney and spleen were extracted at different time points following resuscitation, and mRNA expression levels of hypoxia-induced factor 1-alpha (HIF-1α) and tumor necrosis factor-alpha (TNF-α) were determined. Blood lactate concentrations in the HbV group rapidly returned to baseline levels, whereas elevated lactate concentrations in the LR group were prolonged. There were no significant differences between the two resuscitation groups in terms of HIF-1α and TNF-α expression in the organs examined. HIF-1α and TNF-α expression in the lungs was significantly greater than in other organs. Our results suggest that resuscitation from hemorrhagic shock with HbV did not increase hypoxic or inflammatory effects in major organs, compared with resuscitation using LR solution, despite prolonged elevation of blood lactate.

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“…Early hemoglobin solutions increased the oxygen-carrying capacity of blood, but were associated with anaphylaxis, renal toxicity, and increases in systemic and pulmonary pressures secondary to vasoconstriction. 8,23,24 The mechanism of this adverse vasoactive response is thought to occur secondary to free hemoglobin molecules interacting with nitric oxide and endothelin produced by endothelial cells. 9,11 In solution, dissociated hemoglobin monomers or dimers act as scavengers that bind nitric oxide, a potent vasodilator, leading to systemic vasoconstriction.…”

Section: Discussionmentioning

confidence: 99%

Small-volume Resuscitation with HBOC-201: Effects on Cardiovascular Parameters and Brain Tissue Oxygen Tension in an Out-of-hospital Model of Hemorrhage in Swine

et al. 2002

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Objective: Hemoglobin-based oxygen carriers, such as HBOC-201, offer several potential advantages over conventional resuscitation solutions or banked blood in the acute treatment of hemorrhagic shock. While previous studies with some hemoglobin solutions revealed vasoactive effects resulting in decreased oxygen delivery, these investigations were performed without directly measuring vital tissue oxygenation. The authors tested the hypothesis that a small-volume bolus of HBOC-201 would improve and sustain brain tissue oxygen tension (PbrO 2 ) without adverse effects on cardiovascular endpoints, when used in an acute out-of-hospital hemorrhage model. Methods: Male Yorkshire swine (n = 7) were hemorrhaged to a mean arterial pressure (MAP) of 40 mm Hg while monitoring standard hemodynamic parameters. In addition, Clark-type polarographic probes were directly inserted into brain tissue to measure PbrO 2 . Following institution of high-flow oxygen (FiO 2 = 1.0), resuscitation was performed with a bolus infusion of HBOC-201 (6 mL/kg). Swine were observed for two hours. Results: Cardiac output (CO), MAP, pulmonary artery diastolic pressure (PAD), and PbrO 2 all decreased significantly with hemorrhage (p < 0.05). Immediately following resuscitation with HBOC-201 (mean volume = 239 mL), MAP and CO were restored to 83% and 84% of baseline levels, respectively. PbrO 2 increased significantly after treatment with HBOC-201, surpassing baseline levels by 66%. PAD rose above baseline levels during observation, but this increase was not significantly different from baseline levels (24.0 mm Ϯ 4.1 vs. 22.7 mm Ϯ 7.4). Conclusions: Small-volume resuscitation with HBOC-201 rapidly restored hemodynamic parameters and PbrO 2 following severe hemorrhage without detrimental vasoactive effects and without compromise to directly monitored brain tissue oxygenation. The results of this preliminary study demonstrate that HBOC-201 could potentially improve current resuscitation measures and that further investigations with HBOC-201 are warranted.

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Pulmonary Hypertension and Systemic Vasoconstriction May Offset the Benefits of Acellular Hemoglobin Blood Substitutes

Abstract: Small-volume infusion of alpha alpha Hb restored mean arterial pressure and brain blood flow, but pulmonary hypertension and low peripheral perfusion may offset benefits for trauma patients.

Cited by 54 publications

References 31 publications

Inhaled Nitric Oxide Enables Artificial Blood Transfusion Without Hypertension

Inhaled Nitric Oxide Enables Artificial Blood Transfusion Without Hypertension

Fluid resuscitation with hemoglobin-vesicle solution does not increase hypoxia or inflammatory responses in moderate hemorrhagic shock

Small-volume Resuscitation with HBOC-201: Effects on Cardiovascular Parameters and Brain Tissue Oxygen Tension in an Out-of-hospital Model of Hemorrhage in Swine

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