| Polynitroxylated pegylated hemoglobin: A novel neuroprotective hemoglobin for acute volume-limited fluid resuscitation after combined traumatic brain injury and hemorrhagic hypotension in mice* | |
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MedLine Citation:
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PMID: 21169820 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OBJECTIVE:: Resuscitation of hemorrhagic hypotension after traumatic brain injury is challenging. A hemoglobin-based oxygen carrier may offer advantages. The novel therapeutic hemoglobin-based oxygen carrier, polynitroxylated pegylated hemoglobin (PNPH), may represent a neuroprotective hemoglobin-based oxygen carrier for traumatic brain injury resuscitation. HYPOTHESES:: 1) PNPH is a unique non-neurotoxic hemoglobin-based oxygen carrier in neuronal culture and is neuroprotective in in vitro neuronal injury models. 2) Resuscitation with PNPH would require less volume to restore mean arterial blood pressure than lactated Ringer's or Hextend and confer neuroprotection in a mouse model of traumatic brain injury plus hemorrhagic hypotension. DESIGN:: Prospective randomized, controlled experimental study. SETTING:: University center. MEASUREMENTS AND MAIN RESULTS:: In rat primary cortical neuron cultures, control bovine hemoglobin was neurotoxic (lactate dehydrogenase release; 3-[4,5-dimethylthiazol-2-yl-]-2,5-diphenyltetrazolium bromide assay) at concentrations from 12.5 to 0.625 μM, whereas polyethylene glycol-conjugated hemoglobin showed intermediate toxicity. PNPH was not neurotoxic (p < .05 vs. bovine hemoglobin and polyethylene glycol hemoglobin; all concentrations). PNPH conferred neuroprotection in in vitro neuronal injury (glutamate/glycine exposure and neuronal stretch), as assessed via lactate dehydrogenase and 3-[4,5-dimethylthiazol-2-yl-]-2,5-diphenyltetrazolium bromide (all p < .05 vs. control). C57BL6 mice received controlled cortical impact followed by hemorrhagic hypotension (2 mL/100 g, mean arterial blood pressure ∼35-40 mm Hg) for 90 min. Mice were resuscitated (mean arterial blood pressure >50 mm Hg for 30 min) with lactated Ringer's, Hextend, or PNPH, and then shed blood was reinfused. Mean arterial blood pressures, resuscitation volumes, blood gasses, glucose, and lactate were recorded. Brain sections at 7 days were examined via hematoxylin and eosin and Fluoro-Jade C (identifying dying neurons) staining in CA1 and CA3 hippocampus. Resuscitation with PNPH or Hextend required less volume than lactated Ringer's (both p < .05). PNPH but not Hextend improved mean arterial blood pressure vs. lactated Ringer's (p < .05). Mice resuscitated with PNPH had fewer Fluoro-Jade C plus neurons in CA1 vs. Hextend and lactated Ringer's, and CA3 vs. Hextend (p < .05). CONCLUSIONS:: PNPH is a novel neuroprotective hemoglobin-based oxygen carrier in vitro and in vivo that may offer unique advantages for traumatic brain injury resuscitation. |
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Authors:
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David K Shellington; Lina Du; Xianren Wu; Jennifer Exo; Vincent Vagni; Li Ma; Keri Janesko-Feldman; Robert S B Clark; Hülya Bayir; C Edward Dixon; Larry W Jenkins; Carleton J C Hsia; Patrick M Kochanek |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2010-12-16 |
Journal Detail:
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Title: Critical care medicine Volume: - ISSN: 1530-0293 ISO Abbreviation: - Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0355501 Medline TA: Crit Care Med Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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From the Safar Center for Resuscitation Research (DKS, LD, XW, JE, VV, KJ-F, RSBC, HB, ED, LWJ, PMK), Pittsburgh, PA; Departments of Critical Care Medicine (DKS, LD, RSBC, HB, PMK) Pediatrics (RSBC, HB, PMK), Neurological Surgery (ED, LWJ), and Anesthesiology (XW), University of Pittsburgh School of Medicine; Pittsburgh, PA; SynZyme Technologies (LM, CJCH), Irvine, CA; and Department of Physics (LM), Georgia Southern University, Statesboro, GA. |
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