Document Detail

Polynitroxylated pegylated hemoglobin: a novel neuroprotective hemoglobin for acute volume-limited fluid resuscitation after combined traumatic brain injury and hemorrhagic hypotension in mice.
MedLine Citation:
PMID:  21169820     Owner:  NLM     Status:  MEDLINE    
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 positive 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.
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Critical care medicine     Volume:  39     ISSN:  1530-0293     ISO Abbreviation:  Crit. Care Med.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-02-18     Completed Date:  2011-04-06     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0355501     Medline TA:  Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  494-505     Citation Subset:  AIM; IM    
Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, USA.
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MeSH Terms
Blood Pressure / drug effects
Brain Injuries / complications,  drug therapy*
Cell Survival
Cells, Cultured
Cerebral Cortex / cytology,  drug effects
Dose-Response Relationship, Drug
Exsanguination / complications,  drug therapy*
Hemoglobins / pharmacology,  therapeutic use*
Hypotension / drug therapy,  etiology
Mice, Inbred C57BL
Neuroprotective Agents / therapeutic use*
Nitrogen Oxides / pharmacology,  therapeutic use
Polyethylene Glycols / pharmacology,  therapeutic use
Rats, Sprague-Dawley
Resuscitation / methods
Grant Support
Reg. No./Substance:
0/Hemoglobins; 0/Neuroprotective Agents; 0/Nitrogen Oxides; 0/Polyethylene Glycols; 0/polynitroxylated pegylated hemoglobin
Comment In:
Crit Care Med. 2011 Mar;39(3):592-3   [PMID:  21330861 ]

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