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Polynitroxylated Pegylated Hemoglobin: A Novel Neuroprotective Hemoglobin for Acute Volume-Limited Fluid Resuscitation After Combined Traumatic Brain Injury and Hemorrhagic Hypotension in Mice
Critical Care Medicine
  • David K. Shellington, University of Pittsburgh School of Medicine
  • Lina Du
  • Xianren Wu
  • Jennifer Exo
  • Vincent A. Vagni
  • Li Ma, Georgia Southern University
  • Keri Janesko-Feldman
  • Robert S. B. Clark
  • Hülya Bayır
  • C. Edward Dixon
  • Larry W. Jenkins
  • Carleton J. C. Hsia, SynZyne Technologies LLC
  • Patrick M. Kochanek
Document Type
Article
Publication Date
3-1-2011
DOI
10.1097/CCM.0b013e318206b1fa
Disciplines
Abstract

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 [mu]M, 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.

Comments

This accepted manuscript was obtained from PMC. The publisher's final edited version of this article is available at the Critical Care Medicine.

Citation Information
David K. Shellington, Lina Du, Xianren Wu, Jennifer Exo, et al.. "Polynitroxylated Pegylated Hemoglobin: A Novel Neuroprotective Hemoglobin for Acute Volume-Limited Fluid Resuscitation After Combined Traumatic Brain Injury and Hemorrhagic Hypotension in Mice" Critical Care Medicine Vol. 39 Iss. 3 (2011) p. 494 - 505
Available at: http://works.bepress.com/li_ma/25/