title: Polynitroxylated Pegylated Hemoglobin-A Novel, Small Volume Therapeutic for Traumatic Brain Injury Resuscitation: Comparison to Whole Blood and Dose Response Evaluation.
abstract: Resuscitation with polynitroxylated pegylated hemoglobin (PNPH), a pegylated bovine hemoglobin decorated with nitroxides, eliminated the need for fluid administration, reduced intracranial pressure (ICP) and brain edema, and produced neuroprotection in vitro and in vivo versus Lactated Ringer's solution (LR) in experimental traumatic brain injury (TBI) plus hemorrhagic shock (HS). We hypothesized that resuscitation with PNPH would improve acute physiology versus whole blood after TBI+HS and would be safe and effective across a wide dosage range. Anesthetized mice underwent controlled cortical impact and severe HS to mean arterial pressure (MAP) of 25-27 mm Hg for 35 min, then were resuscitated with PNPH, autologous whole blood, or LR. Markers of acute physiology, including mean arterial blood pressure (MAP), heart rate (HR), blood gases/chemistries, and brain oxygenation (PbtO2), were monitored for 90 min on room air followed by 15 min on 100% oxygen. In a second experiment, the protocol was repeated, except mice were resuscitated with PNPH with doses between 2 and 100 mL/kg. ICP and 24 h %-brain water were evaluated. PNPH-resuscitated mice had higher MAP and lower HR post-resuscitation versus blood or LR (p < 0.01). PNPH-resuscitated mice, versus those resuscitated with blood or LR, also had higher pH and lower serum potassium (p < 0.05). Blood-resuscitated mice, however, had higher PbtO2versus those resuscitated with LR and PNPH, although PNPH had higher PbtO2versus LR (p < 0.05). PNPH was well tolerated across the dosing range and dramatically reduced fluid requirements in all doses-even 2 or 5 mL/kg (p < 0.001). ICP was significantly lower in PNPH-treated mice for most doses tested versus in LR-treated mice, although %-brain water did not differ between groups. Resuscitation with PNPH, versus resuscitation with LR or blood, improved MAP, HR, and ICP, reduced acidosis and hyperkalemia, and was well tolerated and effective across a wide dosing range, supporting ongoing pre-clinical development of PNPH for TBI resuscitation.
authors.affiliation: 1 Department of Critical Care Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pennsylvania.|3 Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Brockman
authors.affiliation: 1 Department of Critical Care Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pennsylvania.
authors.forename: Travis C
authors.initials: TC
authors.lastname: Jackson
authors.affiliation: 2 Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pennsylvania.|5 Department of Neurological Surgery, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.affiliation: 1 Department of Critical Care Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pennsylvania.|3 Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.|4 Pittsburgh Center for Free Radical and Antioxidant Health , Pittsburgh, Pennsylvania.
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayɪr
authors.affiliation: 1 Department of Critical Care Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pennsylvania.|3 Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Robert S B
authors.initials: RS
authors.lastname: Clark
authors.affiliation: 2 Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pennsylvania.
authors.forename: Vincent
authors.initials: V
authors.lastname: Vagni
authors.affiliation: 2 Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pennsylvania.
authors.forename: Keri
authors.initials: K
authors.lastname: Feldman
authors.affiliation: 2 Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pennsylvania.
authors.forename: Catherine
authors.initials: C
authors.lastname: Byrd
authors.affiliation: 6 Department of Physics, Georgia Southern University , Statesboro, Georgia .
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: 7 SynZyme Technologies , LLC, Irvine, California.
authors.forename: Carleton
authors.initials: C
authors.lastname: Hsia
authors.affiliation: 1 Department of Critical Care Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pennsylvania.|3 Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
mesh_terms: D000818:Animals; D001804:Blood Transfusion, Autologous / Q000379:methods*; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000188:drug therapy*; D002417:Cattle; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006454:Hemoglobins / Q000008:administration & dosage / Q000494:pharmacology*; D007552:Isotonic Solutions / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D012151:Resuscitation / Q000379:methods*; D000077325:Ringer's Lactate; D012771:Shock, Hemorrhagic / Q000188:drug therapy*
chemical_list: D006454:Hemoglobins; D007552:Isotonic Solutions; D018696:Neuroprotective Agents; D000077325:Ringer's Lactate; C557204:polynitroxylated pegylated hemoglobin
keywords: brain edema; intracranial pressure; secondary insult; traumatic brain injury