Despite decades of basic and clinical research, treatments to improve outcomes after traumatic brain injury (TBI) are limited. However, based on the recent recognition of the prevalence of mild TBI, and its potential link to neurodegenerative disease, many new and exciting secondary injury mechanisms have been identified and several new therapies are being evaluated targeting both classic and novel paradigms. This includes a robust increase in both preclinical and clinical investigations. Using a mechanism-based approach the authors define the targets and emerging therapies for TBI. They address putative new therapies for TBI across both the spectrum of injury severity and the continuum of care, from the field to rehabilitation. They discuss TBI therapy using 11 categories, namely, (1) excitotoxicity and neuronal death, (2) brain edema, (3) mitochondria and oxidative stress, (4) axonal injury, (5) inflammation, (6) ischemia and cerebral blood flow dysregulation, (7) cognitive enhancement, (8) augmentation of endogenous neuroprotection, (9) cellular therapies, (10) combination therapy, and (11) TBI resuscitation. The current golden age of TBI research represents a special opportunity for the development of breakthroughs in the field.

Polynitroxylated-pegylated hemoglobin (PNPH), a bovine hemoglobin decorated with nitroxide and polyethylene glycol moieties, showed neuroprotection vs. lactated Ringer's (LR) in experimental traumatic brain injury plus hemorrhagic shock (TBI þ HS). Hypothesis: Resuscitation with PNPH will reduce intracranial pressure (ICP) and brain edema and improve cerebral perfusion pressure (CPP) vs. LR in experimental TBI þ HS. C57/BL6 mice (n ¼ 20) underwent controlled cortical impact followed by severe HS to mean arterial pressure (MAP) of 25 to 27 mm Hg for 35 minutes. Mice (n ¼ 10/group) were then resuscitated with a 20 mL/kg bolus of 4% PNPH or LR followed by 10 mL/kg boluses targeting MAP470 mm Hg for 90 minutes. Shed blood was then reinfused. Intracranial pressure was monitored. Mice were killed and %brain water (%BW) was measured (wet/dry weight). Mice resuscitated with PNPH vs. LR required less fluid (26.0 ± 0.0 vs. 167.0 ± 10.7 mL/kg, Po0.001) and had a higher MAP (79.4 ± 0.40 vs. 59.7 ± 0.83 mm Hg, Po0.001). The PNPH-treated mice required only 20 mL/kg while LR-resuscitated mice required multiple boluses. The PNPH-treated mice had a lower peak ICP (14.5±0.97 vs. 19.7±1.12 mm Hg, P ¼ 0.002), higher CPP during resuscitation (69.2 ± 0.46 vs. 45.5 ± 0.68 mm Hg, Po0.001), and lower %BW vs. LR (80.3 ± 0.12 vs. 80.9 ± 0.12%, P ¼ 0.003). After TBI þ HS, resuscitation with PNPH lowers fluid requirements, improves ICP and CPP, and reduces brain edema vs. LR, supporting its development. Keywords: blood substitute; cerebral edema; hemoglobin blood oxygen carrier; intracranial pressure; nitroxide; resuscitation INTRODUCTION Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in civilian and military settings and is often accompanied by secondary insults such as hemorrhage. Optimum resuscitation is critical given the severe consequences of hemorrhagic shock (HS) after TBI. Early hypotension is a strong clinical predictor of mortality after TBI, doubling mortality rates with a reduction in systolic blood pressure of as small as 10 mm Hg. 1 In blast polytrauma victims in Operation Iraqi Freedom, sustained hypotension was associated with 100% mortality. 2 Ischemia as a consequence of hypotension greatly worsens outcomes in TBI models. 3 Hypotension leads to impaired energy metabolism, 4 reduced neuroprotective gene expression, 5 and increased neuronal death. 6-8 After TBI, cerebral blood flow (CBF) can also be reduced. 9 Animal models of TBI have revealed impaired autoregulation, exacerbating ischemic injury. 10 At autopsy, most TBI patients show evidence of cerebral ischemia, 11 implicating hypoperfusion in secondary injury after TBI. Journal of Cerebral BloodOptimized resuscitation of TBI patients is critical given the consequences of hypotension, and multiple fluids have been studied. Traditional resuscitation fluids for TBI patients include

Attitudes of patients toward the necessity of physician consent in epidemiologic studies were assessed. Questionnaires were mailed to women with breast, endometrial and ovarian cancers who had previously participated in a personal interview study (N=692). Of respondents (N=514), only 2 per cent would have preferred their physician to have withheld approval, and half considered physician permission necessary. Thirty-five per cent reported that their doctor talked to them about the study prior to the interview. Implications of including physician consent in study protocols are discussed.

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