Secondary - Secondary brain injury is the damage to the brain, after the initial trauma. Most secondary injury occurs within the first 12 - 24 hours after injury, but may also occur during the first 5 - 10 days after injury if the initial injury is very severe. Secondary injury results from physiological disturbances caused by the impact and the initial trauma and from the development of focal areas of cerebral ischemia and disruption of the blood-brain barrier (Marion, 1998; Golding, et al 1999). Physiological disturbances, which involve the release of high levels of oxygen free radicals during the first 24 hours postinjury and the cellular inflammatory response and cause cerebral edema or hyperemia and a subsequent increase in ICP, include:

• Increased EAAs (excitatory amino acids), such as glutamate, aspartate, lactate, pyruvate, and, in a slightly more delayed fashion, adenosine and nitric oxide, (Marion, 1998).  Patients with significantly elevated glutamate values during the 5 days postinjury are most likely to exhibit increased ICP, and patients with contusions may display the highest overall EAAs (Koura, et al 1998).  Patients with focal contusions and ischemic events may therefore be the best  candidates for treatment with glutamate antagonists in the future (Bullock, et al 1998).

  Recovery of aspartate and lactate/pyruvate ratio differ depending on the presence of the apoE4 allele. Patients with the allele had significent increased and sustained levels of aspartate and lactate/pyruvate ratio after TBI. Changes in glutamate were related to severity of illness and were independent of the presence of the apoE4 allele (Kerr, et al 2003)

  More than 19 pharmacologic agents that block EAA neurotransmitter receptor systems have been reported to be efficacious (McIntosh, et al 1997):

  • Competitive NMDA (N-Methyl-D-Aspartate) Receptor Antagonists, which attentuate release of EAAs and may attentuate trauma-induced memory dysfunction and improve neurological motor outcome, such as:
    • APV (2-amino-5-phosphovaleric acid) and CPP (3-(2-carboxypiperizin-4yl)-propy-1-phosphonic acid) which are lipophobic, with poor blood-brain permeability, and require intracranial administration
    • CGS-19755 (cis-4-(phosphomethyl)-2-piperidine carboxylic acid) and LY233053 ((+1-)-(2SR,4RS)-4-(1H-tetrazol-5-ylmethyl) piperidine-2-carboxylic acid) which have a greater blood-brain barrier permeability and may be administered systemically
    • CP-101,606, which has no psychotropic effects, is well tolerated and improves personality and behavioral disturbances in mild or moderate TBI (Merchant, et al 1999).

    However, the case for efficacy of excitatory amino acid inhibitor therapy remains unproven (Willis, et al 2003).

  • NMDA Receptor-Associated Ionophore Blockade Compounds (which prevent the potentially toxic influx of ions into the neuron and may improve neurologic motor outcome and reduce cerebral edema, but which may have inherent neurotoxic and psychotomimetic effects), such as:
    • PCP (phencyclidine), ketamine, dextromethorpham and its derivative dextrorphan
    • Dizocilopine (MK801) and HU-211 (7-hydroxu-tetrahydrocannabinol 1, 1-dimethylheptyl)

  • NMDA Receptor Modulation by Magnesium Therapy, such as exogenous administration of magnesium salts, which restores magnesium homeostasis following brain injury (thereby possibly preventing disruption of NMDA-mediated neurotransmission) and may improve cognitive outcome, decrease neurologic motor function, and decrease cerebral edema formation . However, there is currently no evidence to support the use of magnesium salts in patients with acute traumatic brain injury (Arango & Mejia-Mantilla, 2006). Continuous infusions of magnesium for 5 days given to patients within 8 h of moderate or severe traumatic brain injury were not neuroprotective and might even have a negative effect in the treatment of significant head injury (Temkin, et al 2007).
    

  • NMDA Receptor-Associated Glycine Site Modulation (which serves as an antagonist to the amino acid glycine, essential for NMDA-receptor activation, and may improve motor neurologic outcome and cognitive function), such as:
    • 12CA (indole-2-carboxylic acid)
    • KYNA (kynurenate) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dine)

  • Ifenprodil-Like NMDA Receptor Modulation (which serves as an antagonist to spermidine and spermine, enhancers of NMDA-receptor activation, and may improve cognitive function, and reduce regional cerebral edema) such as ifenprodil and its derivative eliprodil (SL82.0715)

  • AMPA/KA Receptor Modulation (which serves as an antagonist to AMPA/KA receptors, and may improve cognitive outcome), such as KYNA and CNQX which are also glycine site antagonists

  • EAA Release Inhibitors, which inhibit glutamate release and may improve cognitive outcome and neurologic motor function and reduce edema formation, such as:
    • Lamotrigene and its derivatives BW 1003C87
    • BW 619C89
    • Riluzole

• Increased Free Radicals, which can cause edema, cerebral ischemia, spinal cord and brain trauma, and hyperemia, and may be treated with:
  • Alpha tocopherol, ascorbic acid, and superoxide dismutase (SOD), such as Dismutec (PEG-SOD)
  • Dimethyl sulfoxide (DMSO)
  • NON-3144, and MKI-186
  • 21 aminosteroid compounds, such as tirilizad mesylate (Freedox). However, there is no evidence to support the routine use of aminosteroids in the management of TBI (Roberts, 2003)

• Increased Calcium Into Cells, which:
  • May be treated with NMDA receptor antagonists or calcium-channel blockers, such as nimodipine, to prevent free radicals and increased arachidonic acid metabolism. However, the clinical benefit of both nimodipine and nicardipine has been demonstrated only in severely brain-injured patients with marked vasospasm (McIntosh, et al 1997) and with subarachnoid hemorrhage, the latter with an increase in adverse effects that may be due to nimodipine. Considerable uncertainty remains over the effects of calcium-channel blockers (Langham, et al 2002)
  • Causes calpain to be activated, which may be cytotoxic to neurons when activation is prolonged and unregulated. Treatment with calpain inhibitors, such as AK295 and calpain inhibitor 2, is neuroprotective, and may enhance posttraumatic motor and cognitive effects (McIntosh, et al 1997)
  • Also causes changes in gene expression, activation of reactive oxygen species (ROS), expression of neurotrophic factors, and activation of cell death genes (apoptosis) in experimental models (McIntosh, et al 1998)

• Alterations in Immunocompetent Cells, such as infiltration and accumulation of polymorphonuclear leukocytes (PMN), can cause cerebral edema and the secretion of Cytokines, such as tumor necrosis factor (TNF) and interleukin-1 beta and interleukin-6 into the plasma and CSF (Marion, 1998), which can cause post-traumatic neurologic damage. IL-6 plasma level 1 day after injury may be a predictor for short-term prognosis and infectious complications (Woiciechowsky, et al 2002). IL-6 may be an endogenous neuroprotective cytokine produced in response to severe head trauma (Winter, et al 2004). Cytokine blockade or antagonism, with compounds such as BRL 55730 and IL1-RA, may mediate the damage

• Increased Neurotrophic Factors, such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF), brain-derived neuronotrophic factor (BDNF), NT-3, and IGF-1 (insulin-like growth factor 1) which is endogenous to the CNS. Post-traumatic administration of these neurotrophic factors appears to convey significant neuroprotective effects and neurotrophic therapy may be a potential candidate for neuroprotectin following brain injury . The combination of IGF-1 and GH produced sustained improvement in metabolic and nutritional endpoints after moderate to severe acute TBI (Hatton, et al 2006).

• Increased bcl-2 and caspase families, important regulators of programmed cell death (Clark, et al 1999)

• Increased Metabolic Rates for Glucose, particularly surrounding contusions and underlying acute subdural hematomas (Marion, 1998), which begins to resolve within 1 month of injury, regardless of injury severity (Bergsneider, et al 2001)

• Reduction of Cerebral Glucose Utilization during the period of metabolic depression following TBI (Bergsneider, et al 2000)

• Increased Acetylcholine, which may be treated with scopolamine to lessen sensitivity to ischemia. Acetylcholine esterase inhibitors may prove to be beneficial in TBI (Blount, et al 2002)

• Increased Opioids, which may be treated with naloxone or thyrotropin-releasing hormone to prevent decreased cerebral perfusion

• Increased Catecholamines, which may be treated with amphetamines to prevent ischemia

• Increased Extracellular Potassium, which may be treated with ethacrynic acid or indacrinone to prevent edema and seizures

• Increased Arachidonic Acid Metabolism, which may be treated with ibuprofen, meclodenamic acid, or U63447 to prevent leukotrines and free fatty acids

• Decreased Magnesium, which may be treated with magnesium chloride to prevent increased calcium entry into cells

• Increased levels of beta-amyloid peptide, Alzheimer's A beta 1-42, in CSF after severe brain injury and continued elevation for some time (Emmerling, et al 2000). A beta I-42 may be a supportive early predictor for recovery after severe head injury (Franz, et al 2004). However, TBI may reduce the time to onset of Alzheimer's disease among persons at risk for developing the disease (Nemetz, et al 1999). Severe TBI is a risk factor for the development of Alzheimer's disease (Ikonomovic, et al 2004), particularly in patients lacking ApoE (Apolioprotein E) allele (Jellinger, et al 2001). There are differences in beta-amyloid precursor protein pattern, distribution, and intensity in head injury compared to hypoxia/ischemia (Lambri, et al 2001)

• Increased neuron specific enolase and protein 5-100B, which may be markers of neuropsychological dysfunction (Herrmann, et al 2001) and C-tau, proteolytically cleaved MAP-tau, the neuronally-localized intracellualr protein, which is a significant predictor of ICP and clinical outcome, with particular sensitivity for identifying severe TBI patients with good clinical outcome (Zemlan, et al 2002)

• Increased inducible nitric oxide synthase (iNOS) within 6 hours after trauma and with a peak at 8-23 hours (Gahm, et al 2002), and of a NOS by-product, citrulline, also in very early injury (Silberstein, et al 2002)

     Mild to Moderate Hypothermia (33-34 degrees C), which maintains the tissue in relative stasis, lowers metabolism, and can reduce the post-traumatic neurochemical response, has also been shown to be efficacious in attenuating the secondary cascade of brain trauma.