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Secondary Mechanisms in Traumatic Brain Injury: A Nurse's Perspective.

Abstract: Effective management of brain-injured patients requires that nurses have a specialized body of knowledge relating to the pathophysiology and treatment of traumatic brain injury (TBI). Current research in this area has focused on the cascade of secondary injury which leads to the irreversible tissue damage following TBI. Such processes involve excitatory amino acids, neurotransmitters, ion changes, lipid peroxidation, oxygen free radicals, opioids, lactic acidosis and magnesium to name but a few. Given that no accepted treatment paradigm exists to attenuate these secondary processes, nurses may have to autonomously devise individual care plans based on their current understanding of brain injury pathophysiology.


Nurses are involved with the treatment and care of a diverse range of illnesses and injuries. In particular, nurses working within intensive care, emergency, neurological or neurosurgical departments are exposed to many patients with specific care requirements relating to the physiological processes following brain injury. Despite significant mortality and morbidity associated with brain injury, no accepted treatment paradigm exists. Nurses tend to autonomously devise individual care practices based on their current understanding of brain injury pathophysiology. Given the unparalleled importance of brain function to quality of life, it is essential that nursing knowledge concerning the brain and its response to injury is comprehensive and continually updated.

Young children, young adults, people living in high-crime areas and elderly adults are the most prominent victims of traumatic brain injury (TBI). The outcome for the TBI survivor is generally poor with almost 20% requiring hospitalization and nursing care for life-long impairments or illnesses. Moreover, nearly 1% of these victims will spend the rest of their life in a persistent vegetative state,[29] being totally dependent on health professionals, family and societal support. As such, brain injury has been described as one of the most severe and widespread public health problems in the western world in terms of mortality, morbidity and cost to society.[29,69] Despite the human and financial costs of brain injury, developing a treatment has up until recently received little attention in terms research funding. Consequentially medical practitioners have little ammunition to attenuate the destructive secondary, biochemical processes occurring in the brain after the initial trauma. Indeed, brain injury is essentially managed by supportive therapy although edema and intracranial pressure may be pharmacologically managed.

It is well established that irreversible tissue damage following brain trauma is a result of primary and secondary processes. The primary injury occurs at the time of the traumatic event and encompasses mechanical processes such as neuronal shearing, transection and axonal injury.[66] Obviously, these primary events cannot be prevented once the trauma has occurred. However, secondary injury develops over time following the primary traumatic insult. Recent evidence suggests that much of the irreversible damage after TBI is actually caused by these secondary events initiated at the time of trauma but taking hours to days after the insult to resolve.[15] The time factor involved in the secondary injury process suggests that irreversible brain injury may be prevented or at least attenuated. As such, understanding the role of these secondary mechanisms in the injury process permits the implementation of nursing care practices that may potentially minimize irreversible tissue damage. This article provides an up-to-date review of secondary mechanisms of injury thought to occur following traumatic brain injury.

Secondary Injury Mechanisms

Secondary mechanisms thought to occur following TBI include a role for excitatory amino acids, neurotransmitters, ionic changes, lipid peroxidation, oxygen free radicals, opioids, lactate acidosis and magnesium to name but a few.

Excitatory Amino Acids (EM)

Release of excitatory amino acids (EAA), such as glutamate and aspartate, has been implicated in an excitotoxic cascade that occurs subsequent to TBI. The release is thought to culminate in cell death.[20,43] An increase in glutamate and aspartate occurs immediately after TBI with maximum increase at 10 minutes and return to normal levels by 30 minutes to one hour postinjury.[20,34] Such release is thought to activate a number of receptors including ionotropic N-methyl, D-aspartate (NMDA) channels and phospholipase C-linked metabotropic receptors[13,68] Activation of these receptors ultimately results in increased intracellular free calcium concentration either by initiating transmembrane calcium flux or by releasing calcium from intracellular stores. Excess intracellular calcium leads to cell death.

Binding of the glutamate agonist to NMDA receptors leads to a change in the conformation of the ion-conducting channel and activation of ionotropic processes involving sodium and calcium entry (Fig 1). Normally, the channel is blocked by extracellular magnesium; however, trauma-induced membrane depolarization displaces magnesium out of the channel. Binding of glutamate to metabotropic receptors involves guanosine nucleotide-binding protein (G-protein). This results in relatively slow-onset, longer-lasting metabolic changes in the postsynaptic cell because these metabolic changes are mediated by a cascade of second messenger initiated reactions.[68] Many of these metabolites, including protein kinases and the inositol phosphates, are potent regulators of voltage dependent and calcium dependent ion channels in neurons and activate the release of calcium from the endoplasmic reticulum (ER) stores within the cell. The increased calcium concentration is thought to activate a variety of calcium-dependent autodestructive cascades.


Recent studies suggest NMDA receptor antagonists may be beneficial in improving outcome following TBI.[20,34,56] However, efficacy was temporally limited; administration of NMDA antagonists more than 30 minutes after injury proved to be ineffective following TBI. This is in contrast to ischemia where NMDA antagonists are found to be efficacious even when given up to 24 hours after induction of an ischemic insult.[57,80] Moreover, not all NMDA antagonists have shown efficacy, suggesting that NMDA channels alone do not cause neurologic deficits after TBI.[28]

Similar to the NMDA receptor pathway, metabotropic receptors participate in glutamate neurotransmission regulation and modulation of neuronal cell death.[68] However, in contrast to the NMDA receptor pathway, few brain injury studies have examined the role of the glutamate metabotropic pathway following TBI. Recent studies have demonstrated that pharmacological blockade of the glutamate-activated phospholipase-C pathway decreased trauma-induced neuronal damage, implicating phospholipase C in secondary brain injury.[59] Consistent with this study, other investigators have previously demonstrated increased phospholipase C-linked activity following brain injury,[93] an inhibition of which improved metabolic and neurologic outcome following TBI.[27] These observations support the assumption that phospholipase C antagonists and selective glutamate antagonists may have a beneficial therapeutic effect in the treatment of brain injury.[59] However, whether it is the glutamate receptor or other phospholipase C-linked receptors that are involved in the injury process following TBI still remains unclear.


In addition to the excitatory amino acids discussed above, a number of other neurotransmitters have been implicated in tissue damage following TBI. These neurotransmitters include acetylcholine (ACh), serotonin and noradrenaline.[34,54,75] Early research detailed increases in functional activity of cholinergic systems, particularly increased utilization and cortical content of Ach.[71] This work prompted studies examining the protective effects of pharmacologic depletion of ACh following TBI. Acetylcholine antagonists such as scopolamine,[49,50] dicyclomine[70] and others[70] administered prior to or immediately after injury were effective in reducing posttraumatic motor deficits and duration of unconsciousness. This was thought to result from inhibition of the muscarinic brainstem system, activation of which produces components of reflex inhibition associated with profound behavioral suppression.[34,36,44] From these studies it was concluded that mechanisms mediating traumatic unconsciousness are likely to be distinct from those mediating behavioral deficits.[54]

Cortical serotonin metabolism (5-HT) is similarly increased following brain injury and this increase is temporally related to depression of glucose utilization.[64,75] Moreover, administration of the serotonin synthesis inhibitor, p-chlorphenylalanine, attenuated depression of glucose utilization and postinjury increases in cortical serotonin.[64] Based on these results, investigators postulated that activation of serotonergic systems contributes to posttraumatic cerebral metabolic dysfunction and suggested that blockage of this neurotransmitter system may be beneficial in treatment of TBI.[54,64]

Researchers have investigated noradrenergic (NE) and dopaminergic (DA) system involvement in TBI[23-25] and demonstrated that activating NE and DA systems with pharmacological agents can accelerate functional recovery.[24,25] However, while administration of amphetamine (AMP) improved functional recovery, it was not effective in promoting recovery from hemiplegia. In addition, animals had to be tested during the period of AMP action to assess for acceleration of recovery.[23,40] Similarly, administration of intracerebroventricular injections of NE improved rate of recovery following cortical ablation[24] although it too had to be administered during the assessment task. Nonetheless, these studies and others support the concept that inhibition of the NE system results in less favorable functional outcomes while enhancement of NE transmission could promote motor recovery.

In general, clinical efficacy of the above therapies targeting neurotransmission appears to be limited with treatments having to be administered within minutes of the injury. Some, particularly the NMDA antagonists, produce profound and debilitating psychotomimetic side effects. Experimental findings suggest that these pharmacologic interventions may be limited primarily to brain injury models producing significant ischemia or lengthy periods of unconsciousness.

Ion Changes

Changes in ion concentrations, including potassium, sodium and calcium, can have profound deleterious effects on outcome following traumatic brain injury. Studies have shown massive increases in extracellular potassium concentration following trauma[43,81] leading to disrupted energy homeostasis, constriction of cerebral blood vessels and enhanced cerebral glycolysis. It has also been shown to correlate with loss of consciousness or autonomic function and epilepsy following TBI.[54,81] Postulated mechanisms for this posttraumatic potassium increase have included energy failure at the site of the sodium-potassium/ATPase pump, non-specific plasma membrane breakdown, potassium flux through voltage-gated channels associated with neuronal discharge and opening of ligand-gated ion channels.[39,43,81] Extracellular potassium concentration is normally regulated by astrocytic cells.[39] Insults, such as moderate fluid percussion and minor concussion, may result in transient potassium increases.[17] Increased injury severity has been associated with extremely high potassium increases.[43,81] There is little evidence that potassium itself is neurotoxic. However, it has been demonstrated that posttraumatic potassium increase is associated with a glutamate increase following fluid percussion induced TBI and that administration of kynurenic acid (EAA blocker) greatly reduced extracellular potassium increases and improved outcome.[43] It is likely that this protective effect was related to an inhibition of EAA transmission.

Alterations in potassium and sodium concentration following brain injury are associated with the development of intracellular swelling (status spongiosus).[54] A number of investigators have successfully implemented therapeutic approaches to resolve such posttraumatic swelling including modulation of neurotransmitters,[7,8] EAA blockers[43] and inhibition of chloride transport and the chloride/bicarbonate anion transport system.[61] However, the therapeutic potential of these pharmacological approaches may be limited to brain injury conditions producing energy depletion or significant edema.

In addition to alterations in sodium and potassium concentrations, calcium accumulation has also been observed following brain injury and has been implicated in delayed cell destruction, brain engorgement and cerebral hemorrhagic vasospasm,[77,97] Total brain calcium concentrations have been reported to significantly increase in injured neurons, while extracellular calcium has been observed to markedly decrease following TBI. Thus, it has been proposed that calcium moves into the cytosol of the neural cells from the extracellular space, thereby activating the intracellular destructive calcium cascades (Fig. 1). Although calcium appears to play a role in the pathogenesis of traumatic spinal cord injury, the potential role for calcium channel antagonists in CNS trauma is controversial.[54] Moreover, little is known about the role calcium antagonists play in attenuating posttraumatic secondary brain injury. While the calcium antagonists nicardipine, (S)-empomil and nimodipine have been effective in treatment of clinical cerebral vasospasm, ischemia and hemorrhage, little evidence exists supporting their efficacy in TBI.[19]

Lipid Peroxidation and Oxygen Free Radicals

Membrane phospholipid breakdown leads to the formation of arachidonic acid which when metabolized, gives rise to highly reactive oxygen free radicals. These compounds have the potential to initiate a chain reaction, called lipid peroxidation, capable of destroying the phospholipid bilayer of cell membranes and inhibiting a number of critical cell functions including oxidative phosphorylation and transmembrane transport processes.[78] Furthermore, arachidonic acid can be oxidized to yield eicosanoids which, together with platelet-activating factor (PAF), another by-product of phospholipid breakdown, increases the aggregation of blood cell and the constriction of blood vessels.[11] Protective effects of free radical scavengers and antioxidants have been reported in experimental CNS injury including ischemia,[5,32] traumatic spinal cord injury,[31] edema,[12,65] cerebral hemorrhage[74] and TBI.[14,92] Administration of a D, [Alpha]-tocopherol has been shown to decrease lipid peroxidation,[95] neuronal necrosis and reactive gliosis in experimental edema,[96] fluid percussion induced TBI[14] and in in vitro models of injury.[30] Furthermore, free radical scavengers such as superoxide dismutase (SOD),[12] dimethyl sulfoxide,[10] ONO-3144,[42] MK1-186[1] and dimethylthiourea[45] have been shown to also reduce experimental BBB breakdown and ischemic brain edema. Although these scavengers have been shown to provide some efficacy in experimental brain injury models, there is no evidence to suggest that they will be efficacious in clinical studies.

Methylpredinisolone has been demonstrated to improve outcome if given over the first eight hours after traumatic spinal cord injury.[9] Such a protective effect has not been duplicated in traumatic head injury. Superoxide dismutase, however, has been shown to improve outcome in clinical trials, although this improvement is limited and its efficacy unsubstantiated in Phase III trials.[19] Interestingly, no animal studies of SOD have been reported. The therapeutic window in humans may be completely different for free radicals than those that we have assumed from animal models.[19] Certainly, this is the case for glutamate, as the therapeutic window appears to be very different between animals and humans.[18]

Free radical production has been shown to be related, in part, to iron catalyzation of lipid peroxidation. The iron chelator, deferoxamine, has been shown to improve neurologic function following concussive brain injury with hemorrhage.[63] While hemorrhage can occur following TBI, it is not a feature of mild to moderate injury and such treatments targeting iron-dependent components of trauma may therefore have limited use in mild to moderate TBI.


A role for opioid peptides in CNS trauma was first proposed in 1981 in spinal cord injury.[21] Subsequently, in 1990, others speculated that as TBI shares many of the pathological sequelae of spinal cord injury, blocking the release of opioid peptides may reduce the secondary injury following TBI.[35] Naloxone was found to significantly reverse the hypotension and reduction in pulse pressure, improve blood gas and EEG parameters and significantly increase brain perfusion pressure following fluid percussion injury in cats and rodents.[35] Other investigators[89,90] administered opiate receptor antagonists such as nalmefene and nor-binaltorphimine to improve posttraumatic brain bioenergetic status and neurological outcome. More recently, it has been suggested that the detrimental effects of opiates, in particular activation of dynorphin and the [Alpha]-opiate receptor system, are mediated through the glutamatergic receptors, and may involve the activation of calcium cascades.[6] Other studies, however, have shown that any improvement in outcome with opiate antagonists was linked to an increase in free magnesium concentration.[89,90] How opiate antagonists provide brain protection following traumatic injury is still unclear. Recent results suggest opioid peptides influence a wide variety of cellular processes either directly or indirectly.

pH and Lactate Acidosis

Increases in lactate concentration have been reported to be associated with neuronal cell death in ischemia, and by extension, believed to also increase in brain trauma. In brain ischemia, hyperglycemia has been shown to be deleterious by exacerbating ischemic damage while hypoglycemia can reduce ischemic injury and infarct size.[76] On the basis of these findings, a lactic acid concentration of 15 mM has been proposed as a threshold level at which lactic acid accumulation exacerbates injury.[76] However, in contrast to TBI, ischemia involves energy depletion and as such the events occurring during cerebral ischemia may not necessarily extrapolate to TBI. This was demonstrated in pH profiles of brain following trauma. As opposed to the sustained and profound acidosis reported in ischemia studies,[94] only transient increases in tissue and cerebrospinal fluid (CSF) lactate have been observed during the first hour following moderate TBI.[51,55] Similar findings were reported in proton and phosphorus magnetic resonance spectroscopy studies of graded TBI where intracellular pH never declined by more than 0.3 units at either mild, moderate or severe experimental brain injury.[55,87] This concentration is well below the threshold levels that had been previously proposed as minimum accumulation required for induction of injury. Furthermore, the minimal increase in lactic acid was shown to be localized to the injured tissue.[55] Studies by Inao and colleagues[41] further supported these findings, showing posttraumatic brain lactate accumulation was only transient and correlated with modest alterations in pH. Moreover, these authors demonstrated that CSF lactate, which has been previously shown to be a useful prognostic indicator of outcome in clinical studies,[16] did not derive from brain tissue but rather from systemic contributions to the CSF following trauma. These systemic CSF contributions during trauma may explain the contradictory finding of sustained rises in posttraumatic brain lactate in whole brain spectroscopic imaging studies of trauma. Since it has been previously shown that CSF lactate increases and remains elevated following trauma, one would expect in whole brain images an increase in lactate signal from CSF would be observed. This increase would be sustained for as long as the systemic contribution to lactate production was maintained. Thus, unlike in ischemia, brain lactic acid accumulation does not appear to play a significant role in the development of tissue damage at mild to severe levels of injury, although a role in very severe trauma has not been excluded.[39,54,67] At very severe levels of injury there may be contamination of the brain and CSF by complicating factors such as blood brain barrier breakdown allowing penetration of blood products and other foreign elements.

As for the source of the brain lactate production, studies have demonstrated that TBI results in hypermetabolism in the form of increased glycolytic rate. This is consistent with what has been previously reported following ischemia.[76] It was therefore possible that, as in ischemia, blood glucose concentration could contribute to lactic acidosis after trauma. However, studies by Vink et al[86] found that increased blood glucose concentration did not cause increased lactic acid formation following moderate experimental brain injury. Similarly, hypoglycemia did not decrease any transient acidosis or confer any degree of neuroprotection after moderate brain trauma. Thus, blood glucose concentration does not seem to influence degree or duration of acidosis following moderate trauma.[86]

To summarize, TBI results in a transient hypermetabolism that rapidly exhausts endogenous supplies of glucose equivalents. Prominent researchers have proposed that this brief period of hypermetabolism may result in the production of pyruvate at levels which exceed immediate aerobic capacity of the cell, and consequently lead to lactate production.[4] However, since the traumatized brain is relying on endogenous glucose equivalents (perhaps stored glycogen), the degree and duration of acidosis would be limited by the concentration of the glucose store and lactate acid production following TBI would therefore be independent of injury severity.[86] This is consistent with previous studies demonstrating significantly different neurological outcomes with no significant differences in brain lactic acid concentration.[55]


Although the precise role and interrelationship of secondary injury factors in development of irreversible tissue injury is unclear, recent reports have suggested that many of these factors may affect magnesium metabolism.[22,84] Indeed, experimental TBI studies have found brain intracellular free magnesium levels to decrease by approximately 50% within the first two hours after injury.[37,84] Although the initial decline of intracellular free brain magnesium may be similar regardless of the injury severity, the time course of the decline may differ, with length of decline increasing with the injury severity. Similar declines in brain magnesium concentration have also been observed in migraine, alcohol intoxication and cocaine administration.[2] These direct observations of magnesium decline support previously published indirect evidence accumulated by Kwack and Veech[46] who have demonstrated a change in the relative concentration of citrate to isocitrate in a number of different tissues under a variety of pathophysiologic conditions. Because the equilibrium of this ratio is dependent on free magnesium concentration, these authors have long suggested that the intracellular free magnesium changes in accordance with physiologic state.[46]

How magnesium exerts its protective effects in each situation involves a number of different biochemical and physiological mechanisms. Primarily, magnesium has a fundamental, mandatory role in cellular metabolism which is critical to cell function. Following a single traumatic event, the magnesium ion can interact with a multitude of cellular processes which ultimately affect outcome. Some of these processes for which a direct regulatory role for magnesium has been described include energy metabolism,[85] vascular reactivity and membrane stability,[2] RNA aggregation, protein synthesis and DNA replication,[82] activity of excitatory amino acid channels[53] including NMDA channel binding,[26] glutamate release,[72] calcium influx,[13] lipid peroxidation and generation of free radicals,[91] vasospasms and rupture of blood vessels,[2] decreased cerebral blood[3] and activity of specific endogenous opioid peptides.[73]

Having established that magnesium concentration can decline following CNS injury, it would be a superfluous observation unless restoration of the magnesium concentration had a positive therapeutic affect on outcome. Such positive affects have, in fact, been described in cerebral edema, hypoxia, ischemia, stroke, seizures and TBI.[88] With respect to edema, magnesium therapy has been shown to ameliorate edema formation following both spinal cord and brain injury and improve functional outcome.[47,56] Magnesium therapy has also been shown to be protective in human stroke where there is a reduction of substrate and oxygen supply to the brain.[58] Moreover, experimental studies have demonstrated that administration of magnesium can be delayed for up to 24 hours after an ischemic event and still have a beneficial effect on outcome.[83] In traumatic brain injury, magnesium therapy can significantly attenuate posttraumatic neurologic motor deficits and memory dysfunction following experimental brain injury.[38,79,88]

Finally, rapid improvement in functional recovery with administration of magnesium salts has also been observed following seizure activity. Indeed, magnesium sulfate is one of the most commonly used agents for seizure prophylaxis, particularly in pregnancy-induced hypertension,[62] pre-eclampsia and eclamptic or NMDA-induced seizures where it is considered the drug of choice.[48,52] Furthermore, recent studies have demonstrated administration of magnesium to pre-eclamptic and preterm mothers during labor can significantly decrease the incidence of cerebral palsy, especially in the very low birth weight infants.[60] It is generally believed that early supplementation with magnesium is beneficial in these conditions because of its prominent antiepileptic[33] and endogenous cerebral vasodilatory effects mediated by opposing calcium-dependent vasoconstriction.[3] Unfortunately, different magnesium salts have been utilized for these studies, and their selection has been somewhat arbitrary as has the route of administration and the therapeutic window in which to administer each different salt. Although magnesium-based pharmacotherapies have been shown to improve neurological outcome after injury,[38] many of the details for developing effective treatment regimes are still lacking.


As there is currently no one accepted pharmacologic treatment prescribed for brain injury, health professionals must rely on their knowledge of brain injury pathophysiology including secondary injury mechanisms to provide effective care. This article has discussed the role of neurotransmitters, ion changes, lipid peroxidation, oxygen free radicals, opioids and lactic acidosis as secondary injury factors in traumatic brain injury. It is clear that development of irreversible tissue injury after brain trauma is a multifactorial process. As such, what may be necessary for optimal treatment of traumatic brain injury is single drugs that modulate multiple factors within the secondary injury cascade. It is only through the continual review and update of current research findings in secondary injury mechanisms that nurses will be able to play an active role in the management of these critical brain-injured patients.


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Questions or comments about this article may be directed to: Deanne L. Heath, PhD, RN, Associate Lecturer, Department of Physiology and Pharmacology, James Cook University, Townsville, Qld 4811, Australia. E-mail:

Robert Vink, PhD, G.Cert.Ed, is an Associate Professor, Department of Physiology and Pharmacology, James Cook University.
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Author:Heath, Deanne L.; Vink, Robert
Publication:Journal of Neuroscience Nursing
Geographic Code:1USA
Date:Apr 1, 1999
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