Secondary brain injury follows after primary damage, either as a consequence of the TBI itself, or due to systemic injury or "insult". TBI can be responsible for the development of an intracranial haematoma, brain swelling, raised intracranial pressure, and ischaemia, all of which may be worsened by systemic hypoxia, hypotension, or pyrexia.
Since Douglas Miller14,15 and others showed the strong relationship between deranged physiology, which would likely reduce brain oxygen delivery, and outcome, and the autopsy evidence of near universal, widespread, ischaemic brain damage after fatal head injury, investigators have sought to determine the causal pathophysiological mechanisms involved.
Cerebral blood flow has been found to change passively with cerebral perfusion pressures (CPP) after head injuries of differing severity, suggesting that autoregulation is impaired. However, the cerebrovascular response to changes in arterial Paco2 is often preserved. One explanation of pressure passive changes is that the autoregulatory curve has been shifted to the right, so that the minimum acceptable CPP needs to be higher than normal to ensure cerebral blood flow. Jugular venous oxygen saturation data and transcranial Doppler middle cerebral artery flow velocity studies suggest this threshold is a CPP of 70 mmHg, whether due to raised ICP or reduced arterial pressure. A shift of the autoregulatory curve due to a generalised increase in cerebral vascular resistance after TBI may be due to artificial ventilation or spontaneous hyperventilation. Alternatively, the absence or overproduction of luminal and abluminal modulators, such as endothelin and nitric oxide, may contribute to an autoregulatory threshold shift.16,17
Arterial hypotension can occur immediately after trauma due to other injuries such as haemorrhage, cardiac tamponade, haemopneumothorax, myocardial or spinal cord injury. Experimental models of diffuse brain injury such as the impact acceleration model18 produce transient hypotension for minutes after severe injury. Intrinsic myocardial disease, inadequate fluid replacement after osmotic diuretics, aggressive hyperventilation, and anaesthetic drugs (such as barbiturates and proprofol) can all contribute. Sepsis may further conspire to lower the blood pressure.
Pyrexia is defined as a body temperature of greater than 37°C and is common following TBI. There has been much recent interest in the incidence, associations, pathogenesis, affect on outcome, and management. The incidence of pyrexia of greater than 38°C in the first 72 hours following TBI has been reported to be as high as 68% in closed head injury.19 Fever most commonly occurs in patients with closed head injury and intracranial haemorrhage, with the risk increasing with prolonged hospital stay (93% of patients staying longer than 14 days).20
In many patients it is difficult to determine whether an increase in temperature is a consequence of their brain injury, coexisting conditions, or their treatment. Evidence for infection was found in 74% of the febrile patients and 50% of the afebrile patients. This makes it difficult to determine whether there is a causative relationship between hyperthermia and poor outcome, or purely an association.21 Indeed, previously published TBI data showed pyrexia to be prognostically important, but limitations of the modelling process failed to highlight that pyrexia was associated with a favourable outcome.22,23
Several early studies demonstrated an association between fever and a poorer outcome following TBI. More recently there have been attempts to quantify the impact of hyperthermia on outcome. In the paediatric population early hyperthermia was found to be an independent predictor of poor outcome (OR 47) and prolonged ICU admission.
Pilot studies supported the view that hypothermia would be beneficial.24 However, a well constructed randomised controlled trial has recently disproved this promising intervention. Patients in the hypothermia group showed no benefit in functional recovery25 and required more interventions to support their systemic circulation. Treatment with hypothermia, with the body temperature reaching 33°C within eight hours after injury, is not effective in improving outcomes in patients with severe brain injury.26-28
Finally, pulmonary disorders (atelectasis, contusion, infection, or acute respiratory distress syndrome) and a reduced haemoglobin oxygen carrying capacity (anaemia) may compromise tissue oxygen delivery. Reduced oxygen delivery to regions where cerebral blood flow is already compromised may of course worsen ischaemia.
Recently, researchers have combined microdialysis, which continuously monitors the chemistry of a small focal volume of the cerebral extracellular space, and positron emission tomography (PET), which conversely establishes metabolism of the whole brain for the duration of the scan. Both techniques were applied to head-injured patients simultaneously to assess the relationship between microdialysis (measures of oxygen dependent metabolism and glutamate) and PET (oxygen delivery and consumption) parameters. Hyperventilation resulted in a significant increase in oxygen extraction, in association with a reduction in glucose, but no significant change in glutamate.29 The same researchers have reported an estimated ischaemic brain volume of up to 20% of the brain volume (DK Menon, personal communication). Therefore it is surprising that none of the microdialysis probes were able to detect changes associated with ischaemia. One reason might be that the pathology is not a simple failure of oxygen delivery, but rather a failure of oxygen utilisation.30,31
After traumatic brain injury it is hypothesised that there are a number of secondary biochemical processes that result in worsening of neurological damage. Excitotoxicity, free radicals, pro-inflammatory cytokines, and ecosanoids have all been shown in animal models, and some in human studies, to be involved in the processes that occur after traumatic injury to the brain.
The excitatory amino acids aspartate and glutamate are released in a threshold manner in response to a reduction in cerebral blood flow (CBF < 20 ml 100 g-1/min-1) and produce rapid cell death (3-5 minutes) via activation of the N-methyl D-aspartate (NMDA) receptor and associated Ca2+ ion channel. Excitotoxicity may be mediated by an increase in inducible nitric oxide synthase (iNOS) in astrocytes and microglia, NO then forming a "super-radical" after interaction with O2 free radicals.32
The use of antagonists at the NMDA receptor complex has been the subject of extensive investigation; these have failed to show a significant improvement (>10%) in the primary end point for each study. Explanations for such results include: poor study design; confounding influence of systemic secondary insults; and sensitivity of outcome measures.33 As excitatory amino acids may have a role in hyperglycolysis after TBI, interest in this potential mechanism of neuronal injury persists.
Following acute brain injury there is increased intracranial production of cytokines, with activation of inflammatory cascades. McKeating et al. have shown a transcranial 11:1 cytokine gradient in the sera of TBI patients requiring intensive care after acute brain injury.34,35
Adhesion molecules control the migration of leucocytes into tissue after injury and this process may result in still further cellular damage. After TBI altered serum concentrations of soluble intercellular adhesion molecule (sICAM)-1 and soluble L-selectin (sL-selectin) can be correlated with injury severity and neurological outcome.36-38
Despite the strong association demonstrated between these soluble adhesion molecule concentrations in serum and severity of injury and outcome, there have been no successful attempts to beneficially modify this complex process. A phase III trial is recruiting patients to receive Dexanabinol (HU-211).39 This is a cannabinoid with a diffuse range of actions, including anti-inflammatory effects. The intracranial pressure data from the phase II trial support further investigation of this compound. The treatment group (phase II)40 had significantly less intracranial pressure problems on the second and third postinjury days, suggesting that the agent may have modified oedema formation. However, the outcome data were confounded by imbalanced randomisation, resulting in more patients having motor score 2 (extension) in the placebo group. The Glasgow Coma Scale (GCS) is not linear and such patients are much less likely to improve than patients who have motor score 3 or better. Therefore, the randomisation resulted in bias that cannot be "balanced" by more GCS 7 patients.
Direct biochemical evidence for free radical damage and lipid peroxidation in human injury of the central nervous system (CNS) is hampered by methodological difficulties. However, indirect evidence suggests a key role for oxygen radicals. CNS injury results in decompartmentalisation of iron from ferritin, transferrin, and haemoglobin, and Fe2+ catalyses reactions to give free radicals.
Normal cellular function relies upon transitory activation of enzymes by Ca2+. If this Ca2+ signal is excessive, dysfunctional activation of phospholipases, non-lysomal proteases, protein kinases and phosphatases, endonucleases, and NO synthase will ensue. The activation of phospholipases releases free fatty acids which, in excess, cause increased mitochondrial membrane permeability to protons and uncouple oxidative phosphorylation. Activation of phospholipase A2 produces excess arachadonic acid (AA), inducing endothelial dysfunction and derangement of the blood-brain barrier. Moreover, the oxidation of AA by cyclo-oxygenase and lipoxygenase pathways results in excess production of eicosanoids with free radical properties and adverse effects upon the microvasculature. The resultant effect is vasoderegulation, worsening ischaemia, and microvascular thrombosis.
Indirect evidence for the role of failure of calcium homoeostasis after head injury comes from the prospective randomised controlled trials of nimodipine.41 A trend toward more favourable outcomes was noted in patients with traumatic subarachnoid haemorrhage.42,43
Experimental studies of TBI have shown that cerebral hyperglycolysis is a pathophysiological response to ionic and neurochemical cascades induced by injury.44,45 This observation has important implications regarding cellular viability, vulnerability to secondary insults, and the functional capability of affected regions. Post-traumatic hyperglycolysis has also been shown in humans. Hyperglycolysis was documented in six of the 28 patients in whom both flucrodeoxyglucose positron emission tomography (FDG-PET) and cerebral metabolic rate for oxygen (CMRO2) determinations were made within 8 days of injury. Five additional patients were found to have localised areas of hyperglycolysis adjacent to focal mass lesions.46
These clinical data support the experimental results, but unfortunately do not indicate which specific cell types are responsible. It is possible that the cells exhibiting hyperglycolysis are actually peripheral immune cells which have migrated into the brain, the observed metabolic pattern being typical of polymorphonuclear cells.
There is increasing evidence that hyperglycaemia may aggravate ischaemic injury of the CNS, including spinal cord injury. Glucose solutions should therefore not be used during the acute phase of resuscitation and blood glucose must be closely monitored (hourly); serum glucose above 11 mmolL should be treated by insulin infusion.47 Evaluation of the combined effect of hypotension and hyperglycaemia occurring in the first 24 hours after severe head injury showed that mean arterial pressure (MAP) and blood glucose are linearly related to mortality. Regression analysis shows that each has an independent effect. Moreover, the relationship between blood glucose and mortality is stronger than the relationship between MAP and mortality.48 Further studies on the combined effect of hyperglycaemia and hypotension on mortality after head injury are needed because this study suggests, but does not prove, an additive, causal association.
This protein, synthesised by reactive astrocytes, is responsible for transporting lipids to regenerating neurons, promoting repair, and construction of new cell membranes and synapses.
Experimental data have suggested that apolipoprotein E (apoE) is important in the response of the nervous system to trauma. There are three common alleles of the apoE gene, e2, e3, and e4; there is evidence of substantial variation in behaviour of these isoforms. As is now widely recognised, apoE genotype is the most important genetic determinant of susceptibility to Alzheimer's disease, and acts synergistically with a previous history of TBI. A recent study by Teasdale et al. demonstrated a significant genetic association between apoE polymorphism and outcome, supporting the notion of a genetically determined influence. In fact, patients with e4 are more than twice as likely to have an unfavourable outcome as those without.49,50
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