Neurological Emergencies - part 2 pptx

disruption of autoregulation of blood flow. Penetrating injury may be clinically silent, or produce focal neurological deficit, due either to the haematoma or to the underlying neuronal injury. Focal contusions occur both ipsilateral and contralateral to a fracture, as for example bifrontal contusions complicating an occipital fracture. As with subdural haematoma, delayed deterioration may occur in a patient with a brain contusion or intraparenchymal haematoma days after the injury. NEUROLOGICAL EMERGENCIES 38 Figure 2.1 (b) Patients with an acute subdural haematoma are seen after high speed road traffic accidents, falls, or assaults. They are commonly associated with other parenchymal injuries, which may affect outcome as much as the haematoma itself. The haematoma often occurs over the temporal pole either from tearing of bridging veins, or from laceration of the brain and disruption of surface arteries. The common combination of temporal lobe laceration and contusion with an associated subdural haematoma is known as “burst temporal lobe” Brain swelling and raised intracranial pressure Intracranial pressure increases as a consequence of a rapidly developing intracranial mass lesion, hypoxia, hypercarbia, during an epileptic seizure, and in acute hydrocephalus. Brain oedema is defined as an increase in brain volume due to increase in brain water content. Klatzo defined it as “vasogenic” 8 because of disruption of the blood–brain barrier and escape of water and plasma into the extracellular compartment, in contrast to “cytotoxic oedema” in which a noxious factor produces intracellular swelling without increased vascular permeability. 9,10 The oedema around a TRAUMATIC BRAIN INJURY 39 Figure 2.1 (c) Intraparenchymal haematomas occur from disruption of vascular elements. This may be focal from a penetrating injury, or diffuse from rotational acceleration, producing widespread haemorrhage and axonal disruption. Penetrating injury may be clinically silent, or produce focal neurological deficit, due either to the haematoma or the underlying neuronal injury. Focal contusions occur both ipsilateral and contralateral to a fracture, for example, bifrontal contusions complicating an occipital fracture contusion or haematoma was initially thought to be vasogenic; protein rich fluid leaking into the extracellular space, increasing the water and sodium in the brain to produce “mass effect”. Marmarou, however, has shown that most of the water in areas of brain contusion is in fact intracellular and represents “cellular” oedema, caused by ischaemia. 11 This in turn produces astrocytic swelling and increased release of excitatory amino acids and a consequent failure of membrane ion pumps and cellular ionic homoeostasis. This is recognisable radiographically as an increase in the signal on T2 weighted MRI and as radiolucent areas on CT. Alternatively, brain injury may lead to cerebrovascular congestion and an excess cerebral blood volume, resulting in cerebral hyperaemia, that is, an absolute or relative increase in the cerebral blood flow in relation to cerebral metabolic demand. The consequence of raised intracranial pressure is the development of pressure gradients across the midline, between supratentorial and infratentorial compartments, and between the cranial and spinal compartments across the foramen magnum. In 1965 Langfitt showed how raised supratentorial pressure produces a rise in infratentorial pressure which subsequently plateaus and falls as the cisterna ambiens becomes blocked by tentorial herniation. The brain is shifted away from the region of higher pressure, so midline structures are pushed laterally, causing the cingulate gyrus to herniate under the fixed free edge of the falx. This distorts the pericallosal arteries, and may occlude the foramen of Munro. The cerebrospinal fluid (CSF) drainage of the contralateral ventricle is obstructed, so the ventricle dilates; the ipsilateral ventricle may become compressed, giving characteristic features suggesting raised intracranial pressure (ICP) on cross- sectional imaging. Further increases in ICP produce tentorial herniation, with a temporal or parietal lesion compression of the ipsilateral oculomotor nerve and midbrain. Further distortion leads to posterior cerebral artery compression. Bilateral or frontal lesions produce posterior herniation, compressing the tectal plate, resulting in failure of upward gaze and bilateral pupillary abnormalities. Infratentorial masses or further herniation of a supratentorial mass results in herniation through the foramen magnum. As the medulla and NEUROLOGICAL EMERGENCIES 40 cerebellar tonsils are pushed inferiorly, distortion of the vasomotor and respiratory centres leads to circulatory collapse and respiratory arrest. Pathophysiology Mechanisms of primary brain injury after trauma The primary injury, which can be correlated with prolonged coma and impaired motor response, was recognised by Strich in 1961 as a diffuse degeneration of the subcortical matter, subsequently termed diffuse axonal injury (DAI). Experimental work with primates confirms this to be a consequence of inertial loading of the head, with prolonged coronal angular acceleration. Microscopic pathological findings consist of small haemorrhages in the corpus callosum, septum pellucidum, deep grey matter of the cerebral hemisphere, and dorsilateral quadrant of midbrain and pons. Disrupted and swollen axons with globular ends known as “retraction balls of Cajal” are observed at an early stage. After a few weeks clusters of neuroglia form around the severed axons and wallerian degeneration of fibre tracts occurs. 12 Clinically, diffuse axonal injury is thought to be responsible for a broad spectrum of injury from mild concussion in which no structural lesion can be demonstrated and complete clinical recovery ensues, to prolonged coma and death in instances of much greater angular acceleration. The events leading to axonal disruption have recently been examined. Povlishock and others have shown that this is a process requiring several hours to complete and may be reversible before frank axonal disruption occurs, at least in some axons. 13 It should of course be stressed that not all primary injury is diffuse. Focal contusions and lacerations are seen, especially after falls and blows to the head, often involving the inferior (orbital) surface of the frontal lobes and the anterior poles of the temporal lobes. Brain oedema around contusions may lead to late clinical deterioration as a result of mass effect and brain shift. TRAUMATIC BRAIN INJURY 41 Mechanisms of secondary brain injury after trauma 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. Ischaemia Since Douglas Miller 14,15 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 perfusion pressure 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 Pa CO 2 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 Arterial hypotension can occur immediately after trauma due to other injuries such as haemorrhage, cardiac NEUROLOGICAL EMERGENCIES 42 tamponade, haemopneumothorax, myocardial or spinal cord injury. Experimental models of diffuse brain injury such as the impact acceleration model 18 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 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 4·7) 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 TRAUMATIC BRAIN INJURY 43 intervention. Patients in the hypothermia group showed no benefit in functional recovery 25 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 Hypoxia 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. NEUROLOGICAL EMERGENCIES 44 Excitotoxicity 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 Ca 2+ 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 O 2 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. Inflammation 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 TRAUMATIC BRAIN INJURY 45 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. Free radicals 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 Fe 2+ catalyses reactions to give free radicals. Eicosanoids Normal cellular function relies upon transitory activation of enzymes by Ca 2+ . If this Ca 2+ 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 A 2 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 NEUROLOGICAL EMERGENCIES 46 [...]... Care Med 1999 ;25 : 128 2–6 18 Beaumont A, Marmarou A, Czigner A, et al The impact-acceleration model of head injury: injury severity predicts motor and cognitive performance after trauma Neurol Res 1999 ;21 :7 42 54 19 Albrecht RF 2nd, Wass CT, Lanier WL Occurrence of potentially detrimental temperature alterations in hospitalized patients at risk for brain injury Mayo Clin Proc 1998;73: 629 –35 20 Kilpatrick... Neurosurgery 20 00;47:850–6 21 Cairns CJ Andrews PJ Management of hyperthermia in traumatic brain injury Curr Opin Crit Care 20 02; 8:106–10 22 McQuatt A, Sleeman D, Andrews PJ, Corruble V, Jones PA Discussing anomalous situations using decision trees: a head injury case study Methods Information Med 20 01;40:373–9 23 Jones PA, Andrews PJ, Midgley S, et al Measuring the burden of secondary insults in head-injured... Metab 20 02; 22: 735–45 30 Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP Impaired cerebral mitochondrial function after traumatic brain injury in humans J Neurosurg 20 00;93:815 20 63 NEUROLOGICAL EMERGENCIES 31 Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type... References 1 2 3 4 5 6 7 8 9 62 Marshall LF Epidemiology and cost of central nervous system injury Clin Neurosurg 20 00;46:105– 12 Stiell IG, Lesiuk H, Wells GA, et al Canadian CT head rule study for patients with minor head injury: methodology for phase II (validation and economic analysis) Ann Emerg Med 20 01;38:317 22 Luukinen H, Herala M, Koski K, Kivela SL, Honkanen R Rapid increase of fall-related severe... Database Systemat Rev 20 00;CD001048 [update in Cochrane Database Syst Rev 20 02; (1):CD001048;11869586] 27 Signorini DF, Alderson P Therapeutic hypothermia for head injury Cochrane Database Systemat Rev 20 00;CD001048 28 Clifton GL, Miller ER, Choi SC, Levin HS Fluid thresholds and outcome from severe brain injury Crit Care Med 20 02; 30:739–45 29 Hutchinson PJ, Gupta AK, Fryer TF, et al Correlation between cerebral... neurological intervention. 52 The high-risk factors were 100% sensitive (95% CI 92 100%) for predicting need for neurological intervention, and would require only 32% of patients to undergo CT The medium-risk factors were 98·4% sensitive (95% CI 96–99%) and 49·6% specific for predicting clinically important brain injury, and would require only 54% of patients to undergo CT *Data from Stiell et al. 52. .. pressure J Neurotrauma 20 00;17: 507–11 61 Choi SC, Clifton GL, Marmarou A, Miller ER Misclassification and treatment effect on primary outcome measures in clinical trials of severe neurotrauma J Neurotrauma 20 02; 19:17 22 62 Dickinson K, Bunn F, Wentz R, Edwards P, Roberts I Size and quality of randomised controlled trials in head injury: review of published studies Br Med J 20 00; 320 :1308–11 63 Roberts... insults to the injured brain JAMA 1978 ;24 0:439– 42 16 Mascia L, Andrews PJ, McKeating EG, Souter MJ, Merrick MV, Piper IR Cerebral blood flow and metabolism in severe brain injury: the role of pressure autoregulation during cerebral perfusion pressure management Intensive Care Med 20 00 ;26 :20 2–5 17 Mascia L, Piper IR, Andrews PJ, Souter MJ, Webb DJ The role of endothelin-1 in pressure autoregulation of cerebral... TRAUMATIC BRAIN INJURY Table 2. 2 (a) Risk of an operable intracranial haematoma in braininjured patients GCS Risk Other features Risk 15 1 in 3615 None Post-traumatic amnesia (PTA) Skull fracture Skull fracture and PTA No fracture Skull fracture No fracture Skull fracture 1 in 31 300 1 in 6700 9–14 1 in 51 3–8 1 in 7 1 1 1 1 1 1 in in in in in in 81 29 180 5 27 4 Table 2. 2(b) Canadian CT head rule –... able to identify N-acetyl aspartate abnormalities in regions remote from any T2 visible lesions This observation suggests that spectroscopic imaging (of N-acetyl aspartate in particular) will be useful for the diagnosis of diffuse axonal injury It may be possible to use this technique to guide therapy, monitor recovery, and aid outcome prediction Cerebral protection Considerable effort 72 has gone towards . and 1% required neurological intervention. 52 The high-risk factors were 100% sensitive (95% CI 92 100%) for predicting need for neurological intervention, and would require only 32% of patients. PTA 1 in 29 9–14 1 in 51 No fracture 1 in 180 Skull fracture 1 in 5 3–8 1 in 7 No fracture 1 in 27 Skull fracture 1 in 4 Table 2. 2(b) Canadian CT head rule – minor head Injury* Five high-risk factors: 1 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