Other therapies

The mechanism of the remarkable effect of glucocorticoids such as dexamethasone on focal, relatively chronic, cerebral lesions remains incompletely understood. Patients deteriorating with a cerebral tumour or an abscess rapidly improve within 24 hours of administration of dexamethasone. Much controversy has surrounded the use of very high dose steroids in head injury, but carefully controlled trials have shown no benefit and in one study the outcome of the treatment group was worse.152-156 Currently the use of steroids in head-injured patients is not recommended.68 A megatrial (CRASH) of methylprednisolone in head injury has recently started in the Uk.157 One purported mechanism of action for steroids involves inhibition of lipid peroxidation and generation of free radicals.157,158 Up to 2% of oxygen consumed by the brain is used to form semireduced oxygen intermediates: superoxide, hydrogen peroxide, and hydroxyl free radicals. These may be used as part of normal biochemistry or if the safety mechanisms fail then such reactive oxygen species may attack nucleic acids, proteins, carbohydrates, and particularly lipids in the brain. Ferrous iron from blood clots is also active along with such reactive oxygen species. Cerebrovascular effects of acute hypertension and subarachnoid haemorrhage may involve free radical mechanisms damaging the endothelium. Non-glucocorticoid steroid analogues of methylprednisolone as well as methylprednisolone itself weakly inhibit lipid peroxidation. Tirilazad, a 21-amino-steroid, is a potent inhibitor of lipid peroxidation and has a vitamin E sparing effect.159 Various experimental models of head and spinal injury and focal or global ischaemia have shown a variable degree of protection after treatment with Tirilazad or related compounds.160 However, large scale clinical trials in head injury,161 stroke,162 and subarachnoid haemorrhage have failed to show efficacy.163,164

Indometacin is a potent cerebral vasoconstrictor and reduces ICP effectively. In five patients with injury with cerebral contusion and oedema, in whom it was not possible to control ICP by hyperventilation and barbiturate sedation, indometacin (bolus injection of 30 mg, followed by 30 mg/h for seven hours) reduced ICP below 20 mmHg for several hours.165 Cerebral blood flow was reduced at two hours without any changes in cerebral arteriovenous oxygen or lactate differences. Rectal temperature also fell from 386 to 373°C. However, because of the intense vasoconstriction, and evidence from primates, there is serious concern about the possibility that indometacin will cause ischaemia. Certainly, cerebral oxygen delivery is seriously impaired when indometacin is given to very early preterm infants undergoing treatment for patent ductus arteriosus.166 At present indometacin can only be considered an experimental treatment in head-injured patients.

It is interesting that the iron chelator desferrioxamine may be helpful in treating the coma of cerebral malaria and experimental vasogenic oedema. Results in severe head injuries with the oxygen radical scavenger polyethylene glycol conjugated superoxide dismutase have recently been reported, but a much larger trial is required to establish efficacy.167 Impressive experimental data have led to phase III trials of glutamate receptor antagonists in patients after severe head injury, but the results have been negative.168,169 Finally, intravenous lidocaine (lignocaine) (15 mg/kg) may have a place in lowering ICP.170 This dose is as effective as 3 mg/kg of intravenous thiopentone.

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