Oxford Meeting - November 2002

Intravenous Anaesthetics and Cerebral Protection

Dr Mike Higgins, Senior Lecturer in Anaesthesia, Department of Cardio-thoracic Surgery, Glasgow Royal Infirmary

Central nervous tissue is exquisitely sensitive to hypoxic or ischaemic damage. Over the last three decades or so an increasingly detailed knowledge of the cellular mechanisms underlying this susceptibility has emerged. Processes have been discovered with time courses lasting from tens of seconds to days and weeks. Important mechanisms include the effects of energy deprivation on ionic gradients across neuronal cell membrane, glutamate toxicity,

uncontrolled increases in intracellular calcium, changes in hydrogen ion concentration, free radical generation, nitric oxide toxicity, inflammatory activation and apoptosis. This new knowledge has lead to the real possibility of pharmacological intervention, both to mitigate the ongoing effects of insults that have already occurred and as prophylaxis to extend the tolerance of the CNS to prospective ischaemia. However, despite encouraging successes in tissue and animal models there has been a general inability to translate this success into robust clinical effects. The reasons for this are many and have been much discussed. One of several factors is the specificity of many effects to the models in which they are demonstrated. Thus, for instance, tissue preparations can not take into account effects on the haemodynamics of cerebral perfusion, Similarly, animal models of focal ischaemia, where there is a volume of brain with partially preserved perfusion, may behave quite differently to models of global ischaemia.

The picture with regard to intravenous anaesthetic agents is not different from the picture regarding pharmacological neuroprotectants generally. There are good theoretical reasons why a number of agents should be neuroprotective. There is a growing body of animal and in vitro work showing that potentially useful neuroprotection or relevant neuroprotective mechanisms can be demonstrated. Convincing clinical evidence however remains elusive. Thiopentone has shown neuroprotective ability, mainly in models of focal ischaemia. Thiopentone depresses cerebral metabolism in a concentration-dependent manner until the point ofEEG suppression. Higher concentrations of thiopentone then produce no further metabolic depression. Thiopentone thus decreases cerebral metabolism as a result of its inhibitory action on neuronal activity (action potentials) but has no effect on the basal metabolic rate of quiescent neuronal tissue. This was elegantly demonstrated in a classic paper by Michenfelder in 1974[1] On the assumption that metabolic depression was main mechanism for the neuroprotective effect of thiopentone, this lead to the clinical practice of titrating thiopentone to 'burst suppression' (near electrical silence) of the EEG. More recent animal studies have suggested that maximal neuroprotection is obtained at much lower concentrations of thiopentone which still permit EEG activity. This suggests that other neuroprotective effects must be operating other than metabolic suppression. More recent animal studies, performed in the knowledge of the confounding effects of hypothermia, tend to show thiopentone causing lesser (though still potentially useful) degrees of maximum neuroprotection than the studies of the 70s and early 80s. There is little evidence that thiopentone provides useful neuroprotection against global ischaemia. 

One randomised trial in humans shows a neuroprotective effect of thiopentone titrated to burst suppression in patients undergoing heart valve surgery under cardiopulmonary bypass [2.] A similar study in coronary artery surgery patients did not demonstrate a protective effect.[3] Temporary occlusion of the carotid artery for endarerectomy is probably the closest clinical situation to the animal models in which neuroprotective efficacy for thiopentone has been demonstrated. Despite this, no randomised controlled clinical trials seem to have been carried out in this area.

There is interest, theoretical rationale and experimental evidence for neuroprotective effects of the 'newer' intravenous agents such as etomidate, ketamine and particularly propofol. Studies showing clinical evidence are lacking. One fairly recent, careful study of propofol, titrated to burst suppression, in patients undergoing heart valve surgery involving cardiopulmonary bypass failed to demonstrate any protective effect.[4]

References

1. Michenfilder JD. The interdependency of cerebral functional and metabolic effects following massive doses of thiopental in the dog. Anesthesiology 1974; 41:232-236

2. Nussmeier NA, Arlund C, Slogoff S. Neuropsychiatric complications after cardiopulmonary bypass: cerebral protection by a barbiturate Anesthesiology 1986; 64:165-170.

3. Zaidan JR, Klochany A, Martin W. Effect of thiopental on neurologic outcome following coronary artery bypass grafting. Anesthesiology 1991; 74: 406-414.