Identificación de los problemas en la toma de decisiones para el manejo de

Clearly, the ability to monitor brain metabolism in vivo by NMR spectroscopy has potential therapeutic implications. The threshold area, when ischaemic changes first appear in the NMR spectra, is o f particular interest because there is more potential for recovery from this range of flows than from the range associated with severe ischaemia. Therefore it is valuable to be able to manipulate the blood flow as is possible with the carotid snare system.

Other workers have also used snares as an alternative to clips (Gyulai et al> 1987; Hope et al, 1987), where the snare is either closed or open. The advantages of the gerbil system are that the snares are not only adjustable for a range of partial occlusion, but more importantly that they are used in conjunction with a feedback system to monitor the changes in blood flow. This permits the CBF to be held in the critical threshold region. Also, CBF and NMR measurements can be made within seconds o f the remote control manipulation.

I---1--- 1---1--- 1---1--- 1--- 1 15 10 5 0 - 5 - 1 0 - 1 5 - 2 0

ppm

Figure 5.15

Hypothermia and ischaemia

This shows two 31P spectra from the same animal. In (A) the animal was kept at 37°C during bilateral ischaemia, and has a CBF of 13 ml 100 g'1 min*1, with decreased PCr and ATP and increased Pj. In (B) the gerbil was cooled to 31°C without releasing the snares, and the spectra showed a degree of recovery. Flow was essentially unchanged at 12 ml 100 g'1 min1.

Many authors have reported an abrupt change in energy metabolism when CBF is reduced (Astrup et al, 1977; Branston et al, 1977). In earlier studies by this group a sudden change in metabolic state when flow is reduced below 20 ml lOOg'1 min*1 has also been demonstrated (Crockard et al, 1987). Strong et al (1983), however, have suggested that this change may be more gradual, reflecting the different metabolic requirements of different cells.

A limitation of the earlier technique using clips was that the flow during occlusion was dependent on the cerebral anatomy of the gerbil, and it was impossible to predict prior to occlusion what the post-occlusive CBF would be. Using the more sophisticated approach described above, it can now be confirmed that large metabolic changes occur at flow values of 20 ml 100 g'1 m in1 and below, and that above 30 ml 100 g'1 min'1 the metabolic state remains normal. The outcome of cerebral ischaemia is dependent both on the decrease in CBF and its duration, and there are well-established thresholds of CBF for electrical and ionic pump failure. The earliest threshold is that for electrical failure, which in a variety of species has been shown to occur at CBF’s of 18-20 ml 100 g'1 min'1 (Heiss et al, 1976). This is clearly the threshold detected when there is a marked deterioration in metabolic state at flows of 20 ml 100 g'1 min'1 and below, suggesting that the threshold for electrical function is directly dependent on an adequate energy status.

In the region between 20 and 30 ml 100 g*1 min'1 43 % of the animals (6/14) show a relatively small increase in the ratio of ^/(PCr+Pj) above control. According to the creatine kinase reaction, free ADP will also increase. This may indicate that some cells (presumably neurones) are already undergoing energy failure. An alternative explanation is that these small increases in P* and ADP are not a reflection of energy failure, but represent a control mechanism to stimulate glycolytic and oxidative metabolism when CBF is approaching limiting values. This threshold region of 20 to 30 ml 100 g'1 m in1 is a more realistic target against which to evaluate various therapies, rather than the more severely ischaemic region, where cells may be damaged beyond repair. Using this model, the effects of, for example, a cerebral protective agent could be assessed, using the animal as its own control. This has

much to commend it instead of the batch-testing techniques currently employed.

With this in mind, a known physiological mechanism, hypothermia, was used in a preliminary study to alter cerebral metabolism. The decline in energy status at reduced flow values was less severe when the core temperature was reduced to 30 ±

1°C than under normothermic conditions. The protective effects of cooling, well known clinically, are clearly demonstrated in Figure 5.15, in which the temperature reduction resulted in recovery of high energy phosphates. Preliminary conclusions suggest that this moderate hypothermia "protects” the brain at blood flow levels in the region o f 12-25 ml 100 g'1 min1. This is in the area of recoverable ischaemia and reversible ischaemic oedema formation (Iannotti et al, 1983; Crockard et al, 1980).

It is generally held that hypothermia protects the brain from ischaemic damage by decreasing the cerebral metabolic rate. However, there are other possibilities, for example Welsh et al (1990), have suggested that it decreases the release of neurotransmitters such as glutamate which have potentially adverse effects on post-synaptic neuronal elements. Probably, hypothermia is protective because o f its effect on a number of parameters.

This gerbil model provides an effective approach for evaluating the effect of therapy on the brain in stroke. Its value lies in the ability to control individual animals’ CBF accurately during a period of observation, and the model is preferable to the on-off occlusion method which results in an unpredictable and variable degree of ischaemia. The preliminary study suggests that further, more detailed investigations into the effects o f hypothermia and/or drug therapy will be of value.

5.5 Summary

A remote control method has been developed for adjusting the CBF while measuring energy metabolism using NMR spectroscopy. Small changes in energy metabolism were seen at flows between 20 and 30 ml 100 g 1 min*1, with a marked deterioration of energy metabolism at flows below 20 ml 100 g'1 min'1. Hypothermia has been examined in a preliminary study, and has been shown to exert a protective effect.

CHAPTER 6

STUDIES OF ENERGY METABOLISM AND CEREBRAL BLOOD FLOW