Evolución de la teoría de cadena de suministros globales

The results of these simulations demonstrated that (within the simulations at least) the relative temperature differences between different tissue segments, as well as the absolute temperature reduction achieved in each tissue segment were dependent on the

combination of CBF and CMR. Conversely, the rate of cooling was independent of these factors and was driven instead by the rate of blood cooling. Predictably, the higher the rate of CBF and the lower the rate of CMR in a given segment of tissue, the greater the depth of

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cooling that was achieved in that tissue. It is noteworthy that the temperature of the penumbral tissue was reduced to below 34°C (which is considered a therapeutic level of hypothermia) in all simulations, regardless of CBF or CMR.

The effects of CBF and CMR were interdependent. In the scenarios where CMR was universally elevated (Figure 5.2.3), the temperature of the ischaemic tissue varied by as much as 0.5°C within each tissue segment as a result of variations in CBF. Conversely, when CMR was universally reduced (Figure 5.2.2) the temperature of each tissue segment did not vary by more than 0.1°C between simulations of different CBF levels. Similarly, the temperature difference between healthy and ischaemic tissue did not exceed 0.2°C when CMR was universally reduced.

The level of CBF in adjacent healthy tissue (including tissue experiencing oligaemia) did affect the final temperature of the penumbra, but the magnitude of this temperature difference was no more than 0.1°C in the infarct, and even less in the penumbra (compare the results from CBF set 2 to those from CBF set 3 in Figures 5.2.1-5.2.3). The level of CBF in the infarct, on the other hand, did contribute to significant temperature heterogeneity across the penumbra, particularly when the CMR in the infarct was not zero. This suggests that the precise anatomy of the ischaemic region (the relative size and position of the infarct and penumbra, for example) could have a significant effect on the level of cooling achieved in the penumbra, especially if the infarct were still metabolically active.

5.2.4.2 Interpretation of results with respect to potential failings of the conceptual model

It is highly likely that the results of these simulations underestimate the temperature differences between different tissue segments, just as the simulations of uncooled stroke were found to (See Chapter 5.1). These simulations indicate that any level of CBF that is sufficient to prevent immediate cell death (i.e. infarct core) will also be sufficient to cool the tissue to a therapeutic level. This, unfortunately, is unlikely to translate to clinical practice due to the discrepancy between the simulations and in vivo data mentioned above. It is, nonetheless, interesting to note that the absolute level of CBF in the penumbra is not itself a factor that would prevent effective cooling.

The finding that reduced CMR not only reduced overall brain temperature but also

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model does appear to accurately simulate the direction of temperature gradients found in the brain, if not their magnitude. Drugs that reduce CMR, such as barbiturates have previously been shown to reduce brain temperature [44] and it is possible that they would help minimise temperature differences across the stroke-affected brain. The investigation of this possibility would be a worthwhile project for the future.

In these simulations the rate of temperature change in the blood was found to be the primary factor affecting the rate of temperature change in the brain. What limited

experimental data are available suggest that this is the case in non-ischaemic brain [90] but it is not yet known whether this applies to ischaemic tissue. From the results in Chapter 5.1 it appears that there are factors besides the CBF, CMR and arterial blood temperature affecting the equilibrium temperature of ischaemic brain tissue. Whatever these factors are, it is possible that they will affect both the rate of cooling, and the magnitude of temperature change that can be achieved in ischaemic tissue.

5.2.5 Conclusions

Models such as the one developed in this thesis can provide useful insight into the processes they simulate even if the simulations themselves do not completely match reality. This model obviously requires further development before it can be used to guide treatment for individual patients, but the trends identified in this chapter still have clinical significance. The absolute rate of CBF found in the penumbra is not in itself a factor that will prevent effective cooling of the penumbra. Further research is still required to identify what factors will limit cooling of the penumbra, and these are likely to include the details of the path the blood takes through the arterioles and microvasculature in the ischaemic tissue, as described in Chapter 5.1.4. This research can be guided in part by the finding that absolute CBF rate is unlikely to be important. The utility of reducing CMR by

pharmacological means is also worth investigating. In particular, the possibility that a reduction in overall CMR could help minimise the temperature difference between ischaemic and healthy tissue deserves further research. The geometry of the ischaemic region, in particular the relative size and CBF/CMR rates of the infarct, penumbra and oligaemia may have an effect on the temperature profile of the ischaemic region. Therefore, due to the complexity of the geometry of any real brain (and the ischaemic region inside it), some form of automation for the creation of a geometric model from

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patient scans (in particular from CT-perfusion scans[20]) would be extremely helpful if the model is ever developed to the point where it can be applied to modelling individual patients and guiding their treatment. The software required for this automation could be developed while the heat transfer model itself is improved.

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Part VI:

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