Physiological Determinants of RCBF and RCBV

Flow-metabolism Coupling

Increases in local neuronal activity are accompanied by increases in regional cerebral metabolic rate (rCMR). Until recently, the increases in rCBF and oxygen consumption produced during such functional activation were thought to be closely coupled to the cerebral metabolic rate of utilization of O2 (CMRO2) and glucose (CMRglu). However, it has now been clearly shown that increases in rCBF during functional activation tend to track glucose utilization but may be far in excess of the increase in oxygen consumption.19 This results in regional anaerobic glucose utilization and a consequent local decrease in oxygen extraction ratio and increase in local haemoglobin saturation. The resulting local decrease in deoxyhaemoglobin levels is used by functional MRI techniques to image the changes in rCBF produced by functional activation. Despite this revision of the proportionality between increased rCBF and CMRO2 during functional activation in the brain, the relationship between rCBF and CMRglu is still accepted to be linear.

The cellular mechanisms underlying these observations are elucidated by recent publications which have highlighted the role played by astrocytes in the regulation of cerebral metabolism.20 These data suggest that astrocytes utilize glucose glycolytically and produce lactate which is transferred to neurones, where it serves as a fuel in the citric acid cycle.21 Astrocytic glucose utilization and lactate production appear to be, in large part, coupled by the astrocytic reuptake of glutamate released at excitatory synapses (Fig. 2.3).

The regulatory changes involved in flow-metabolism coupling have a short latency ( Is) and may be mediated by either metabolic or neurogenic pathways. The former category includes the increases in perivascular K+ or adenosine concentrations that follow neuronal depolarization. The cerebral vessels are richly supplied by nerve fibres and the mediators thought to play an important part in neurogenic flow-metabolism coupling are acetylcholine22 and nitric oxide,23 although roles have also been proposed for 5-hydroxytryptamine, substance P and

Figure 2.3

Relationship of astrocytes to oxygen and energy metabolism in the brain. Glucose taken up by astrocytes undergoes glycolysis for generation of ATP to meet astrocytic energy requirements (for glutamate reuptake, predominantly). The lactate that this process generates is shuttled to neurones, which utilize it aerobically in the citric acid cycle.

Figure 2.3

Relationship of astrocytes to oxygen and energy metabolism in the brain. Glucose taken up by astrocytes undergoes glycolysis for generation of ATP to meet astrocytic energy requirements (for glutamate reuptake, predominantly). The lactate that this process generates is shuttled to neurones, which utilize it aerobically in the citric acid cycle.

neuropeptide Y. More recent publications implicate dopamineric neurones (see later). Autoregulation

Autoregulation refers to the ability of the cerebral circulation to maintain CBF at a relatively constant level in the face of changes in CPP by altering cerebrovascular resistance (CVR) (Fig. 2.4). While autoregulation is maintained irrespective of whether changes in CPP arise from alterations in MAP or ICP, autoregulation tends to be preserved at lower levels when falls in CPP are due to increases in ICP rather than decreases in MAP due to hypovolaemia.2425 One possible reason for this may be the cerebral vasoconstrictive effects of the massive levels of catecholamines secreted in haemorrhagic hypotension, since lower MAP levels are tolerated in hypotension if the fall in blood pressure is induced by sympatholytic agents26 27 or occurs in the setting of autonomic failure.28 Autoregulatory changes in CVR probably arise from myogenic reflexes in the resistance vessels but these may be modulated by activity of the sympathetic system or the presence of chronic systemic hypertension.29 Thus, sympathetic blockade or cervical sympathectomy shifts the autoregulatory curve to the left while chronic hypertension or sympathetic activation shifts it to the right. These modulatory effects may arise from angiotensinmediated mechanisms. Primate studies suggest that nitric oxide is unlikely to be important in pressure autoregulation.30

In reality, the clearcut autoregulatory thresholds seen with varying CPP in Figure 2.4A are not observed; the autregulatory 'knees' tend to be more gradual and there may be wide variations in rCBF at a given value of CPP in experimental animals and even in neurologically normal individuals.31 It has been demonstrated that symptoms of cerebral ischaemia appear when the MAP falls below 60% of an individual's lower autoregulatory threshold.32 However, generalized extrapolation from such individualized research data to the production of 'safe' lower limits of MAP for general clinical practice is hazardous for several reasons. First, there may be wide individual scatter in rCBF autoregulatory efficiency, even in normal subjects. Second, the coexistence of fixed vascular obstruction (e.g. carotid atheroma or vascular spasm) may vary the MAP level at which rCBF reaches critical levels in relevant territories. Third, the autoregulatory curve may be substantially modulated by the mechanisms used to produce hypotension. Earlier discussion made the distinction between reductions in CPP produced by haemorrhagic hypotension, intracranial hypertension and pharmacological hypotension. The effects on autoregulation may also vary with the pharmacological agent used to produce hypotension. Thus, neuronal function is better preserved at similar levels of hypotension produced by halothane, nitroprusside or isoflurane in comparison with trimetaphan.33 Finally, autoregulatory responses are not immediate: estimates of the latency for compensatory changes in rCVR range from 10 to 60 s.34

Figure 2.4

Effect of changes in CPP, PaCO2 and PaO2 on CBF. (A) Note the increase in slope of the CBF/PaCO2 curve as basal CBF increases from 20 m/100g/min (white matter) to 50-70 ml/100g/min (grey matter). (B) Note that maintenance of CBF with reductions in CPP are achieved by cerebral vasodilatation which results in reductions in cerebrovascular resistance. This leads to an increase in CBV, which has no detrimental effects in healthy subjects. However, these CBV increases may cause critical ICP increases in patients with intracranial hypertension, who operate on the steep part of the intracranial pressure-volume curve.

Figure 2.4

Effect of changes in CPP, PaCO2 and PaO2 on CBF. (A) Note the increase in slope of the CBF/PaCO2 curve as basal CBF increases from 20 m/100g/min (white matter) to 50-70 ml/100g/min (grey matter). (B) Note that maintenance of CBF with reductions in CPP are achieved by cerebral vasodilatation which results in reductions in cerebrovascular resistance. This leads to an increase in CBV, which has no detrimental effects in healthy subjects. However, these CBV increases may cause critical ICP increases in patients with intracranial hypertension, who operate on the steep part of the intracranial pressure-volume curve.

Some recent studies suggest that, especially in patients with impaired autoregulation, the cardiac output and pulsatility of large vessel flow may be more important determinants of rCBF than CPP itself.35

PaCO2

CBF is proportional to PaCO2, subject to a lower limit below which vasoconstriction results in tissue hypoxia and reflex vasodilatation and an upper limit of maximal vasodilatation (Fig. 2.4A). On average, in the middle of the physiological range, each kPa change in PaCO2 produces a change of about 15 ml/100g/min in CBF. However, the slope of the PaCO2/CBF relationship depends on the baseline nonnocapnic rCBF value, being maximal in areas where it is high (e.g. grey matter: cerebrum) and least in areas where it is low (e.g. white matter: cerebellum and spinal cord). Moderate hypocapnia (PaC02 3.5 kPa) lias long been used to reduce CBV in intracranial hypertension but this practice is under review for two reasons. The CO2 response is directly related to the change in perivascular pH; consequently, the effect of a change in PaCO2 tends to be attenuated over time (hours) as brain ECF bicarbonate levels fall to normalize interstitial pH.36 Second, it has now been shown that 'acceptable' levels of hypocapnia in head-injured patients can result in dangerously low rCBF levels.12,37 Prostaglandins may mediate the vasodilatation produced by CO238 and more recent work suggests that nitric oxide may also be involved,39 perhaps in a permissive capacity.40

PaCO2:

Grubb et al41 studied the CBF/PaCO2 response curve in primates and demonstrated that the CBF changed by approximately 1.8 ml/100g/min for each mmHg change in PaCO2. However, in the same experiment, the CBV/PaCO2 curve was much flatter (about 0.04 ml/100g/mmHg (0.3ml/100g/kPa) change in PaCO2). It follows from these figures that while a reduction in PaCO2 from 40 to 30 mmHg (5.3 to 4 kPa) would result in about a 40% reduction in CBF (from a baseline of about 50 ml/100g/min), it would only result in a 0.4% reduction in intracranial volume. This may seem trivial but in the presence of intracranial hypertension, the resultant 5 ml decrease in intracranial volume in an adult brain could result in a halving of ICP since the system operates on the steep part of the intracranial compliance curve.42

PaO2 and CaO2

Classic teaching is that CBF is unchanged until Pa02 levels fall below approximately 7 kPa but rises sharply with further reductions43

(Fig. 2.4A). However, recent TCD data from humans suggest cerebral thresholds for cerebral vasodilatation as high as 8.5 kPa ( 89-90% SaO2).44 This non-linear behaviour is because tissue oxygen delivery governs CBF and the sigmoid shape of the haemoglobin-O2 dissociation curve means that the relationship between CaO2 (arterial O2 content) and CBF is inversely linear. These vasodilator responses to hypoxaemia appear to show little adaptation with time45 but may be substantially modulated by PaCO2 levels.4647 Nitric oxide does not appear to play a role in the vasodilatory response to hypoxia.39

Figure 2.5

Relative effects of PaCO2 on CBF and CBV. Hyperventilation is aimed at reducing CBV in patients with intracranial hypertension but may be detrimental because of its effects on CBF. Note that the slope of CBF reactivity to PaC02is steeper than that for CBV

Figure 2.5

Relative effects of PaCO2 on CBF and CBV. Hyperventilation is aimed at reducing CBV in patients with intracranial hypertension but may be detrimental because of its effects on CBF. Note that the slope of CBF reactivity to PaC02is steeper than that for CBV

C 25%/kPa PaC02vs 20%/kPa PaC02respectively).

Some studies suggest that hyperoxia may produce cerebral vasoconstriction, with a 10—14% reduction on CBF with inhalation of 85— 100% O2 and a 20% reduction in CBF with 100% O2 at 3.5 atmospheres.48 Human data suggest that this effect is not clinically significant.49

Haematocrit

As in other organs, optimal O2 delivery in the brain depends on a compromise between the oxygen-carrying capacity and flow characteristics of blood; previous experimental work suggests that this may be best achieved at a haematocrit of about 40%. Some recent studies in the setting of vasospasm following subarachnoid haemorrhage have suggested that modest haemodilution to a haematocrit of 30-35% may improve neurological outcome by improving rheological characteristics and increasing rCBF. However, this may result in a reduction in O2 delivery if maximal vasodilatation is already present and since clinical results in the setting of acute ischaemia have not been uniformly successful, this approach must be viewed with caution.

Autonomic Nervous System

The autonomic nervous system mainly affects the larger cerebral vessels, up to and including the proximal parts of the anterior, middle and posterior cerebral arteries. ßj-adrenergic stimulation results in vasodilatation while a2-adrenergic stimulation vasoconstricts these vessels. The effect of systemically administered a or ß-agonists is less significant. However, significant vasoconstriction can be produced by extremely high concentrations of catecholamines (e.g. in haemorrhage) or centrally acting a2-agonists (e.g. dexmedetomidine).

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