The cerebral circulation (Applied clinical physiology and pharmacology) Part 3

Pharmacological modulation of cerebral blood flow

Hie importance of understanding drug effects on cere-brovascular physiology cannot be stressed enough. Drugs can exert changes in CBF, CMR and CPP, and therefore on CBV and ICP (Fig. 2.7). hese effects may either be desirable (e.g. reducing intracranial volume (ICV) and ICP) or undesirable (e.g. increasing ICV and ICP thereby predisposing to brain herniation in patients with intracranial hypertension). In addition to causing changes in CPP, CBF, CMRO2 , CBV and ICP and altering production or reabsorption of CSF, pharmacological agents may modulate autoregulation, the flow-metabolism coupling and vascular responses to changes in PaCO2 and PaO2 .

Halogenated volatile anaesthetic agents

Effects on cerebral blood flow, cerebral perfusion pressure, intracranial pressure and cerebral metabolic rate of oxygen All potent fluorinated volatile anaesthetic agents affect CBF and CMR non-linearly and have been shown to increase CBF and ICP and reduce CMRO2 (Fig. 2.8). he initial enthusiasm of halothane as a neuroanaes-thetic agent was halted by the discovery of its potent vasodilatory effects, reducing CVR by 20-40% in nor-mocapnic individuals at 1.2-1.5 minimum alveolar concentration (MAC). In another study, 1% halothane was shown to result in clinically significant elevations in ICP in patients with intracranial space-occupying lesions.

Studies with enflurane and isoflurane suggest that these agents might produce smaller increases in CVR at equivalent doses. As enflurane may produce epi-leptogenic activity, its use in the context of neuroan-aesthesia has decreased. Several studies compared the effects of isoflurane and halothane on CBF, with conflicting results. While some studies showed that halo-thane produced larger decreases in CVR, others found no difference. Examination of the patterns of rCBF produced by these two agents provides some clues to the origin of this discrepancy. Halothane selectively increases cortical rCBF while markedly decreasing subcortical rCBF, while isoflurane produces a more generalized reduction in rCBF. Comparisons of the CBF effects of the two agents suggests that estimated CBF using techniques that preferentially looked at the cortex (e.g. 133Xe wash-out) tended to show that halo-thane was a more potent vasodilator, while most studies that have used more global measures of hemispheric CBF (e.g. the Kety-Schmidt technique) have found little difference between the two agents at levels of around 1 MAC (Fig. 2.9).


 Effect of drugs used in anaesthetic practice and hypocapnia on cerebral metabolic rate (CMR) and cerebral blood flow (CBF). Note that hyperventilation and the resulting hypocapnia can lead to vasoconstriction (decreased CBF) and an increase in CMR, a particularly unfavourable situation. Note also that increasing the inhalational anaesthetic agent concentration (minimum alveolar concentration, MAC) does not decrease CMR below a lower limit. However, it does increase CBF, thereby increasing CBV and intracranial pressure. This is hazardous for patients with poor intracranial compliance.

Fig. 2.7. Effect of drugs used in anaesthetic practice and hypocapnia on cerebral metabolic rate (CMR) and cerebral blood flow (CBF). Note that hyperventilation and the resulting hypocapnia can lead to vasoconstriction (decreased CBF) and an increase in CMR, a particularly unfavourable situation. Note also that increasing the inhalational anaesthetic agent concentration (minimum alveolar concentration, MAC) does not decrease CMR below a lower limit. However, it does increase CBF, thereby increasing CBV and intracranial pressure. This is hazardous for patients with poor intracranial compliance.

Effects of fluorinated volatile anaesthetic agents on cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO2).

Fig. 2.8. Effects of fluorinated volatile anaesthetic agents on cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO2).

Both agents tend to reduce global CMR, but the regional pattern of such an effect may vary, with is oflurane producing greater cortical metabolic suppression (reflected by its ability to produce EEG burst suppression at higher doses). B oth the rCBF and rCMR effects of the two anaesthetics are markedly modified by baseline physiology and other pharmacological agents. hus, CBF increases produced by both agents are attenuated by hypocapnia (more so with isoflurane), and thiopentone attenuates the relative preservation of cortical rCBF seen with halothane. It is difficult to predict accurately what the effect of either agent would be on CBF in a given clinical situation, but this would be a balance of its suppressant effects on rCMR (with autoregulatory vasoconstriction) and its direct vasodilator effect (which is partially mediated via both endothelial and neuronal nitric oxide.

Although initial reports suggested that halothane could ‘uncouple’ flow and metabolism, more recent studies have clearly shown that, at concentrations commonly used for neuroanaesthesia, neither halo-thane, isoflurane nor desflurane completely disrupts flow-metabolism coupling, although their vasodilator effects may alter the slope of this relationship, due to changes in the fl ow/metabolism ratio with increases in anaesthetic concentration. hus, although increases in metabolism are matched by increases in flow at all levels of anaesthesia, fl ow is higher at higher volatile anaesthetic concentrations at the same level of metabolism. In practice, the metabolic suppressant effects of the anaesthetics are more prominent at lower concentrations and when no other metabolic suppressants are used. Conversely, these vasodilator effects may become more prominent at higher concentrations or when the volatile agents are introduced on a baseline of low or suppressed cerebral metabolism (such as that produced by intravenous anaesthesia).

Comparison of mean cerebral blood flow (CBF) in animals anaesthetized with 0.5-1.5 minimum alveolar concentration (MAC) of isoflurane or halothane, either in the same study or in comparable studies from a single research group with identical methodology within a single publication. In studies shown on the left, CBF was estimated using techniques likely to be biased towards cortical flow (e.g. 133Xe wash-out), showing that halothane produces greater increases in CBF. In the studies on the right, CBF was estimated using techniques that measured global cerebral blood flow (e.g. the Kety-Schmidt method); the difference in effects on CBF between the two agents is much less prominent.

Fig. 2.9. Comparison of mean cerebral blood flow (CBF) in animals anaesthetized with 0.5-1.5 minimum alveolar concentration (MAC) of isoflurane or halothane, either in the same study or in comparable studies from a single research group with identical methodology within a single publication. In studies shown on the left, CBF was estimated using techniques likely to be biased towards cortical flow (e.g. 133Xe wash-out), showing that halothane produces greater increases in CBF. In the studies on the right, CBF was estimated using techniques that measured global cerebral blood flow (e.g. the Kety-Schmidt method); the difference in effects on CBF between the two agents is much less prominent.

While initial studies suggested that desflurane and sevoflurane had effects on the cerebral vasculature that appeared very similar to those of isoflurane, more recent studies have shown distinct differences between these agents. While high-dose desflurane, like isoflurane, can produce EEG burst suppression, this effect may be attenuated over time. It is not known whether this adaptation represents a pharmacokinetic or phar-macodynamic effect. Initial clinical reports suggest that desflurane may cause a clinically significant rise in ICP in patients with supratentorial lesions, despite its proven ability to reduce CMRO2 as documented by EEG burst suppression. hese increases in ICP, which are presumably related to cerebral vasodilation, appear to be independent of changes in systemic haemodynam-ics. In humans, sevoflurane produces some increase in TCD flow velocities at high doses (>1.5 MAC), but these appear to be less marked than desflurane, and were reported to be unassociated with increases in ICP in patients with supratentorial space-occupying lesions. In other studies, 1.5 MAC sevoflurane caused no increase in middle cerebral artery flow velocities and did not affect carbon dioxide reactivity or pressure autoregulation. his may be partially explained by sevoflurane’s weak direct vasodilator effect, especially in humans.

Effect on cerebrospinal fluid production

Most anaesthetic agents either increase the secretion or reduce the reabsorption of CSF. Halothane, up to a 0.5 MAC, reduces CSF production in haemodynam-ically stable animals, mediated by vasopressin-related mechanisms. Enflurane increases the production of CSF and provides increased resistance to the reuptake of CSF, partially explaining increases in ICP following its use. Isoflurane, on the other hand, reduces CSF production and enhances reabsorption.

Non-halogenated inhaled anaesthetic agents

Nitrous oxide

In equi-MAC doses, nitrous oxide (N2O) is probably a more powerful vasodilator than either halothane or isoflurane. N2O has been shown to produce cerebral stimulation with increases in CMRO2 , glucose utilization and a coupled increase in CBF. Furthermore, the vasodilation produced by N2O is not decreased by hypocapnia, although the resulting increases in ICP can be attenuated by the administration of other CMR depressants such as the barbiturates. he increase in ICP reduces CPP and hence can compromise cerebral oxygen delivery, while the neural excitation increases oxygen demand, a combination that is particularly unfavourable in patients with raised ICP.

Xenon

Xenon has been used as an anaesthetic agent since 1950. However, its use was abandoned due to cost. Neverthless, since 1990, there has been renewed interest in its use. Xenon may offer a number of advantages for neuroanaesthesia, including rapid induction and emergence due to its low blood gas coefficient, possible neuroprotective effects (demonstrated in animal studies with focal ischaemia), probably via N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolole propionate (AMPA) antagonism. In healthy volunteers, xenon anaesthesia induces a uniform reduction in rCMRglu and a reduction in rCBF, but with an increase in rCBF/rCMRglu ratio, particularly in the insula, anterior and posterior cingulate, and in the somatosensory cortex.

Intravenous anaesthetics

Thiopentone, etomidate and propofol all reduce global CMR to a minimum of approximately 50% of baseline, with a coupled reduction in CBF. Reductions in CBV have been demonstrated with barbiturates, and probably occur with propofol and etomidate as well. Maximal reductions in CMR are reflected in an isoelectric EEG, although burst suppression is associated with only slightly less CMR depression. Initial doubts that CBF reductions produced by propofol were secondary to falls in MAP have proved to be unfounded. Even high doses of thiopentone or propofol do not appear to affect autoregulation, carbon dioxide responsiveness or flow-metabolism coupling.

Opiates

Although high doses (3 mg kg-1) of morphine and moderate doses of fentanyl (15 |xg kg-1) have little effect on CBF and CMR, high doses of fentanyl (50-100 |xg kg-1) and sufentanil depress CMR and CBF. Results with alfentanil, in doses of 0.32 mg kg-1, show no reduction in rCBF. hese effects are variable and may be prominent only in the presence of N2O, where CMR may be reduced by 40% from baseline. Bolus administration of large doses of fentanyl or alfentanil may be associated with increases in ICP in patients with intracranial hypertension, probably due to reflex increases in CBF that follow an initial decrease in CBF (due to reductions in MAP and cardiac output produced by large bolus doses of these agents). hese effects are unlikely to be clinically significant if detrimental haemodynamic and blood gas changes can be avoided. Opioids do not appear to affect autoregulation.

Other drugs

Ketamine can increase global CBF and ICP, with specific increases in rCMR and rCBF in limbic structures, which may be partially attenuated by hypocapnia, ben-zodiazepenes or halothane. he ICP and CBF increases produced by ketamine are also attenuated by other general anaesthetic agents. Sedative doses of benzodi-azepines tend to produce small decreases in CMR and CBF; however, there is a ceiling effect, and increasing doses do not produce greater reductions in these variables. a2-Agonists such as dexmedetomidine reduce CBF in humans. here are good data, in animal models at least, that CBF reductions produced by intraven-tricular dexmedetomidine are probably due to direct vascular effects and are not exclusively the consequence of either systemic hypotension or coupled falls in rCBF arising from reductions in neuronal metabolism.

Most non-depolarizing neuromuscular blockers have little effect on CBF or CMR, although large doses of D-tubocurarine may increase CBV and ICP secondary to histamine release and vasodilation. In contrast, succinylcholine can produce increases in ICP, probably secondary to increases in CBF mediated via muscle spindle activation. However, these effects are transient and mild, and can be blocked by prior precurarization if necessary; they provide no basis for avoiding suc-cinylcholine in patients with raised ICP when its rapid onset of action is desirable for clinical reasons.

Cerebral blood flow in disease

Ischaemia

Graded reductions in CBF are associated with specific electrophysiological and metabolic consequences, all of which are triggered at specific levels of CBF (Table 2.1). Some of these thresholds for metabolic events are well recognized, but others, such as the development of acidosis, cessation of protein synthesis and the failure of osmotic regulation, have only recently received attention. Ischaemia is thus a continuum between normal cellular function and cell death; cell death, however, is not merely a function of the severity of ischaemia but is also dependent on its duration and several other circumstances that modify its effects. hus, the effects of ischaemia may be ameliorated by the CMR depression produced by hypothermia or drugs, and exacerbated by increased metabolic demand associated with excitatory neurotransmitter release or compounded by other mechanisms of secondary injury (such as cellular calcium overload or reperfusion injury).

Table 2.1 Electrophysiological and metabolic consequences of graded reductions in cerebral blood flow (CBF).

CBF (ml (100 g)-1 min-1)

Electrophysiological/metabolic consequence

tmpA2-26

Normal neuronal function

tmpA2-27

Immediate-early gene activation

tmpA2-28

Cessation of protein synthesis

tmpA2-29

Cellular acidosis

20-23

Reduction in electrical activity

12-18

Cessation of electrical activity

8-10

ATP rundown, loss of ionic homeostasis

<8

Cell death (also depends on other modifiers: duration, cerebral metabolic rate, etc.)

 

Relationship of cerebral blood flow (CBF) to the presence of ischaemia under conditions of varying metabolism. Changes in CBF levels compared with physiological levels may be misleading, as a diagnosis of ischaemia or hyperaemia demands that CBF levels be assessed in the context of metabolic requirements. MET, cerebral oxygen metabolism.

Fig. 2.10. Relationship of cerebral blood flow (CBF) to the presence of ischaemia under conditions of varying metabolism. Changes in CBF levels compared with physiological levels may be misleading, as a diagnosis of ischaemia or hyperaemia demands that CBF levels be assessed in the context of metabolic requirements. MET, cerebral oxygen metabolism.

It is important to recognize that reductions in CBF do not always equate to ischaemia – a diagnosis of ischaemia depends on showing that CBF is inadequate to meet oxygen demands, and any given level of CBF needs to be interpreted in the light of metabolic requirements. For example, reductions in CBF associated with coupled reductions in CMROt (e.g. following intravenous barbiturates) represent appropriate hypoperfusion. Indeed, in this setting, if CBF is increased (e.g. by hypercapnia), even if absolute levels of CBF are lower than normal, this represents hyperaemia. Conversely, increases in CBF that do not meet increased metabolic demand (e.g. with seizures in the context of intracranial hypertension) can be interpreted as hyperperfusion but in reality represent ischaemia.

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