Vasoactive Drugs (also see Chapter 16 )

A large number of drugs with intrinsic vascular effects are used in contemporary anesthetic practice, including both anesthetics and numerous vasoactive drugs used specifically for hemodynamic manipulation. This section will deal with the latter. The actions of anesthetics are discussed in a later section.

Systemic Vasodilators

Most drugs used to induce hypotension (including sodium nitroprusside, nitroglycerin, hydralazine, adenosine, and calcium channel blockers) also cause cerebral vasodilation. As a result, CBF either increases or is maintained at prehypotensive levels. In addition, CBF is maintained at a lower MAP when hypotension is induced with a cerebral vasodilator rather than either hemorrhage or a noncerebral vasodilator such as the ganglionic blocker trimethaphan.^[95] In contrast to direct vasodilators, the angiotensin-converting enzyme inhibitor enalapril does not have any significant impact on CBF.^[96] Anesthetics that vasodilate the cerebral circulation simultaneously cause increases in cerebral blood volume (CBV) with the potential to increase ICP. The ICP effects of these drugs are empirically less dramatic when hypotension is induced slowly, ^[97] probably because of the more effective interplay of compensatory mechanisms (CSF and venous blood shifts) when changes occur more slowly.

Catecholamine Agonists/Antagonists

Numerous drugs with agonist and antagonist activity at catecholamine receptors (α₁ , α₂ , β, and dopamine) are in common use. The effects of these drugs on cerebral physiology are dependent on basal blood pressure, the magnitude of the systemic blood pressure changes that occur as a result of administration of the drug of interest, the status of the autoregulation mechanism, and the status of the BBB. A given drug may have direct effects on cerebral vascular smooth muscle or indirect effects, or both, that are mediated by the cerebral autoregulatory response to changes in systemic blood pressure. When autoregulation is preserved, increases in systemic pressure would be expected to increase CBF if basal blood pressure is either below or above the lower and upper limits of autoregulation, respectively. When basal pressure is within the normal autoregulation range, an increase in systemic pressure does not affect CBF significantly because the normal autoregulatory response to rising MAP entails cerebral vasoconstriction (an increase in cerebral vascular resistance) to maintain constant CBF. When autoregulation is defective, CBF will vary in direct relation to systemic pressure. The information in the following sections and in Table 21-3 emphasizes data obtained from investigations of pressor agents in intact preparations and gives greatest weight to results obtained in humans and higher primates.

α₁ -Agonists

A frequently encountered clinical concern is that the administration of drugs with α₁ -agonist effects (phenylephrine, norepinephrine) will lead to a reduction in CBF. Data derived from studies in both humans and nonhuman primates do not support this belief. Intracarotid infusion of norepinephrine in doses that raised MAP from 95 to 117 mm Hg and intravenous infusion that raised MAP from 95 to 142 mm Hg resulted in no change in CBF.^[98] Intracarotid infusion of norepinephrine in baboons in a dose sufficient to increase MAP by 10% had no effect on CBF.^[99] Administration of phenylephrine to patients maintained on cardiopulmonary bypass did not decrease CBF.^[100] There are, however, some species differences with regard to the CBF response to α-agonists. α₁ -Agonists also do not appear to cause cerebral vasoconstriction in rats,^{[101] [102] [103] [104]} but they do produce modest decreases in CBF in dogs and goats; this reduction in CBF can be blocked by α₁ -antagonists.^{[105] [106] [107] [108]}

CBF increases have been attributed to norepinephrine. Such increases might occur if autoregulation were defective

819

In summary, it seems likely that circulating α₁ -agonists will have little direct influence on CBF in humans, with the exception that norepinephrine may cause vasodilation when the BBB is defective.

β-Agonists

β-Adrenergic receptor agonists, in small doses, have little direct effect on the cerebral vasculature. In larger doses and in association with physiologic stress, they can cause an increase in CMR with an accompanying increase in CBF.^[111] The β₁ -receptor is probably the mediator of these effects.^[112] Olesen ^[98] observed no change in CBF in unanesthetized human volunteers in response to an intracarotid infusion of approximately 6 µg/min of epinephrine, a dose that caused no change in MAP. However, when King and colleagues ^[113] administered a larger dose of epinephrine, 37 µg/min intravenously (a dose sufficient to increase MAP from 91 to 109 mm Hg), CBF and CMRO₂ rose by 22% and 24%, respectively.

Evidence has shown that a BBB defect enhances the effect of β-agonists. ^{[99] [110] [114]} Intracarotid norepinephrine does not have an effect on CBF and CMR in normal baboons. However, when the BBB is disrupted by intracarotid injection of hypertonic urea, norepinephrine increased CBF and CMR.^[99] Artru and associates demonstrated that epinephrine causes an elevation in CMRO₂ in dogs, but only when the BBB was made permeable.^[110] Note that in neither of these studies were CBF/CMR changes observed without a BBB abnormality. These observations beg the interpretation that β-agonists will increase CBF and CMR only when the BBB is injured. However, in the human study of King and coworkers (mentioned earlier), MAP was apparently not excessively high and CBF/CMR increases nonetheless occurred. Accordingly, it does not appear that BBB injury is a necessary condition in humans for the occurrence of β-mediated increases in CBF and CMR, although it will probably exaggerate the phenomenon.

β-Adrenergic Blockers

β-Blockers reduce or have no effect on CBF and CMR. In two investigations in humans, propranolol, 5 mg intravenously,^[115] and labetalol, 0.75 mg/kg intravenously,^[116] had no effect on CBF and CBF volume (CBFV), respectively. Dubois and associates observed modest reductions in CBF when labetalol was administered to craniotomy patients who became hypertensive during emergence from anesthesia.^[117] Esmolol shortens seizures induced by electroconvulsive therapy (ECT), thus suggesting that it does cross the normal BBB.^[118] Esmolol was reported in abstract form to have no effect on CBF and CMR as long as CPP was maintained.^[119] Catecholamine levels at the time of administration of β-adrenergic blockers or the status of the BBB (or both) may influence the effect of these drugs. The database with respect to these possibilities is incomplete. However, data suggest that β-blockers are unlikely to have adverse effects on patients with intracranial pathology, other than effects secondary to changes in perfusion pressure.

Dopamine

Dopamine is widely used in the treatment of hemodynamic dysfunction. In addition, it is commonly used to augment the function of the normal cardiovascular system when elevation of MAP is desired as an adjunct to the treatment of focal cerebral ischemia, especially in the setting of vasospasm. Nonetheless, its effects on CBF and CMR have not been defined with certainty. Taken together, the available data ^{[103] [106] [120] [121] [122] [123]} suggest that the predominant effect of dopamine in the normal cerebral

820

α₂ -Agonists

Interest in α₂ -agonists is currently high because of their apparent analgesic and sedative effects. This class includes dexmedetomidine and clonidine, with the latter being a much less specific and less potent α₂ -agonist. A number of investigations have demonstrated that dexmedetomidine decreases CBF with no effect on CMRO₂ .^{[125] [126] [127] [128] [129]} Dexmedetomidine-induced constriction of isolated cerebral vessels^[130] and reversal of this effect with the simultaneous administration of an α₂ -antagonist suggest that vasoconstriction is mediated by postsynaptic α₂ -receptors. ^[131] In addition, α₂ -agonists may act at a central site, such as the locus ceruleus,^[70] and cause neurogenically mediated vasoconstriction.

Two investigations in human volunteers have confirmed the ability of dexmedetomidine to decrease CBF. Dexmedetomidine dose-dependently decreased middle cerebral artery (MCA) flow velocity, with the maximum reduction being approximately 25%.^[132] In a more recent investigation, dexmedetomidine (1-µg/kg load and infusion at either 0.2 or 0.6 µg/kg/hr) decreased CBF by about 30%.^[133] Although dexmedetomidine reduced MAP modestly, the reduction was not outside the normal limits of autoregulation. Of interest was the observation that the reduction in CBF was apparent even after the dexmedetomidine infusion had been discontinued for 30 minutes. The dose of dexmedetomidine that was administered resulted in significant sedation. Although it is possible that the reduction in CBF was associated with a reduction in CMR, the experimental studies cited earlier argue otherwise. These data provide reasonable evidence for the notion that dexmedetomidine is a cerebral vasoconstrictor. Accordingly, caution should be exercised in its use in patients in whom CBF is compromised.