Factors affecting cerebral blood flow

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CHAPTER 42

Factors affecting cerebral blood flow

Kirstin M. Erickson, MD

Cerebral metabolic rate (CMR), autoregulation, CO₂ reactivity, and O₂ reactivity are the main factors affecting cerebral blood flow (CBF). The relationships among the latter three are depicted in Figure 42-1. Temperature and anesthetic medications also each influence CBF.

Figure 42-1 The relationship between cerebral blood flow (CBF) and mean arterial pressure (MAP) shows autoregulation of CBF across the range of MAP from 65 to 150 mm Hg. The relationship between PaCO₂ and CBF is linear. The PaO₂ also influences CBF at extreme values.

The cerebral metabolic rate

The brain consumes O₂ at a high rate. Although accounting for only about 2% of total body weight, the brain receives 12% to 15% of cardiac output. Normal CBF is approximately 50 mL·100 g⁻¹·min⁻¹. Normal CMR for O₂ (CMRO₂) is 3.0 to 3.5 mL·100 g⁻¹·min⁻¹. Increases in regional brain activity lead to local increases in CMR that, in turn, lead to proportional changes in CBF. This relationship is carefully maintained and is called flow-metabolism coupling.

Mechanisms involved are, as yet, undefined but appear to include local byproducts of metabolism (potassium, H⁺, lactate, adenosine triphosphate), glutamate, and nitric oxide. Peptides (vasoactive peptide, substance P, and others) exert effects on the nerves that innervate cerebral vessels. Neurogenic control of CBF occurs by sympathetic innervation and is independent of the influence of PaCO₂.

The CMR decreases during sleep, increases with increasing mental activity, and may reach an extremely high level with epileptic activity. The CMR is globally reduced in coma and may be only locally impaired after brain injury.

Autoregulation is defined as the maintenance of CBF over a range of mean arterial pressure (MAP) (see Figure 42-1). Cerebral vascular resistance (CVR) is adjusted to maintain constant CBF. Cerebral perfusion pressure equals MAP minus intracranial pressure (ICP). Because ICP (and therefore cerebral perfusion pressure) is not commonly available, MAP is used as a surrogate of cerebral perfusion pressure.

Autoregulation occurs when MAP is between 70 and 150 mm Hg in the normal brain (see Figure 42-1). This is a conservative estimate, given that considerable interindividual variation occurs. The lower limit of autoregulation (LLA) is the point at which the autoregulation curve deflects downward and CBF begins to decrease in proportion to MAP.

CVR varies directly with blood pressure to maintain flow, taking 1 to 2 min for flow to adjust after an abrupt change in blood pressure. In hypertensive patients, the autoregulatory curve is shifted to the right (Figure 42-2). A hypertensive patient may be at risk for developing brain ischemia at a MAP of 70 mm Hg, for example, because the LLA will be higher than in a nonhypertensive patient. Several weeks of blood pressure control may return the curve to normal. Following significant hypotension (lower than the LLA), autoregulation is impaired, and hyperemia may occur when MAP returns to the normal range. CO₂ reactivity remains intact, and inducing hypocapnia may attenuate hyperemia.

Figure 42-2 The relationship between cerebral perfusion pressure (CPP) and mean arterial pressure (MAP) shows autoregulation of CPP across a range of MAP. The curve is shifted to the right in patients with chronic hypertension. (From Erickson KM, Cole DJ. Arterial hypotension and hypertension. In: Brambrink A, Kirsch JR, eds. Neuroanesthesia and Critical Care Handbook. New York: Springer Publishing; 2010.)

Autoregulatory vasodilation may be limited by background sympathetic vascular tone. Systemic vasodilators (nitroprusside, nitroglycerin, hydralazine, adenosine, and calcium channel blockers) may extend the lower limit of tolerable hypotension (shift the LLA to a lower pressure). Other than their effect on global cerebral perfusion pressure, β-adrenergic receptor blocking agents likely have no adverse effects on patients with intracranial pathology.

Autoregulation is impaired in areas of relative ischemia, surrounding mass lesions, after grand mal seizures, after head injury, and during episodes of hypercarbia or hypoxemia. Figure 42-3 shows how lost autoregulation may lead to dangerously low CBF. Regional or global ischemia may ensue.

Figure 42-3 A representation of the effect of increasing the concentration of a inhalation anesthetic agent on autoregulation of cerebral blood flow. Dose-dependent cerebral vasodilation leads to attenuation of autoregulation, and both upper and lower thresholds are shifted to the left. MAP, Mean arterial pressure. (From Patel PM, Drummond J. Cerebral physiology and the effects of anesthetic drugs. In: Miller RD, ed. Miller’s Anesthesia. 7th ed. Vol. 2. Philadelphia: Elsevier; 2009:309.)

CO₂ reactivity

PaCO₂ levels profoundly affect CBF by changing the H⁺ concentration in the extracellular fluid surrounding smooth muscle in arteriolar cell walls. CBF varies directly with PaCO₂ (see Figure 42-1). The effect is greatest in the normal physiologic range of PaCO₂. CBF changes 1 to 2 mL·100 g⁻¹·min⁻¹ for each 1-mm Hg change in PaCO₂. As PaCO₂ increases from 30 to 60 mm Hg, for example, CBF doubles. Below a PaCO₂ level of 25, the response is attenuated.

Mild hypocapnia (PaCO₂ 30-34 mm Hg) in patients with large space-occupying lesions (“tight heads”) undergoing craniotomy is used only selectively to facilitate surgical access. At a PaCO₂ of 20 mm Hg, cerebral ischemia may occur because of a left shift in the oxyhemoglobin dissociation curve and decreases in CBF. With a PaCO₂ below 20 mm Hg to 25 mm Hg, O₂ consumption decreases, and anaerobic metabolism ensues.

Changes in cerebral blood volume (CBV) due to PaCO₂ occur in cerebral arterial vasculature. Hypercarbia has the greatest effect on vessels that are smaller than 100 μm in diameter.

The mechanism of CO₂ vasoactivity is thought to be secondary to changes in local H⁺ in arteriolar walls on the brain side of the blood-brain barrier (BBB). Respiratory acidosis, not metabolic acidosis, leads to vasodilation because HCO₃⁻ does not initially cross the BBB but CO₂ does. The lowered pH of the periarteriolar cerebrospinal fluid causes vasodilation in 20 to 30 sec. The pH of the cerebrospinal fluid normalizes with active changes in HCO₃⁻ concentration, and CBF returns to normal in 6 to 8 h. CO₂ responsiveness in gray matter is greater than that in white matter owing to increased vascular density. Pathologic states, including trauma, tumor, or ischemia, decrease CO₂ responsiveness.

A “Robin Hood effect” may exist in which areas of focal ischemia (where CO₂ reactivity is likely lost) receive increased flow if normal vasculature is exposed to hypocapnia; however, this effect is unpredictable. Normocapnia should be maintained when regional ischemia is a risk. Following a period of hypocapnia, an abrupt return to normocapnia may cause acidosis in the cerebrospinal fluid and rebound in CBF and ICP. Cerebral ischemia is a risk if intracranial elastance is poor.

O₂ reactivity

PaO₂ has little direct effect on CBF at values between 60 mm Hg and more than 300 mm Hg. A PaO₂ level below 60 mm Hg markedly increases CBF if blood pressure is maintained (see Figure 42-1). This effect is not well understood. A variety of chemoreceptors and local humeral effects may be involved. At PaO₂ levels above normal, up to 1 atm (760 mm Hg), only a very slight decrease in CBF has been measured.

Hypothermia

Hypothermia (between 28° C and 37° C) acutely reduces, but does not uncouple, CMRO₂ and CBF. CO₂ reactivity is also maintained during hypothermia. The effects of hypothermia on CMRO₂ are discussed in Chapter 131, Cerebral Protection.

Effects of anesthetic drugs

In general, anesthetic agents, except for ketamine and N₂O, depress CMR.

Intravenously administered anesthetic agents

Intravenously administered anesthetic agents typically cause parallel declines in CMRO₂ and CBF, with preservation of PaCO₂ responsiveness. Ketamine, however, increases both CBF and CMRO₂.

Propofol decreases CMRO₂ by approximately 50% and subsequently decreases CBF, CBV, and ICP. Autoregulation is preserved, even at propofol doses sufficient to produce burst suppression on the electroencephalogram.

Thiopental decreases CMRO₂ and CBF in a dose-dependent manner, up to 50% at induction of isoelectric electroencephalographic tracings. No further reduction in CMRO₂ results when additional thiopental is given after electroencephalographic suppression. This response suggests that thiopental and other depressant anesthetic agents reduce the component of cerebral metabolism associated with electrical brain activity, rather than with homeostasis. Autoregulation is preserved.

The effects of etomidate on CMRO₂ and CBF are similar to those of barbiturates. However, exacerbation of ischemic injury has been demonstrated, and on this basis, the use of etomidate is avoided. The effects of etomidate on autoregulation have not been studied. Etomidate is epileptogenic in patients with seizure disorders but not in patients without seizure disorders.

Benzodiazepines decrease CMRO₂ and CBF in a dose-dependent manner. Positron emission tomographic studies have shown selective decreases in brain regions associated with attention, arousal, and memory in patients treated with benzodiazepines.

Fentanyl modestly reduces CMRO₂ and CBF, although data on this topic are very limited. Sufentanil causes either a modest reduction in these parameters or no change. Alfentanil causes no change in CMRO₂ or CBF in dogs. Sedative doses of remifentanil can increase CBF slightly; large doses suppress CBF. High-dose fentanyl and sufentanil cause epileptiform activity, but smaller clinical doses are unlikely to precipitate seizures. Modest doses of alfentanil provoke seizures in patients with epilepsy. This property of alfentanil is occasionally used in the operating room to assist the surgeon in locating an epileptogenic focus for resection under general anesthesia.

Morphine depresses CMRO₂ and CBF by a small to moderate degree. Histamine release can cause cerebral vasodilation, and CBF and CBV will be dependent on MAP.

Dexmedetomidine reduces CBF and CMRO₂ in parallel. Reduction in MAP reduces the margin of safety in patients dependent on collateral perfusion pressure.

Mannitol causes a transient increase in CBV, which returns to normal after approximately 10 min.

Inhaled anesthetic agents

Inhaled anesthetic agents reduce CMRO₂ (see Chapter 67, Central Nervous System Effects of the Inhalation Agents). Decreases in CMRO₂ are dose dependent and nonlinear below 1 minimum alveolar concentration (MAC) of the agent; a precipitous drop is followed by a more gradual, linear decline as MAC is increased. Maximal reduction occurs with electroencephalographic suppression. Differences among the CMRO₂ effects of isoflurane, desflurane, and sevoflurane are minor.

Autoregulation is impaired by volatile anesthetic agents in a dose-dependent manner (see Figure 42-3). Sevoflurane impairs autoregulation less than does isoflurane or desflurane, which do so less than halothane. (This pattern follows the vasodilatory potency of each gas.)

Inhalation anesthetic agents are direct cerebral vasodilators. The correlation between CBF and CBV is not direct. With vasodilation induced by a inhalation agent, CBV increases, whereas CBF may be unchanged or reduced. Increased CBV may result in significant increases in ICP.

CO₂ responsiveness is preserved with the use of inhalation anesthetic agents. Hypocapnia attenuates the increased ICP caused by halothane when hypocapnia is instituted before the use of halothane, whereas the ICP effects of isoflurane and desflurane can be attenuated with simultaneous use of hypocapnia in patients with normal intracranial elastance. Hypocapnia may not effectively block a inhalation gas–induced increase in ICP in patients with intracranial tumors because impairments of normal brain physiology disable both PaCO₂ responsiveness and autoregulation.

When administered alone, N₂O increases CMRO₂, CBF, and ICP. These effects are moderated or obliterated when N₂O is used in combination with intravenously administered drugs. The addition of N₂O to a inhalation anesthetic agent causes a moderate increase in CBF.