Agents used in anesthesia may affect CMRO₂ and CBF.

1. Inhalation anesthetics produce a dose-related reduction in CMRO₂ while causing an increase in CBF.
   1. Nitrous oxide can increase CMRO₂, CBF, and ICP. These effects are greatly attenuated or abolished when N₂O is administered in conjunction with IV anesthetic agents. Nitrous oxide should be avoided when air-filled intracranial airspaces (eg, pneumocephalus) exist because it diffuses more rapidly into these spaces than nitrogen diffuses out and may thereby produce an acute increase in ICP.
   2. Volatile agents cause increases in CBF due to their direct vasodilatory actions. Autoregulation can be attenuated or abolished by increasing the concentrations of these drugs, but cerebrovascular responsiveness to carbon dioxide is preserved (Table 23.1). The vasodilatory effect of inhalational agents is clinically insignificant in patients with normal intracranial compliance. These agents should be used with caution in patients with compromised intracranial compliance (eg, large intracranial mass lesion and acute intracranial hematoma).

      Table 23-1 Cerebral Physiologic Effects of Inhalational Anesthetics

      Nitrous Oxide Desflurane Sevoflurane Isoflurane CBF ↑ ↑↑ ↑ ↑↑ CPP ↓ ↓↓ ↓ ↓↓ ICP ↔/↑ ↔/↑ ↔/↑ ↔/↑ Metabolic demands ↑ ↓ ↓ ↓ CO2 reactivity ↔ ↔ ↔ ↔ Seizure threshold ↓ ↓ ↓ ↓

      CBF, cerebral blood flow; CPP, cerebral perfusion pressure; ICP, intracranial pressure.

   3. Volatile anesthetics produce dose-dependent reductions in metabolism (CMRO₂), probably by depressing neuronal electrical activity. Isoflurane is the most potent in this respect and is the only volatile agent that induces an isoelectric electroencephalogram (EEG) at clinically relevant concentrations (2 × minimum alveolar concentration).
2. IV anesthetics generally cause coupled reduction in CBF and CMRO₂ in a dose-dependent manner. This is due to the depression of cerebral metabolism. Barbiturates, etomidate, and propofol markedly decrease CBF and CMRO₂ and can produce isoelectric EEGs. Etomidate has been associated with seizures and is best avoided in seizure-prone patients. Lidocaine in therapeutic doses decreases both CBF and CMRO₂. Ketamine, by contrast, increases CBF and CMRO₂ and is used infrequently in neuroanesthesia. Opioids and benzodiazepines produce minimal changes in CBF and CMRO₂. Autoregulation and carbon dioxide responsiveness appear to be preserved with IV agents.
3. Muscle relaxants have no direct effect on CBF and CMRO₂ but may alter cerebral hemodynamics indirectly through their effects on blood pressure. Succinylcholine produces a transient, modest increase in ICP, likely caused by arousal phenomena, which can be attenuated by prior administration of a barbiturate or a defasciculating dose of a nondepolarizing muscle relaxant.
4. Vasoactive drugs
   1. Adrenergic agonists.α-Adrenergic agonists and low-dose β-adrenergic agonists have little influence on CBF if MAP is within the limits of autoregulation. Larger doses of β-adrenergic agonists can produce an increase in CMRO₂ and CBF that can be exaggerated in the setting of a defect in the blood-brain barrier. Dopamine causes an increase in CBF with little change in CMRO₂.
   2. Vasodilators. Sodium nitroprusside, nitroglycerin, hydralazine, nimodipine, and nicardipine can increase CBF and ICP by direct cerebral vasodilation if MAP is maintained. β-Adrenergic–blocking agents probably have minimal effects. Despite these profiles, all these agents have been used safely during neuroanesthesia, particularly if CPP is maintained.
5. Cerebral protection
   1. Focal versus global cerebral ischemia
      1. Focal ischemia is characterized by an area of densely ischemic tissue that is surrounded by nonischemic brain, which may provide collateral flow to the penumbral margins. This residual blood flow may allow neurons to survive for varied periods of time (eg, thrombolysis within 3 hours after stroke onset may prevent a full infarct due to reperfusion).
      2. Complete global ischemia is characterized by absent CBF (eg, cardiac arrest). Tolerance for surviving global ischemia is on the order of minutes. Therapeutic hypothermia (see section on hypothermia, below) after cardiac arrest may improve survival and decrease neural dysfunction.
   2. Agents
      1. IV anesthetic agents: High-dose barbiturates may slightly improve neurologic recovery from focal ischemia, possibly by decreasing metabolic rate or more likely by a direct pharmacologic effect. Propofol may also reduce focal ischemic cerebral injury, although it is not as extensively studied as barbiturates. Etomidate aggravates ischemic brain injury. Early clinical reports suggest that prophylactic low-dose lidocaine may have neuroprotective effects in nondiabetic patients.
      2. Volatile anesthetic agents may provide some cerebral protection, but data are conflicting, and it is unclear whether this neuroprotection is sustained.
      3. The 1,4-dihydropyridine calcium channel blocker nimodipine has beneficial effects on cerebral vasospasm after subarachnoid hemorrhage (SAH). These effects are well established and are likely mediated through neuronal rather than vascular effects. Clinical trials failed to detect a beneficial effect for patients with acute stroke.
      4. Steroids have not been found to be beneficial after stroke or severe head injury. Their effects on recovery after traumatic spinal cord injury are also controversial.
      5. Magnesium confers significant neuroprotection in animal studies. However, a large clinical trial did not show protection in acute stroke victims.
      6. Hypothermia reduces metabolism for both neuronal and cellular functions and therefore may be beneficial in the setting of decreased cerebral perfusion. Induced mild hypothermia (maintaining core temperature between 34 °C and 36 °C for 12-24 hours) has been shown to be effective in reducing morbidity in patients who sustain cardiac arrest. By contrast, two clinical studies did not demonstrate improved outcome when induced mild hypothermia was used in patients after significant head injury or intraoperatively for aneurysm surgery.
      7. Hyperthermia profoundly worsens outcome from focal cerebral ischemia and should be avoided.
      8. Moderate hyperglycemia (>170 mg/dL) exacerbates neurologic injury after an ischemic insult. There are human data suggesting that normalizing blood glucose causes higher incidence of good outcome in patients with stroke.
      9. Other physiologic variables: In addition to the abovementioned variables of temperature and glucose, meticulous management of perfusion pressure, PCO₂, PO₂, pH normalization, and seizure prophylaxis contributes significantly to improved neurologic outcome in the setting of cerebral ischemia. Maintenance of a high-normal CPP can augment collateral CBF. By contrast, hypotension reduces CBF and exacerbates the injury. Normocapnia should be maintained. Seizures, which can increase CBF and ICP and decrease CPP, should be prevented and rapidly treated.
   3. There is preliminary evidence that female sex hormones may confer some neuroprotection after traumatic brain injury or spinal cord injury.