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| Intravenous Drugs | Inhalational Drugs | Muscle Relaxants |


Effect on cerebral blood flow (CBF) and cerebral oxygen consumption (Table-1). Barbiturates were the first anesthetics to be examined for their cerebral vascular effects. Thiopental decreases CBF and cerebral metabolic rate for oxygen consumption (CMRo2) in a parallel fashion up to the point of isoelectricity on the electroencephalogram (EEG). The changes in CBF are thought to be secondary to the changes in CMRo2 (a coupled decrease in flow and metabolism). The component of CMRo2 that is affected is related to electrical brain function; there is minimal effect on the component of CMRo2 associated with cellular homeostasis. At the point at which an isoelectric EEG occurs after the administration of thiopental, an approximately 50% decrease in CMRo2 occurs with no cerebral metabolic evidence of toxicity. If barbiturates are used clinically for the purpose of cerebral protection, the endpoint of EEG burst suppression is often used to provide near-maximal metabolic suppression. The reduction in mean arterial pressure (MAP) associated with the high doses of thiopental needed to provide EEG burst suppression may require concomitant use of a vasopressor to maintain cerebral perfusion pressure (CPP), the difference between MAP and ICP. Methohexital differs from other barbiturates in regard to epileptiform activity in that it may induce seizures in patients who have epilepsy and thus increase CMRo2 and CBF.
Table-1. Effects of anesthetic agents on cerebral blood flow, cerebral metabolic rate for oxygen consumption, and intracranial pressure
Anesthetic CBF CMRo2 ICP
Thiopental Decrease Decrease Decrease
Etomidate Decrease Decrease Decrease
Propofol Decrease Decrease Decrease
Fentanyl 0/Decrease 0/Decrease 0/Decrease
Alfentanil 0/Decrease/increase 0/Decrease 0/Decrease/increase
Sufentanil 0/Decrease/increase 0/Decrease 0/Decrease/increase
Ketamine Increase 0/Increase Increase
Midazolam Decrease Decrease 0/Decrease
Nitrous oxide Increase 0/Increase Increase
Isoflurane Increase Decrease Increase
Desflurane Increase Decrease Increase
Sevoflurane Increase Decrease Increase
CBF: cerebral blood flow; CMRo2: cerebral metabolic rate for oxygen consumption; ICP: intracranial pressure.

Effect on autoregulation and CO2 reactivity. Thiopental, even in high doses, does not appear to abolish cerebral autoregulation or CO2 reactivity.
Effect on CSF dynamics (Table-2). Low doses of thiopental cause no change in the rate of CSF formation (Vf) and either no change or an increase in the resistance to reabsorption of CSF (Ra). This would predict no change or an increase in ICP. High doses of thiopental cause a decrease in Vf and either no change or a decrease in Ra with a predicted decrease in ICP.
Effect on ICP. As a result of the reduction in both CBF and cerebral blood volume (CBV), barbiturates lower ICP. Barbiturates are used clinically for this purpose and may even be effective when other methods for reducing ICP have failed.
Effect on spinal cord blood flow (SCBF) and metabolism. Barbiturates produce a significant reduction in SCBF. Autoregulation of SCBF remains intact under barbiturate anesthesia (as demonstrated with thiopental) with an autoregulatory range of approximately 60 to 120 mm Hg. Pentobarbital has been shown to decrease local utilization of glucose in the spinal cord, although the magnitude of this effect is smaller than that seen in the brain.

Table-2. Effects of intravenous drugs on rate of cerebrospinal fluid formation, resistance to reabsorption of cerebrospinal fluid, and the predicted effect on intracranial pressure
Intravenous drug Vf Ra Predicted ICP effect
Low dose 0 +, 0* +, 0*
High dose - 0, -* -
Low dose 0 0 0
High dose - 0, -* -
Propofol 0 0 0
Ketamine 0 + +
Low dose 0 +, 0* +, 0*
High dose - 0, +* -, ?*
Vf, rate of CSF formation; Ra, resistance to CSF reabsorption; ICP, intracranial pressure; 0, no change; +, increase; -, decrease; *, effect dependent on dose; ?, uncertain.

Effect on CBF and CMRo2. Etomidate, like the barbiturates, reduces CBF and CMRo2. An isoelectric EEG can be induced with etomidate, and, as with thiopental, there is no evidence of cerebral toxicity as reflected by normal brain metabolites. In addition, no further reduction in CMRo2 occurs when additional doses are given after EEG burst suppression is achieved. Myoclonus produced by the drug has the disadvantage of being misinterpreted as seizure activity in neurosurgical patients. Prolonged use of etomidate may suppress the adrenocortical response to stress. However, this may not be an issue in patients who have intracranial tumors because they are already receiving steroids frequently. Less cardiovascular depression with etomidate as compared to thiopental makes this drug advantageous for the induction of anesthesia in trauma patients and older neurosurgical patients who have multiple medical problems.
Effect on autoregulation and CO2 response. Reactivity to CO2 is maintained with the administration of etomidate. The effect of etomidate on autoregulation has not been evaluated.
Effect on CSF dynamics. Low-dose etomidate causes no change in Vf and Ra with no predicted effect on ICP. High-dose etomidate causes a decrease in Vf and either no change or a decrease in Ra with a predicted decrease in ICP.
Effect on ICP. Etomidate has been shown to reduce ICP without decreasing CPP and is clinically useful in neurosurgical patients for this purpose.
Effect on CBF and CMRo2. Propofol produces dose-related reductions in both CBF and CMRo2. In neurosurgical patients who are hypovolemic, the reduction in MAP might be substantial when they receive large bolus doses of propofol. Either the intravascular volume of these patients should be restored before the administration of propofol or an alternative induction drug should be used. A continuous infusion of propofol may be used intraoperatively as part of a total intravenous technique. The combination of an infusion of propofol and a narcotic (such as remifentanil) is particularly useful when the monitoring of evoked potentials precludes the use of other than low concentrations of inhalational drugs. Propofol is also useful for sedation during awake craniotomies and as a substitute for an inhalational drug at the end of a general anesthetic to shorten the wake-up time.
Effect on autoregulation and CO2 response. Autoregulation and CO2 response are preserved during the administration of propofol.
Effect on CSF dynamics. Propofol causes no change in Vf or Ra with no predicted effect on ICP.
Effect on ICP. Propofol reduces ICP. Because it also reduces MAP, its effect on CPP must be carefully monitored. Nonetheless, propofol's ICP-lowering effect makes it useful in the intensive care unit (ICU) for the sedation of patients in whom elevated ICP is a concern. Propofol has the advantage of allowing prompt awakening which is advantageous in patients whose neurologic status needs to be evaluated serially. In the operating room, moderately deep sedation with propofol does not increase ICP in comparison to no sedation in patients undergoing stereotactic biopsy for brain tumors. During craniotomy for resection of brain tumors, ICP has been shown to be lower in patients who receive propofol-fentanyl in comparison to patients anesthetized with isoflurane-fentanyl or sevoflurane-fentanyl. The antinausea effect of propofol is also advantageous in neurosurgical patients because many of them receive moderate to large doses of narcotics, which are associated with a high incidence of nausea and vomiting. This can be particularly deleterious because nausea-induced retching and vomiting might increase ICP. Careful attention to sterile technique is essential when using propofol as an infusion because the solubilizing agent in which propofol is prepared provides an excellent medium for bacterial growth.
Effect on spinal cord metabolism. Propofol decreases local spinal cord metabolism in both the gray and white matter, as expressed by local reductions in glucose utilization.

Effect on CBF and CMRo2. The effects of narcotics on CBF are difficult to characterize accurately because of conflicting experimental reports. It appears, however, that low doses of narcotics have little effect on CBF and CMRo2 whereas higher doses progressively decrease both CBF and CMRo2.
The baseline anesthetic state also plays a role. If a cerebral vasodilator is used to achieve the control anesthetic state to which a narcotic is added, a decrease in CBF and CMRo2 occurs. If either an anesthetic possessing cerebral vasoconstricting properties or no anesthetic is used as the control, narcotics have little effect on CBF. The observed reductions in CBF and CMRo2 parallel progressive slowing of the EEG. However, burst suppression and an isoelectric EEG are never achieved. High doses of narcotics have been shown to produce seizures in laboratory animals but rarely in humans. Seizures have been reported with high-dose fentanyl. Normeperidine, a metabolite of meperidine, is a known convulsant.
Effect on autoregulation and CO2 reactivity. Cerebral autoregulation and CO2 reactivity are maintained with narcotics.
Effect on CSF dynamics (Table-3). At low doses, fentanyl, alfentanil, and sufentanil cause no change of Vf and a decrease in Ra with a predicted decrease in ICP. At high doses, fentanyl decreases Vf and causes either no change or an increase in Ra with either a predicted decrease or an uncertain effect on ICP. At high doses, alfentanil causes no change in Vf and Ra with no predicted effect on ICP. High doses of sufentanil cause no change of Vf and either no change or an increase in Ra, predicting either no change or an increase in ICP.

Table-3. Effects of narcotics on rate of cerebrospinal fluid formation, resistance to reabsorption of cerebrospinal fluid, and the predicted effect on intracranial pressure
Narcotic Vf Ra Predicted ICP effect
Fentanyl, alfentanil, and sufentanil (low dose) 0 - -
Fentanyl (high dose) - 0, +* -, ?*
Alfentanil (high dose) 0 0 0
Sufentanil (high dose) 0 +, 0* +, 0*
Vf: rate of CSF formation; Ra: resistance to CSF reabsorption; ICP: intracranial pressure; 0: no change; -: decrease; +: increase; *: effect dependent on dose; ?: uncertain.

Effect on ICP. Under most conditions, narcotics produce either no change or a slight decrease in ICP. Narcotics can, however, increase ICP under certain conditions. For example, the bolus administration of sufentanil has been shown to produce transient but pronounced increases in ICP in patients who have severe head injury. Likewise, the bolus administration of sufentanil and alfentanil has been shown to produce increases in cerebrospinal fluid pressure (CSFP) in patients who have supratentorial tumors. The autoregulation-induced vasodilatation of cerebral vessels from the decrease in MAP may explain the changes in CSFP. Thus, when narcotics are administered to the neurosurgical patient, they should be given in a manner that does not cause a sudden reduction in MAP. The narcotic antagonist naloxone, when carefully titrated, has little effect on CBF and ICP. When used in large doses to reverse narcotic effects, however, the administration of naloxone may be associated with hypertension, cardiac arrhythmias, and intracranial hemorrhage.

Effect on CBF and CMRo2. Ketamine produces an increase in CBF and CMRo2. The mechanism of the increase in CBF may be severalfold: respiratory depression with mild hypercapnia in spontaneously ventilating subjects, regional neuroexcitation with a concomitant increase in cerebral metabolism, and direct cerebral vasodilatation as demonstrated by an increase in CBF during normocapnia and in the absence of changes in cerebral metabolism. Although seizures have been reported in epilepsy patients receiving ketamine, generally no epileptiform activity is seen on EEG analysis.
Effect on autoregulation and CO2 reactivity. Cerebral autoregulation and CO2 reactivity are maintained with ketamine.
Effect on CSF dynamics. Ketamine increases Ra and causes no change in Vf, which would predict an increase in ICP.
Effect on ICP. During spontaneous ventilation, ketamine produces an increase in Paco2 and ICP, in both the presence and absence of pre-existing intracranial hypertension. Increases in ICP might also occur in the presence of normoventilation. Interestingly, ketamine is a noncompetitive N-methyl-d-aspartate antagonist. In one animal model of incomplete cerebral ischemia, ketamine was shown to reduce cerebral infarct size. In the clinical arena, however, ketamine is still avoided in most neurosurgical patients, particularly those who have mass lesions and the potential for increased ICP.

Effect on CBF and CMRo2. Benzodiazepines, including diazepam, midazolam, and lorazepam, produce small decreases in CBF and CMRo2 in both small and large doses. A ceiling effect on these parameters is seen, which may represent saturation of receptor-specific binding sites. As with the barbiturates, some of the CBF-lowering effect of benzodiazepines is thought to be secondary to a reduction in CMRo2. Electroencephalographic effects include a shift from alpha to low-voltage beta and then theta waves, although an isoelectric EEG is not produced. Benzodiazepines are known anticonvulsants and are used clinically for this purpose.
Effect on cerebral autoregulation and CO2 reactivity. CBF autoregulation and CO2 reactivity are maintained with benzodiazepines.
Effect on CSF dynamics. Midazolam causes no change in Vf at low doses and a decrease in Vf at high doses. Ra is either not changed or increased. The predicted effect on ICP from these changes in CSF dynamics is uncertain.
Effect on ICP. ICP effects are small with benzodiazepines, which cause either no change or a slight reduction in ICP. Midazolam is commonly used as a premedication in neuroanesthesia, with small intravenous doses titrated to the patient's response, and as an anesthetic adjuvant. Large doses are generally avoided, however, because of the potential for prolonged sedation. Flumazenil is a receptor-specific benzodiazepine antagonist that can increase CBF and ICP when used in large doses to reverse midazolam sedation. Seizures can also be precipitated by the administration of large doses of flumazenil.


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