Pharmacological Complications

Hypnotic/Sedative Agents

These are used both in the perioperative and critical care settings. In patients with reduced cerebral compliance, a small increase in cerebral blood volume can cause a life-threatening increase in intracranial pressure (ICP). Most sedative–hypnotic drugs cause a proportional reduction in cerebral metabolism (CMRO ₂ ) and cerebral blood flow (CBF), resulting in a decrease in ICP. The effect of intravenous anesthetic drugs on cerebral dynamics is depicted in Table 1 . Although a decrease in CMRO ₂ probably provides only a modest degree of protection against cerebral ischemia or hypoxia, some hypnotics appear to possess cerebroprotective potential. Most IV hypnotics have similar electroencephalographic (EEG) effects. At high concentrations, a burst-suppressive pattern develops with an increase in the isoelectric periods.

Barbiturates produce a proportional decrease in CMRO ₂ and CBF, thereby lowering ICP. The maximal decrease in CMRO ₂ (55%) occurs when the EEG becomes isoelectric (burst-suppressive pattern). An isoelectric EEG can be maintained with a thiopental infusion rate of 4–6 mg/kg/h (resulting in plasma concentrations of 30–50 mg/mL). Because the decrease in systemic arterial pressure is usually less than the reduction in ICP, thiopental should improve cerebral perfusion and compliance. Therefore, thiopental is widely used to improve brain relaxation during neurosurgery and to improve cerebral perfusion pressure (CPP) after acute brain injury. Although barbiturate therapy is widely used to control ICP after brain injury, the results of outcome studies are no better than with other aggressive forms of cerebral antihypertensive therapy. Based on evidence from experimental studies, it has been concluded that barbiturates have no place in the therapy following resuscitation of a cardiac arrest patient. In contrast, barbiturates are frequently used for cerebroprotection during incomplete brain ischemia (e.g., carotid endarterectomy, temporary occlusion of cerebral arteries, profound hypotension, and cardiopulmonary bypass).

Continuous infusions of thiopental have been used to treat refractory status epilepticus. However, low doses of thiopental may induce spike wave activity in epileptic patients. Common complications seen with thiopental are hypotension and infections. A rare but serious complication of paralytic ileus leading to bowel ischemia was reported following continuous infusion of thiopental. Methohexital has well-established epileptogenic effects in patients with psychomotor epilepsy. Low-dose methohexital infusions are frequently used to activate cortical EEG seizure discharges in patients with temporal lobe epilepsy. It is also the IV anesthetic of choice for electroconvulsive therapy.

The true epileptogenic activity of methohexital needs to be differentiated from the myoclonic-like phenomena seen with etomidate. Myoclonic activity is generally considered to be the result of an imbalance between excitatory and inhibitory subcortical centers, produced by an unequal degree of suppression of these brain centers by low concentrations of hypnotic drugs.

Evidence for a possible neuroprotective effect has been reported in in vitro preparations, and the use of propofol to produce EEG burst suppression has been proposed as a method for providing neuroprotection during aneurysm surgery. However, when larger doses are administered, the marked depressant effect on systemic arterial pressure can significantly decrease CPP. Propofol appears to possess profound anticonvulsant properties. Propofol has been reported to decrease spike activity in patients with cortical electrodes implanted for resection of epileptogenic foci and has been used successfully to terminate status epilepticus. Propofol produces a decrease in the early components of somatosensory (SSEPs) and motor evoked potentials (MEPs) but does not influence the early components of the auditory evoked potentials. On the other hand, propofol is not devoid of complications. They include pain on injection, hemodynamic instability especially in dehydrated patients, hypertriglyceridemia and propofol infusion syndrome. Use of propofol along with opioids like fentanyl results in hypotension with bradycardia. This may be detrimental in cases with increased ICP.

The other dreaded complication is propofol infusion syndrome, rarely seen with continuous infusion of propofol at a dose of 4 mg/kg/h over 24–48 h, especially in children and neurocritical care settings. Continuous infusion of propofol is indicated in special situations like patients with severe traumatic brain injury (TBI), increasing ICP, and status epilepticus. Other predisposing factors include young age, severe critical illness of other central nervous system or respiratory origin, exogenous catecholamine or glucocorticoid administration, inadequate carbohydrate intake, and subclinical mitochondrial disease. These patients may present with findings of cardiac decompensation such as acute bradycardia refractory, ultimately leading to asystole. This is associated with metabolic acidosis, rhabdomyolysis, hyperlipidemia, renal failure, hyperkalemia, and an enlarged or fatty liver. The proposed mechanism involves either a direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism. Management includes prompt recognition, early intervention in the form of discontinuation of propofol infusion, and supportive therapy in the form of hemodialysis or hemoperfusion with cardiorespiratory support.

Other rare complications include acute pancreatitis. Cautious use of these agents in neurosurgical practice in both perioperative and critical care settings is warranted.

Analogous to the barbiturates, etomidate decreases CMRO ₂ , CBF, and ICP. However, the hemodynamic stability associated with etomidate will maintain adequate CPP. Etomidate has been used successfully for both induction and maintenance of anesthesia for neurosurgery. Although clear evidence for a neuroprotective effect in humans is lacking, etomidate is frequently used during temporary arterial occlusion and intraoperative angiography (for the treatment of cerebral aneurysms). Etomidate’s well-known inhibitory effect on adrenocortical synthetic function limits its clinical usefulness for long-term treatment of elevated ICP. Other complications include pain on injection and myoclonic movements. Etomidate can induce convulsion-like EEG potentials in epileptic patients without the appearance of myoclonic or convulsant-like motor activity, a property that has been proven useful for intraoperative mapping of seizure foci. Etomidate also possesses anticonvulsant properties and it has been used to terminate status epilepticus. Etomidate produces a significant increase of the amplitude of SSEPs while only minimally increasing their latency. Consequently, etomidate can be used to facilitate the interpretation of SSEPs when the signal quality is poor.

Ketamine has been traditionally contraindicated for patients with increased ICP or reduced cerebral compliance because it increases CMRO ₂ , CBF, and ICP. Prior administration of thiopental or benzodiazepines can blunt ketamine-induced increases in CBF. Ketamine has been reported to have little effect on MEPs.

Benzodiazepines decrease both CMRO ₂ and CBF analogous to the barbiturates and propofol. However, in contrast to these compounds, midazolam is unable to produce a burst-suppressive (isoelectric) pattern on the EEG. Accordingly, there is a “ceiling” effect with respect to the decrease in CMRO2 produced by increasing doses of midazolam. Midazolam induces dose-dependent changes in regional cerebral perfusion in the parts of the brain that subserve arousal, attention, and memory. In patients with severe head injury, a bolus dose of midazolam may decrease CPP with little effect on ICP. Although flumazenil does not appear to change CBF or CMRO ₂ following midazolam anesthesia for a craniotomy, acute increases in ICP have been reported in head-injured patients receiving flumazenil.