Benzodiazepines - Intravenous Anesthetics

BENZODIAZEPINES

Benzodiazepines commonly used in the perioperative period include midazolam, lorazepam, and less frequently, diazepam. Benzodiazepines are unique among the group of intravenous anes-thetics in that their action can readily be terminated by adminis-tration of their selective antagonist, flumazenil. Their most desired effects are anxiolysis and anterograde amnesia, which are extremely useful for premedication.

Pharmacokinetics in the Anesthesia Setting

The highly lipid-soluble benzodiazepines rapidly enter the CNS, which accounts for their rapid onset of action, followed by redis-tribution to inactive tissue sites and subsequent termination of the drug effect.

Despite its prompt passage into the brain, midazolam is con-sidered to have a slower effect-site equilibration time than propo-fol and thiopental. In this regard, intravenous doses of midazolam should be sufficiently spaced to permit the peak clinical effect to be recognized before a repeat dose is considered. Midazolam has the shortest context-sensitive half-time, which makes it the only one of the three benzodiazepine drugs suitable for continuous infusion (Figure 25–8).

Organ System Effects

A. CNS Effects

Similar to propofol and barbiturates, benzodiazepines decrease CMRO₂ and cerebral blood flow, but to a smaller extent. There appears to be a ceiling effect for benzodiazepine-induced decreases in CMRO₂ as evidenced by midazolam’s inability to produce an isoelectric EEG. Patients with decreased intracranial compliance demonstrate little or no change in ICP after the administration of midazolam. Although neuroprotective properties have not been shown for benzodiazepines, these drugs are potent anticonvulsants used in the treatment of status epilepticus, alcohol withdrawal, and local anesthetic-induced seizures. The CNS effects of benzodiazepines can be promptly terminated by administration of the selective benzodiazepine antagonist flumazenil, which improves their safety profile.

B. Cardiovascular Effects

If used for the induction of anesthesia, midazolam produces a greater decrease in systemic blood pressure than comparable doses of diazepam. These changes are most likely due to peripheral vaso-dilation inasmuch as cardiac output is not changed. Similar to other intravenous induction agents, midazolam’s effect on sys-temic blood pressure is exaggerated in hypovolemic patients.

C. Respiratory Effects

Benzodiazepines produce minimal depression of ventilation, although transient apnea may follow rapid intravenous administration of midazolam for induction of anesthesia, especially in the presence of opioid premedication. Benzodiazepines decrease the ventilatory response to carbon dioxide, but this effect is not usually significant if they are administered alone. More severe respiratory depression can occur when benzodiazepines are administered together with opioids. Another problem affecting ventilation is airway obstruction induced by the hypnotic effects of benzodiazepines.

D. Other Effects

Pain during intravenous and intramuscular injection and subse-quent thrombophlebitis are most pronounced with diazepam and reflect the poor water solubility of this benzodiazepine, which requires an organic solvent in the formulation. Despite its better solubility (which eliminates the need for an organic solvent), midazolam may also produce pain on injection. Allergic reactions to benzodiazepines are rare to nonexistent.

Clinical Uses & Dosage

Benzodiazepines are most commonly used for preoperative medi-cation, intravenous sedation, and suppression of seizure activity. Less frequently, midazolam and diazepam may also be used to induce general anesthesia. The slow onset and prolonged duration of action of lorazepam limit its usefulness for preoperative medica-tion or induction of anesthesia, especially when rapid and sus-tained awakening at the end of surgery is desirable. Although flumazenil (8–15 mcg/kg IV) may be useful for treating patients experiencing delayed awakening, its duration of action is brief (about 20 minutes) and resedation may occur.

The amnestic, anxiolytic, and sedative effects of benzodiaz-epines make this class of drugs the most popular choice for preop-erative medication. Midazolam (1–2 mg IV) is effective for premedication, sedation during regional anesthesia, and brief therapeutic procedures. Midazolam has a more rapid onset, with greater amnesia and less postoperative sedation, than diazepam. Midazolam is also the most commonly used oral premedication for children; 0.5 mg/kg administered orally 30 minutes before induction of anesthesia provides reliable sedation and anxiolysis in children without producing delayed awakening.

The synergistic effects between benzodiazepines and other drugs, especially opioids and propofol, can be used to achieve bet-ter sedation and analgesia but may also greatly enhance their combined respiratory depression and may lead to airway obstruc-tion or apnea. Because benzodiazepine effects are more pro-nounced with increasing age, dose reduction and careful titration may be necessary in elderly patients. 

General anesthesia can be induced by the administration of midazolam (0.1–0.3 mg/kg IV), but the onset of unconsciousness is slower than after the administration of thiopental, propofol, or etomidate. Delayed awakening is a potential disadvantage, limiting the usefulness of benzodiazepines for induction of general anesthe-sia despite their advantage of less pronounced circulatory effects.