Preoperative Sedation, Anxiolysis, and Anterograde Amnesia
For preoperative sedation, anxiolysis, and anterograde amnesia, midazolam is used IM or IV in adult or pediatric patients; the drug also is used orally in pediatric patients. When administered preoperatively, the drug relieves anxiety and provides sedation, light anesthesia, and anterograde amnesia of perioperative events.
The efficacy of oral midazolam as a premedicant to sedate and calm pediatric patients prior to the induction of general anesthesia was compared across 3 different doses in a randomized, double-blind, parallel-group study. Patients of ASA physical status I, II, or III were stratified to one of 3 age groups (6 months to younger than 2 years, 2 to younger than 6 years, and 6 to younger than 16 years of age) and to one of 3 dosing groups (250 mcg/kg, 500 mcg/kg, and 1 mg/kg up to a maximum of 20 mg). More than 90% of treated patients achieved satisfactory sedation and anxiolysis at least one timepoint within 30 minutes post-treatment. Similarly high proportions of patients exhibited satisfactory ease of separation from parent or guardian and were cooperative at the time of mask induction with nitrous oxide and halothane administration. Onset time of satisfactory sedation or anxiolysis occurred within 10 minutes of treatment for greater than 70% of patients who started with an unsatisfactory baseline rating. Pairwise comparisons (250 mcg/kg versus 500 mcg/kg and 500 mcg/kg versus 1 mg/kg groups) on satisfactory sedation were not clinically different; however, comparative analysis of the clinical response between the higher and lower doses demonstrated that a higher proportion of patients in the 1 mg/kg group exhibited satisfactory sedation and anxiolysis compared with the 250 mcg/kg group.
Like other benzodiazepines, midazolam is especially useful as a preoperative medication when relief of anxiety and diminished recall of events associated with the surgical procedure are desired. The duration of anterograde amnesia following IM administration of midazolam is about 1 hour. Anterograde amnesia about events 30 and 60 minutes after IM injection occurs in approximately 40-75 and 25-40% of patients, respectively. Concomitant preoperative administration with scopolamine may potentiate this effect slightly. Because the degree and duration of anterograde amnesia appear to be dose related, patients receiving large doses of midazolam theoretically may have a more prolonged amnesic effect.
IM administration of midazolam usually results in less irritation at the site of injection than some other agents commonly used for preoperative sedation, including hydroxyzine or diazepam. In addition, IM midazolam appears to produce a more rapid onset of sedative effects, more pronounced anxiolytic effects during the first hour following administration, and more pronounced anterograde amnesia when compared with IM hydroxyzine. Because of midazolam's relatively rapid onset and short duration of effect and improved local tolerance at the site of injection compared with other currently available parenteral benzodiazepines, some clinicians consider midazolam the benzodiazepine of choice for preoperative use associated with short surgical procedures.
Midazolam also is used IV for preoperative sedation and anxiolysis with good results.
For procedural sedation, anxiolysis, and amnesia, midazolam is used IV in adult and pediatric patients, and orally in pediatric patients, either alone or in combination with an opiate agonist. The drug provides sedation without loss of consciousness and also provides relief of anxiety and anterograde amnesia when administered prior to dental or minor surgical procedures, or diagnostic, therapeutic, or endoscopic procedures such as upper GI endoscopy, bronchoscopy, cystoscopy, cardiac catheterization, coronary angiography, oncology procedures, radiologic procedures (e.g., computerized tomography), suture of lacerations, and other procedures, either alone or in combination with other CNS depressants. Like other benzodiazepines, midazolam is particularly useful for sedation when relief of anxiety and diminished recall of events associated with such procedures are desired.
Because laryngospasm and increased cough reflex may occur during peroral endoscopic procedures, concomitant use of topical anesthesia generally is recommended; facilities and equipment for respiratory and cardiovascular assistance should be readily available. The manufacturer recommends that an opiate agonist be used concomitantly as premedication for bronchoscopic procedures.
Anterograde amnesia occurs within 1-5 minutes following IV administration of midazolam and generally persists for 20-40 minutes after IV injection of a single dose. However, onset and duration of action depend on many factors, including the dose of midazolam, rate of administration, and on any concurrently administered drug.
(See Pharmacokinetics: Absorption.)
Midazolam generally produces less pain and venous irritation (e.g., thrombophlebitis) at the site of IV injection than diazepam. In addition, IV midazolam may have a slightly more rapid onset of action and more pronounced anterograde amnesic effect when compared with IV diazepam. Although data are conflicting, there is some evidence that midazolam's duration of action following IV administration may be slightly shorter than that of diazepam, but further comparative studies are needed; the duration of action of midazolam is substantially shorter than that of IV lorazepam. Because of the drug's relatively rapid onset and short duration of action, pronounced amnesic effect, and improved local tolerance at the site of injection compared with other currently available IV benzodiazepines, some clinicians consider midazolam the benzodiazepine of choice for moderate sedation (formerly known as conscious sedation) prior to short procedures.
Induction and Maintenance of Anesthesia
Midazolam is used IV for induction of general anesthesia prior to administration of other anesthetic agents. Induction with IV midazolam results in anxiolysis, anterograde amnesia, and dose-related hypnotic effects (progressing from sedation to loss of consciousness), but not analgesia. Midazolam also is used as a component of balanced anesthesia (e.g., nitrous oxide and oxygen) for maintenance of anesthesia during short surgical procedures; use of the drug for maintenance of anesthesia in relatively long surgical procedures has not been fully evaluated to date.
There is substantial interpatient variation in induction time and in the dose of midazolam required for induction of anesthesia, especially in young patients and/or patients who have not received premedication with an opiate agonist. Premedication with an opiate agonist results in more rapid and reliable induction of anesthesia within a narrower midazolam dosage range, and smaller doses of midazolam generally are required.
Compared with IV diazepam, induction with IV midazolam appears to cause less local irritation at the site of injection, comparable or more pronounced anterograde amnesic effect, and less variation in response to a given dose; midazolam also has a more rapid onset and shorter duration of action. The incidence of postoperative emergence delirium, nausea, and vomiting is relatively low following midazolam administration as compared with other anesthetic agents. Limited data suggest that midazolam attenuates both the postoperative emergence delirium and the cardiovascular stimulation associated with the use of ketamine during surgery.
When compared with IV thiopental (no longer commercially available in the US) for induction and maintenance of anesthesia, IV midazolam appears to produce more pronounced anterograde amnesia and more gradual induction of anesthesia and usually requires fewer adjuvant anesthetic agents to maintain an acceptable depth of anesthesia, but thiopental induces anesthesia more rapidly, produces a less variable response (particularly in young and/or non-premedicated patients), and requires a shorter recovery period. Apnea appears to occur less frequently and may be of shorter duration in patients receiving IV midazolam than in those receiving IV thiopental. Limited data suggest that IV midazolam also produces somewhat less severe adverse cardiovascular effects than IV thiopental, but further comparative studies are necessary. Midazolam appears to be an acceptable alternative to thiopental for induction of anesthesia, but midazolam's slow onset and long duration of action and variability in response relative to those of thiopental preclude it from becoming the drug of choice for induction of anesthesia in most patients, particularly outpatients and patients undergoing short surgical procedures. Midazolam may prove to be particularly useful as an alternative agent in patients with cardiac disease, geriatric patients, and patients in whom IV barbiturates are not tolerated or are contraindicated. In addition, because of midazolam's pronounced anterograde amnesic effect and good patient acceptability and because the drug generally requires fewer dosage increments and adjuvant anesthetics to maintain anesthesia than thiopental, some clinicians consider midazolam superior to thiopental for maintenance of balanced anesthesia; however, further comparative studies are needed. Midazolam appears to be a relatively safe and effective alternative to IV barbiturates for induction of anesthesia in patients with intracranial pathology (e.g., intracranial mass lesions, hydrocephalus, abnormal intracranial compliance) because midazolam produces little change in intracranial pressure (ICP); however, midazolam does not fully attenuate the increase in ICP associated with laryngoscopy and intubation.
Midazolam should not be used alone for maintenance of anesthesia; the drug usually is given in conjunction with inhalation anesthetic agents, balanced anesthesia (e.g., nitrous oxide and oxygen), and/or opiate agonists (e.g., fentanyl). Concurrent use of an opiate agonist usually is necessary to maintain adequate anesthesia.
Because midazolam does not appear to increase intraocular pressure, the drug appears to be safe for use in patients undergoing surgery for ocular trauma. Use of midazolam in patients without underlying ocular disease may result in moderate reduction of intraocular pressure.
Midazolam generally has been well tolerated in patients with ischemic heart disease, although mild to moderate alterations in cardiovascular function may occur. Severe hypotension has occurred, however, when midazolam was used with high-dose fentanyl anesthesia in patients undergoing coronary artery bypass grafting procedures.
Sedation in Critical-Care Settings
Midazolam is used as a continuous IV infusion for sedation of intubated and mechanically ventilated adults, pediatric patients, and neonates during treatment in a critical-care setting (e.g., an ICU) or as a component of anesthesia. The drug has been shown to be as effective as propofol in terms of sedation and appears to have a better adverse effect profile (e.g., less hypotension); however, midazolam appears to have a more variable effect on recovery of consciousness and time to recovery of function after cessation of therapy than propofol. In addition, results of several clinical studies indicate that midazolam is as effective as lorazepam in terms of level of sedation, the time required to achieve adequate sedation, and usually, the number of daily dose adjustments. However, in one study, midazolam IV infusions did require more frequent dosage adjustments to maintain the desired level of sedation than did lorazepam.
Because of the rapid onset and short duration of action of single doses of midazolam, some clinicians recommend midazolam as one of the preferred drugs for sedation in acutely agitated patients in critical-care settings. It is recommended, however, that midazolam be used only for short-term sedation (up to 24 hours), because the effects of the drug on awakening and time to extubation are unpredictable when infusions of the drug are administered over longer periods (e.g., exceeding 48-72 hours).
Parenterally administered midazolam has been used in the management of acute agitation.
Midazolam has decreased EEG interictal spike activity in some patients, suggesting that the drug possesses anticonvulsant activity, but the efficacy of the drug for the management of seizure disorders has not been fully determined.