MIDAZOLAM D. John Doyle MIDAZOLAM: Executive Summary Midazolam is a short-acting, water soluble benzodiazepine (t╫ = 1.7-4 h vs. 20-70 h for diazepam) with sedative, hypnotic, anxiolytic and marked amnestic properties making it suitable for dental, endoscopic and diagnostic procedures or as an adjunct to regional or general anaesthesia. Because it is water soluble, there is minimal pain on injection or venous thrombosis when given intravenously. Unlike diazepam, it can be given intramuscularly, but an oral preparation of midazolam is not available. The drug is 3-4 times as potent as diazepam, and much more expensive ($3.00 for 5 mg). Clinical Properties Of MIDAZOLAM Midazolam is a benzodiazepine with a fused imidazole ring which makes it different from the earlier benzodiazepines, and accounts for its stability in aqueous solution and its rapid metabolism. The table below gives some of its properties. MIDAZOLAM structure: imidazo benzodiazepine molecular weight: 362 pKa: 6.15 compatibility: D5W, Saline, Ringer's plasma protein binding: 96 - 97% pharmacokinetics (healthy patients) steady state volume of distribution: 0.8 - 1.5 L/kg plasma clearance: 6 - 9 ml/min/kg elimination half-life: 1.7 - 4 hrs metabolism: hydroxylation/ conjugation Cerebral Effects Midazolam reduces the cerebral metabolic rate for oxygen (CMRO2) and cerebral blood flow (CBF) in a dose-related manner. The electroencephalogram (EEG) shows a shift to beta activity (16 - 30 Hz). Midazolam also results in dose-related protection against cerebral hypoxia, at least in mice exposed to 5% oxygen. Following midazolam administration, little change in intracranial pressure (ICP) occurs in patients with intracranial mass lesions or decreased intracranial compliance, but midazolam does not protect against ICP increases following intubation or the administration of ketamine. As such, midazolam would appear to be an acceptable alternative to thiopental in patients with elevated intracranial pressure. Behavioural Effects Depending on the dose given, patient effects may range from slight sedation to complete unconsciousness. Performance of psychomotor tests (e.g., choice reaction time, critical flicker fusion, digit symbol test) are impaired. Clinically, mental slowing and slurred speech may be apparent. Antegrade amnesia, as studied by postcard testing, occurs to a large extent, especially in the first 15 minutes following an administered dose (vide infra). Amnestic Effects The profound amnestic effect which often occurs with midazolam use may be either beneficial or detrimental to the patient, depending on circumstances. Situations where the amnestic effect is desirable include: (1) suspected intraoperative awareness, (2) where repeated uncomforatble procedures are necessary (e.g. bronchoscopic monitoring after lung transplantation), (3) where a painful procedure must be carried out in the absence of general anaesthesia (e.g. cardioversion in the conscious hypotensive patient with ventricular tachycardia) or (4) in any patient who "just doesn't want to remember what went on". Situations where the amnestic effect is undesirable include (1) obstetrical anaesthesia (most mothers wish to recall their birth experience), and (2) where patients must remember to follow specific instructions postoperatively. The amnestic effects of midazolam may even occur at doses which do not result in full sedation, and these effects may last for many hours after the procedure is completed and the patient appears to be fully awake. Any postoperative patient instructions should be in writing. Do not loan patients money during this period. Respiratory Effects Midazolam produces dose-related respiratory depression as evidenced by laboratory studies and reports of clinical misadventures. In healthy volunteers given midazolam at 0.15 mg/kg the ventilatory response to inspired CO2 was impaired. (In COPD patients the effect is stronger and lasts much longer than in healthy volunteers). Midazolam appears to have no effect on respiratory mechanics, suggesting that the respiratory depression is CNS mediated. In a survey from many studies, the incidence of midazolam- induced apnea varied from 18 to 78% depending on the dose and speed of administration (faster = more apnea). Apnea is more frequent with narcotic premedication. In IV doses of 0.1 mg/kg in healthy volunteers, tidal volumes decrease while respiratory rates increase to keep minute volume constant. MIDAZOLAM In The Induction Of General Anaesthesia Midazolam may be used in conjunction with other agents ("co-induction") or alone to induce general anaesthesia. Premedication with a narcotic is frequently used to increase the speed and predictability of induction and the rapidity of recovery. The faster the injection of midazolam, the more rapid the induction. With slow injection, induction of anaesthesia is prolonged and the total dose may be needlessly increased, adversely affecting patient recovery. Onset of action of midazolam is slower than for thiopental (1 - 2 minutes vs. 30 - 40 seconds), which some patients perceive as a more pleasant induction. However, this property makes the drug unsuitable for rapid sequence inductions. The duration of action for midazolam in this setting is about 6 - 15 minutes, as opposed to the 3 - 5 minutes obtained with thiopental. This allows plenty of time to add additional agents for the maintenance phase of the anaesthetic. One problem with midazolam used for the induction of general anaesthesia is the fairly wide dosing range encountered, depending on whether the patient is premedicated, whether concomitant use of narcotics is employed, and on the age and health of the patient. Further complicating this is the fact that the dose may need to be increased for chronic users of alcohol or benzodiazepines and reduced for patients who have recently taken barbiturates, alcohol, CNS depressants, or who are chronic cimetidine users. The actual delivery of the drug generally involves a two stage process: (1) the drug is given as a single bolus injection over 5 seconds (see Table below) and (2) wait two minutes and if the patient is not yet asleep, give another ╪ of the initial dose or add 1 - 2 mg/kg of thiopental to complete the induction. Rough dosage guidelines for anaesthetic induction with midazolam Premedicated Not premedicated ASA I-II and age < 55 0.1 to 0.2 mg/kg 0.3 to 0.35 ASA III-IVor age > 55 0.05 to 0.15 mg/kg 0.15 to 0.25 Because midazolam has no analgesic properties, it is helpful to proceed the midazolam with 1 -2 mcg/kg of fentanyl or to use an IM narcotic for premedication. Recovery of consciousness following anaesthetic induction with midazolam is slower than for thiopental, but is more rapid than with diazepam. In the outpatient setting, midazolam may be suboptimal as an induction agent because of lingering postoperative sedation and its profound amnestic effect. MIDAZOLAM Misadventures From the period of March 1986 (when midazolam was released in the USA), to August 1988, the US Food and Drug Administration (FDA) received 69 reports of serious cardiorespiratory events associated with the use of the drug (FDA Drug Bulletin 1988; 18: 15 - 16). This resulted in the addition of a boxed warning on midazolam labeling to the effect that respiratory depression and even apnea can occur at doses within the usual recommended dosage range. This problem appears to be due to two sources: (1) excessive dosing, likely due to an underestimation of the potency of midazolam relative to diazepam, and (2) patients given parenteral midazolam appear more awake than those given diazepam when they have depressed respiratory function. These findings emphasize the need for complete monitoring (including pulse oximetry) in all patients receiving large doses of midazolam for conscious sedation. In addition, the manufacturer recommends that for IV conscious sedation the drug be given incrementally (e.g. 0.5 - 1.0 mg at a time) titrated to clinical effect rather than given in a rapid or single-bolus fashion. These concerns are especially true in the elderly or frail patient, the patient with chronic obstructive lung disease (COLD) or with the concomitant use of other respiratory depressants (e.g. fentanyl).