Over the last 20 years standardized techniques have been employed for the investigation of intravenous hypnotics, psychotropic and neuroleptic drugs. Sleep has been studied with the help of EEG measures and side-effects have been evaluated by psychometric tests. The EEG is a proven parameter with regard to dosage determination and as objective means to find sleep-inducing quantities of drugs. By means of vigilosomnograms we have established dose-effect curves and have made comparisons between related drugs in the form of equivalence studies.
Midazolam is an imidazobenzodiazepine with unique properties when compared with other benzodiazepines. It is water soluble in its acid formulation but is highly lipid soluble in vivo. Midazolam also has a relatively rapid onset of action and high metabolic clearance when compared with other benzodiazepines. The drug produces reliable hypnosis, amnesia, and antianxiety effects when administered orally, intramuscularly, or intravenously.
Midazolam and alfentanil were infused in a totally i.v. anesthetic technique (TIVA) to patients undergoing hysterectomy. Correlations of midazolam plasma concentrations and effects were made during recovery. Due to the high doses of midazolam administered during TIVA, metabolism and not redistribution mainly governed the duration of effects post-infusion. The concomitant administration of alfentanil contributed to the sedative effect, as illustrated by a shift of the concentration-response curve to the left. As a result of these effects, recovery was prolonged and extended over 2-6 h.
The displacement of midazolam, a new water-soluble, short acting benzodiazepine, from its plasma binding sites by sodium valproate, has been studied in man. An increase of its free fraction (ranging from 2.71 to 5.35%) in plasma from epileptic patients receiving sodium valproate was observed. A similar situation was created in rabbits by pretreatment with sodium valproate (600 mg kg-1 day-1) and posterior hypnosis with midazolam.
The effects of alfentanil on the midazolam dose-response curve for hypnosis was studied with response to the verbal command as an end point in 95 patients. The analgesic effect of alfentanil was studied by measuring the threshold for pain caused by pressure on the trapezius muscle with the use of a dolorimeter in 21 patients. The study was randomized, double-blind, and performed on the unpremedicated patients with ASA physical status I or II. Alfentanil was found to reduce the midazolam ED50 value for the induction of anesthesia in a dose-dependent fashion.
The midazolam-morphine interactions in relation to the sedative effect and in relation to the hypnotic effect were studied in rats. Two series of experiments (sedative and hypnotic) were performed. In the sedative series, doses that inhibited locomotor activity to 10% or more of the control level were determined when the agents were given singly or in combination. Dose-response curves were determined with a probit procedure. The ED50 values of both agents and their combination were compared with algebraic (fractional) and isobolographic analyses in one subseries of experiments.
A new benzodiazepine-type drug, midazolam, was administered intramuscularly as a premedicant to 155 patients aged from 16 to 81 years with ASA status 1 or 2. The hypnotic action and the effect on the upper airway tract of midazolam were evaluated. Hypnosis appeared 5 minutes after the administration of midazolam, reached its plateau after 20 minutes and started to decline after 30 minutes. The hypnotic effect showed dose-dependent increase in doses ranging from 0.05 to 0.20 mg.kg-1.
This study examined the interaction between i.v. administered midazolam and thiopentone on the loss of response to verbal command ("hypnosis") and the loss of response to transcutaneous electrical stimulation of the ulnar nerve ("anaesthesia") in patients presenting for minor elective surgery. Dose-response curves for thiopentone and midazolam individually and in combination were determined using the two end-points in 300 unpremedicated patients.
Midazolam concentration curves versus time were analysed in 10 otherwise healthy patients (ASA I-II) with inferior limb pathologies. The benzodiazepine was used as an adjuvant agent to epidural anaesthesia in view of its lower residual effect compared with other intravenous benzodiazepines. Midazolam pharmacokinetics in these patients fitted an open two-compartment model. The plasma levels versus time corresponded to a biexponential process with a very rapid distribution phase (t1/2a = 5.7 +/- 2.4 min) and an elimination phase (t1/2 beta = 66 +/- 37 min).
In a randomized, double-blind study, we administered placebo and flumazenil to 40 healthy Chinese boys, aged 3-12 yr, undergoing circumcision. The children received midazolam 0.5 mg kg-1 orally for premedication and 0.5 mg kg-1 i.v. during induction. After operation the patients were given 0.1 ml kg-1 of a blinded solution followed by 0.05 ml kg-1 min-1 until either they awoke or the 10-ml ampoule of solution was empty.