Premedication with midazolam in children. Effect of intranasal, rectal and oral routes on plasma midazolam concentrations

We report a study performed to compare the time and plasma drug concentrations necessary to achieve a similar state of sedation after midazolam premedication given by various routes in children of 2-5 years old. Children were randomly allocated to one of three groups to receive midazolam 0.2 mg.kg-1 given intranasally, 0.5 mg.kg-1 given orally or 0.3 mg.kg-1 given rectally. Sedation was measured regularly until venepuncture was possible in a cooperative child. At this time, a first blood sample was taken to measure plasma concentration, followed by another 10 min later. Anaesthesia consisted of intravenous propofol supplemented with regional analgesia. At recovery from anaesthesia, a third blood sample was taken. Adequate sedation occurred sooner (7.7, SD 2.4 min) with intranasal than oral (12.5, SD 4.9 min) or rectal (16.3, SD 4.2 min) midazolam. The initial blood levels were lower when the drug was given by the alimentary routes despite higher doses (146, SD 51 ng.ml-1 in 11.5, SD 3.9 min; 104, SD 34 ng.ml-1 in 21 +/- 6 min; and 93, SD 63 ng.ml-1 in 23.1, SD 3.5 min for the intra nasal, rectal and oral routes respectively). Duration of surgical procedures, and of propofol infusion, and recovery from anaesthesia was similar for the three groups. The only problem arose in a 30-month-old boy in the intranasal group who developed respiratory depression with a plasma midazolam concentration of 169 ng.ml-1. Intranasal midazolam is an excellent alternative for rapid premedication provided that respiratory monitoring is used.     

Observations on the use of midazolam for sedation, and induction of anaesthesia with midazolam in combination with ketamine in the goat

Midazolam hydrochloride administered intramuscularly at a dosage of 0.4 mg/kg induced sedation and sternal recumbency in goats. Increasing the dosage to 1 mg/kg resulted in rapid onset of ataxia followed by lateral recumbency, and loss of consciousness. Light surgical anaesthesia lasted for a period of 7-15 min and was suitable for non-painful procedures. Heart rate was significantly increased (p < 0.05) at both dosage rates, while respiration rate was only increased after midazolam at 0.4 mg/kg. The combination of midazolam (0.4 mg/kg) and ketamine hydrochloride (4 mg/kg) increased heart and respiration rate significantly (p < 0.05). A light plane of surgical anaesthesia suitable for endotracheal intubation was induced, which lasted for a period of 16-39 min.     

Comparison of midazolam with propofol for sedation in outpatient bronchoscopy

Two children are described who had microphthalmia (one with unilateral and one with bilateral) noted at birth, and whose early onset of poor linear growth and weight gain led to a diagnosis of hypopituitarism prior to two years of age. Both children had growth hormone and thyroid-stimulating hormone deficiencies, and evidence of partial ACTH deficiency. Administration of growth hormone resulted not only in rapid linear growth but it also reversed the poor weight gain and head growth noted in these children. These cases suggest that hypopituitarism and microphthalmia may be associated with each other more frequently than has been recognized previously.     

Population pharmacokinetics of midazolam administered by target controlled infusion for sedation following coronary artery bypass grafting

BACKGROUND: Midazolam is commonly used for short-term postoperative sedation of patients undergoing cardiac surgery. The purpose of this multicenter study was to characterize the pharmacokinetics and intersubject variability of midazolam in patients undergoing coronary artery bypass grafting. METHODS: With institutional review board approval, 90 consenting patients undergoing coronary artery bypass grafting were enrolled at three study centers. All subjects received sufentanil and midazolam via target-controlled infusions. After operation, midazolam was titrated to maintain deep sedation for at least 2 h. It was then titrated downward to decrease sedation for a minimum of 4 h more and was discontinued before tracheal extubation. Arterial blood samples were taken throughout the study and were assayed for midazolam and 1-hydroxymidazolam. Midazolam population pharmacokinetic parameters were estimated using NONMEM. Cross-validation was used to estimate the performance of the model. RESULTS: The pharmacokinetics of midazolam were best described by a simple three-compartment mammillary model. Typical pharmacokinetic parameters were V1 = 32.2 l, V2 = 53 l, V3 = 245 l, Cl1 = 0.43 l/min, Cl2 = 0.56 l/min, and Cl3 = 0.39 l/min. The calculated elimination half-life was 15 h. The median absolute prediction error was 25%, with a bias of 1.4%. The performance in the cross-validation was similar. Midazolam metabolites were clinically insignificant in all patients. CONCLUSIONS: The intersubject variability and predictability of the three-compartment pharmacokinetic model are similar to those of other intravenous anesthetic drugs. This multicenter study did not confirm previous studies of exceptionally large variability of midazolam pharmacokinetics when used for sedation in intensive care settings.     

The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam

We studied the interaction of azole antimycotics with intravenous (IV) and oral midazolam using a cross-over design in 12 volunteers, who ingested placebo, itraconazole, or fluconazole for 6 days. A 7.5-mg dose of midazolam was ingested on the first day, 0.05 mg/kg was administered IV on the fourth day, and 7.5 mg orally on the sixth day. Itraconazole reduced the clearance of IV midazolam by 69% and fluconazole reduced the clearance of IV midazolam by 51% (P < 0.001). A single dose of itraconazole and fluconazole increased the area under the oral midazolam concentration-time curve [AUC(0-infinity)] 3.5-fold (P < 0.001) and the peak concentration two-fold (P < 0.05) compared to placebo. On the sixth day the AUC(0-infinity) of oral midazolam was almost seven times greater with itraconazole (P < 0.001) and 3.6 times greater with fluconazole (P < 0.001) than without the antimycotics. The psychomotor effects of midazolam were also profoundly increased (P < 0.001). The psychomotor tests demonstrated only a weak interaction between the antimycotics and IV midazolam. When bolus doses of midazolam are given for short- time sedation, the effect of midazolam is not increased to a clinically significant degree by itraconazole and fluconazole, and it can be used in normal doses. However, the use of large doses of IV midazolam increases the risk of clinically significant interactions also after IV midazolam. Use of oral midazolam with itraconazole and fluconazole should be avoided.     

Benzodiazepine withdrawal reaction in two children following discontinuation of sedation with midazolam

OBJECTIVE: To report the occurrence of recurrent benzodiazepine withdrawal reactions in two very young children following discontinuation of sedation with midazolam. CASE SUMMARY: A 15-month-old boy with apneic episodes was sedated with midazolam for 12 days with constant infusion. Half a day after discontinuation of the midazolam the boy became restless, tachycardic, and hyperpyrexic. When midazolam was readministered, all symptoms disappeared. Four days later midazolam was again discontinued and within 12 hours the same signs and symptoms reappeared. Midazolam infusion was restarted, and the signs and symptoms disappeared for the second time. After thoracotomy, a 14-day-old boy received intravenous midazolam for sedation for 29 days. Within 12 hours after discontinuation of midazolam he became restless, developed a bulging stomach secondary to aerophagia, and was vomiting. Midazolam therapy was reinstituted and continued for another 2 months by constant infusion. Thereafter, the boy was successfully weaned from artificial ventilation in 5 days under sedation with midazolam. About 12 hours after discontinuation of midazolam the boy became restless, tachycardic, again developed a bulging stomach because of aerophagia, and vomited. When the child was sedated with clorazepate by continuous infusion, the signs and symptoms disappeared. DISCUSSION: Case reports describing benzodiazepine withdrawal reaction upon discontinuation of midazolam were reviewed and compared. The symptoms observed in the children we present resemble those mentioned in the three children and two adults reported previously. Unique in the very young children in this article is the occurrence of gastrointestinal symptoms, which most likely are the result of air being swallowed secondary to severe agitation. CONCLUSIONS: Midazolam withdrawal reactions in adults and children, particularly in an intensive care unit, can be significant. Considerable caution must be taken with relatively long-term administration and abrupt discontinuation of midazolam.     

The dose-dependent effects of oral premedication with midazolam

OBJECTIVE: The aim of this study was to examine the psychological effects, well-being and side effects after various doses of oral midazolam medication. METHODS: After informed consent has been obtained and following the approval by the institutional ethical committee, 80 adult patients in the ASA physical status I and II were randomly assigned to one of five different premedication groups: 3.75, 7.5, 11.25, 15 mg midazolam, and placebo. The medication was given in a double-blind fashion 60 min before induction of general anaesthesia for various surgical procedures. At 3 definite stages (before premedication, 30 and 60 min after premedication), blood pressure, heart rate, transcutaneous oxygen saturation and respiratory rate were measured. Sedation and well-being were graded according to a 5-point scale, and the subjective anxiety level was assessed according a visual analogue scale (range 0-100 mm). Anterograde and retrograde amnesia were measured by recall of auditive and visual stimuli. Finally, patients were asked whether in case of future surgery they would prefer the same or a different medication. RESULTS: Demographic data were similar in all groups. There was no significant difference in respiratory rate, oxygen saturation, blood pressure or heart rate. Alertness declined only after 60 min in the groups treated with 7.5 mg and more midazolam. During the entire measurement period, anxiolysis was not different from placebo in any of the midazolam groups. In comparison to placebo, all midazolam groups showed a statistically significant and dose dependent anterograde amnesia for visual stimuli. Subjective well-being scores showed no differences between the groups. Only few side effects were seen following doses of 7.5 mg and higher, including ptosis, strabismus, diplopia, speech disorders, disorientation and vertigo. The majority of patients in all groups indicated a wish for the same medication in case of future anaesthesia for surgical interventions. CONCLUSIONS: Midazolam administered orally prior to surgical procedures showed marked interindividual variability. Sedation and amnesia were dose-dependent and were evaluated by the patients as acceptable. Anxiolysis was not significantly different from placebo. A dose of 7.5 mg midazolam showed the best relation between desirable and undesirable effects. Adequate attention given to the patient by the anaesthesiologist prior to surgery seems to be as important and beneficial as oral medication with midazolam.     

Overnight sedation with midazolam or propofol in the ICU: effects on sleep quality, anxiety and depression

OBJECTIVE: To assess and compare the impact of overnight sedation with midazolam or propofol on anxiety and depression levels, as well as sleep quality, in non-intubated patients in intensive care. DESIGN: Open, comparative prospective, randomised study. SETTING: Surgical intensive care unit (ICU) in a university hospital. PATIENTS: 40 conscious patients expected to stay in the ICU for at least 5 days who were admitted following trauma or elective orthopaedic, thoracic or abdominal surgery. MEASUREMENTS AND RESULTS: Evaluation of a self-assessment scale (Hospital Anxiety and Depression Scale, HAD) on the day following the 1st, 3rd and 5th night of sedation with either midazolam or propofol. Heart rate, pulse oximetry and blood gases were monitored. Eight patients were excluded from the analysis. The level of anxiety was severe (HAD > 10) in 31% of the patients receiving midazolam and in 26% (p = 0.1) receiving propofol after the first night of sedation with no significant improvement over the next few days. The levels of depression remained high (> 10) in 54% of patients receiving midazolam, and in 16% of the patients receiving propofol (p = 0.15). Sleep quality tended to improve during the study in the two groups. CONCLUSIONS: These data show that half of the patients in the ICU experienced high levels of anxiety and depression during the first 5 post-operative or post-trauma days in the ICU. The beneficial effects of sedation on sleep quality were comparable for midazolam and propofol, regardless of a lack of improvement in anxiety and depression. However, an improved quality of sleep could help to re-establish a physiological night and day rhythm.     

Complications of sedation with midazolam in the intensive care unit and a comparison with other sedative regimens

Small angle X-ray diffraction was used to examine arterial smooth muscle cell (SMC) plasma membranes isolated from control and cholesterol-fed (2%) atherosclerotic rabbits. A microsomal membrane enriched with plasma membrane obtained from animals fed cholesterol for up to 13 weeks showed a progressive elevation in the membrane unesterified (free) cholesterol:phospholipid (C/PL) mole ratio. Beyond 9 weeks of cholesterol feeding, X-ray diffraction patterns demonstrated a lateral immiscible cholesterol domain at 37 degrees C with a unit cell periodicity of 34 A coexisting within the liquid crystalline lipid bilayer. On warming, the immiscible cholesterol domain disappeared, and on cooling it reappeared, indicating that the immiscible cholesterol domain was fully reversible. These effects were reproduced in a model C/PL binary lipid system. In rabbits fed cholesterol for less than 9 weeks, lesser increases in membrane C/PL mole ratio were observed. X-ray diffraction analysis demonstrated an increase in membrane bilayer width that correlated with the C/PL mole ratio. This effect was also reproduced in a C/PL binary lipid system. Taken together, these findings demonstrate that in vivo, feeding of cholesterol causes cholesterol-phospholipid interactions in the membrane bilayer that alter bilayer structure and organization. This interaction results in an increase in bilayer width peaking at a saturating membrane cholesterol concentration, beyond which lateral phase separation occurs resulting in the formation of separate cholesterol bilayer domains. These alterations in structure and organization in SMC plasma membranes may have significance in phenotypic modulation or aortic SMC during early atherogenesis.     

Timing and side effects of flumazenil for dental outpatients receiving intravenous sedation with midazolam

We studied the timing and side effects of flumazenil treatment for 10 healthy volunteers and 46 dental outpatients who received intravenous sedation with midazolam. For the volunteers, vital signs were monitored before and after intravenous injection of midazolam and flumazenil. In addition, grip strength, signs and symptoms, and performance on the Romberg's test and addition tests were evaluated 30 min and 60 min after midazolam injection as well as after flumazenil injection. There were no significant changes in vital signs before, immediately after, or 50 min after injection of flumazenil, the latter time corresponding to the half-life of the drug. Thus, awakening from sedation was associated with no effects on the cardiovascular or respiratory systems. Distinct effects of flumazenil were demonstrated by the Romberg's test and the assessment of sedation status. Flumazenil had no effect on the outcome of the addition test. For the outpatients, sedation status and signs and symptoms were studied in patients undergoing procedures lasting 30 min or less (group S) and those undergoing procedures lasting 31 to 60 min (group L). Three patients in group S and one in group L had signs and symptoms of resedation. After treatment with flumazenil, abnormalities such as excitability and nausea were reported by only two patients in group L. One patient in group S had drowsiness that did not resolve after injection of flumazenil and continued until the following day. Our results indicate that flumazenil should be given at least 60 min after intravenous sedation with midazolam in dental outpatients. Moreover, caution should be exercised with regard to the potential side effects of flumazenil.     

Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats

We investigated the effect of dexamethasone (80 mg/kg per day for 2 days) and prednisolone (600 mg/kg per day for 2 days, equivalent to dexamethasone for glucocorticoid (GC) potency) on both pharmacokinetics and pharmacodynamics of midazolam (MDZ), a substrate for cytochrome P450 (CYP) 3A, in 8-week-old male Sprague-Dawley rats. Animals received a single injection of MDZ (pharmacokinetic study, 10 mg/kg; pharmacodynamic study, 55.5 mg/kg) in the tail vein 24 h after the last dose of GC or placebo. The elimination half-life (t(1/2)) and the area under the concentration-time curve of MDZ were significantly reduced by pretreatment with dexamethasone to 58.9% and 44.7% of the control value, respectively, and the clearance of MDZ was significantly increased by dexamethasone. Similar changes observed by prednisolone pretreatment did not reach significance. The t(1/2) of the dexamethasone pretreatment group (14.4+/-0.7 min) was significantly shorter than that of the prednisolone group (20.9+/-1.5 min). The amount of CYP3A2 protein and the activity of erythromycin N-demethylase were significantly increased by dexamethasone and prednisolone pretreatments, but dexamethasone showed a greater effect than prednisolone. Sleeping time was significantly shortened by dexamethasone and prednisolone pretreatment to 38.7% and 57.1% of control value, respectively. The current study demonstrates that the anesthetic effect of MDZ would be reduced in patients treated with dexamethasone or prednisolone, and that the CYP3A induction was greater by dexamethasone than by prednisolone, implying that the potency of CYP3A induction may differ among GCs even when GC activity is the same.     

Upper airway obstruction during midazolam/nitrous oxide sedation in children with enlarged tonsils

Steatocystoma multiplex is a rare condition characterized by multiple subcutaneous nodules classically located on the anterior chest. Diagnosis usually is made clinically or by biopsy. The lesions may be numerous, and surgical treatment may not be practical or the results may be unsatisfactory. Three patients with multiple subcutaneous nodules underwent fine needle aspiration, which produced smears with acellular debris. A diagnosis was possible in the first patient because of close collaboration with a dermatologist. The lesions in the other patients were recognized clinically and were confirmed cytologically by fine needle aspiration. A syringe holder allows the use of thin needles (22-gauge) to aspirate very small lesions (4 to 5 mm). Fine needle aspiration may provide a useful alternative to surgical methods in the treatment of these lesions because it is inexpensive, well-tolerated by the patients, and has no associated morbidity.     

The role of atropine premedication in fiberoptic bronchoscopy using intravenous midazolam sedation

OBJECTIVE: Atropine premedication is widely used for fiberoptic bronchoscopy and may help by drying secretions, producing bronchodilatation, or preventing vasovagal reactions. The objective of this study was to see whether atropine premedication is really of practical benefit when patients are sedated with i.v. midazolam. DESIGN: In a double-blind study, patients were randomly allocated to receive i.m. atropine (0.6 mg) or saline placebo (1 mL) as premedication 30 to 60 minutes before they were sedated with progressive doses of i.v. midazolam until judged to be lightly asleep. SETTING: A District General Hospital in England. PARTICIPANTS: One hundred consecutive patients referred for bronchoscopy. MEASUREMENTS AND RESULTS: Samples taken during the procedure were washings for microbiology and cytology and brushings for cytology and biopsy, but no transbronchial biopsies. Peak flow readings were recorded before premedication and before the start of the procedure. During the procedure an estimate was made of pharyngeal and tracheobronchial secretions, bleeding, use of saline to wash out secretions, and local anesthetic needed to control coughing. Patients were monitored for saturation and cardiac rhythm. There was no significant bronchodilatation after premedication in either group, nor were there differences in secretions, use of saline, tracheobronchial bleeding, desaturation, and arrhythmias. More local anesthetic was needed to control coughing in the placebo group (mean 357 mg vs 331 mg in the atropine group, p=0.02), but this was not of practical significance. CONCLUSION: When intravenous midazolam sedation is used for bronchoscopy, atropine premedication is not of benefit.     

Cardiovascular responses, arterial oxygen saturation and plasma catecholamine concentration during upper gastrointestinal endoscopy using conscious sedation with midazolam or propofol

Benomyl (a non-thio fungicide) inhibits hepatic mitochondrial low-Km aldehyde dehydrogenase (mALDH or ALDH2) in ip-treated mice by 50% (IC50) at 7.0 mg/kg, which is surprisingly the same potency range as that for several dithiocarbamate fungicides (and the related alcohol abuse drug disulfiram) and thiocarbamate herbicides previously known for their alcohol-sensitizing action. The mechanism by which benomyl inhibits mALDH was therefore examined, first by comparing the metabolism of benomyl with the aforementioned mono- and dithiocarbamates and second by evaluating the inhibitory potency of the benomyl metabolites. Benomyl in ip-treated mice is converted, via butyl isocyanate, S-(N-butylcarbamoyl)glutathione, and S-(N-butylcarbamoyl)cysteine, to S-methyl N-butylthiocarbamate (MBT), identified as a transient metabolite in liver. MBT is >10-fold more potent than benomyl or butyl isocyanate as an in vivo mALDH inhibitor and is also more potent than the intermediary S-(N-butylcarbamoyl) conjugates. Benomyl and MBT inhibit mouse hepatic mALDH in vitro with IC50s of 0.77 and 8.7 microM, respectively. The potency of MBT is greatly enhanced by fortification of the mitochondria with NADPH alone or plus microsomes giving IC50s of 0.50 and 0.23 microM, respectively. This activation of MBT is almost completely blocked by the cytochrome P450 inhibitor N-benzylimidazole but not by several other cytochrome P450 inactivators. MBT (probably following bioactivation) inhibits mALDH in vivo with an IC50 of 0.3 mg/kg. Two candidate activation products were synthesized for potency determinations. N-Hydroxy MBT (prepared via the trimethylsilyl derivative) was not detected as an MBT metabolite; its low potency also rules against N-hydroxylation as the activation process. MBT sulfoxide, from oxidation of MBT with magnesium monoperoxyphthalate in water, is one of the most potent inhibitors known for mALDH and yeast ALDH in vitro (IC50 0.08-0.09 microM). These findings are consistent with a six-step bioactivation of benomyl, via the metabolites above and N-butylthiocarbamic acid, with MBT as the penultimate and MBT sulfoxide as the ultimate inhibitor of mALDH.     

Comparative validity of two measures of psychomotor function in patients with severe depression

Psychomotor function is a key construct in depressed patients and two measures have been developed for systematic rating. Parker and colleagues utilise an observer-rated scale (CORE) while the scale (DRRS) developed by Widl?cher assesses motor and ideational aspects. Association between the scales and their relative capacity to predict ECT response were investigated in a sample of 81 depressed patients. Both predicted ECT response. While the CORE scale rates a wider variety of phenomena (including non-interactiveness and agitation) and does not rely on the subject's capacity to report aspects of their cognitive function, the study supports the predictive and comparitive validity of both scales.     

Repeated dosing with oral cocaine in humans: Assessment of direct effects, withdrawal, and pharmacokinetics.

Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n = 9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1–4 & Days 9–12, cocaine 175 mg, p.o.; 5 hourly doses; 875 mg/day) separated by a 4-day matched placebo exposure period (Days 5–8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13–40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) two to threefold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects (liking, high, good effects) and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Peripheral vascular effects and pharmacokinetics of the antimigraine compound, zolmitriptan, in combination with oral ergotamine in healthy volunteers

Members of the new class of antimigraine compounds, 5HT1B/1D agonists, as well as ergotamine, may cause vasoconstriction through stimulation of 5HT receptors on peripheral vessels. The cardiovascular effects of 20 mg oral zolmitriptan (Zomig, formerly 311C90), 2 mg oral ergotamine and the combination were assessed in a randomized double-blind, placebo-controlled crossover study in 12 healthy subjects. Pharmacodynamic measures included oscillometric blood pressure, systolic blood pressure at the toe and arm using a strain gauge technique, stroke volume and cardiac output using bioimpedance cardiography, high-resolution ultrasound to measure brachial arterial diameter and a novel Doppler method to measure blood flow velocity. Both drugs produced small degrees of peripheral vasoconstriction, including increases in diastolic blood pressure and blood flow velocity and decreases in arterial diameter and toe-arm systolic pressure gradient. These effects were generally additive with the combination but of no clinical importance. There were no significant changes in cardiac output, stroke volume heart rate or ECG. Zolmitriptan, at eight times the likely therapeutic dose, was generally well tolerated both alone and in combination with ergotamine. Ergotamine had no clinically important effects on zolmitriptan pharmacokinetics.     

Perioperative physiological and cognitive functions following oral premedication with 3.75 mg midazolam in operations with retrobulbar anesthesia

The number of surgical procedures performed as day surgery has significantly increased in recent years. Therefore, a safe and short postoperative recovery period has become increasingly important. The aim of the present study was to investigate perioperative cognitive and physiological function after oral premedication with low-dose midazolam (3.75 mg), especially during the postoperative period. METHODS: Forty-seven men (age > 69 years, weight 50-90 kg) scheduled for elective cataract surgery under retrobulbar anaesthesia (RBA) were included in the study. The patients were randomly assigned to either group 1 (n = 28), receiving 3.75 mg midazolam p.o. (Dormicum), or group 2 (n = 19), receiving a placebo orally 30 min before RBA. We measured the following parameters: sedation (modified Glasgow coma scale); anxiety (visual analogue scale); numerical and verbal memory (digit span and reproduction of previously presented words); concentration (Revisions test of Stender/Marschner). To identify depression of ventilation, pulse oximetry and nasal end-tidal PCO2 were monitored intraoperatively. RESULTS: After premedication with 3.75 mg midazolam, patients were significantly more sedated (P < 0.01) and systolic blood pressures were significantly reduced (P < 0.05); 30 min after midazolam premedication only concentration was significantly (P < 0.05) decreased. The results of the other cognitive functions did not differ. No differences in cognitive and physiological functions between and groups could be found 2 h after the operation (293 +/- min after premedication). Intraoperatively, there were no significant differences in end-tidal PCO2 and oxygenation between the groups. In both groups anxiety and blood pressure were significantly higher pre- than postoperatively. CONCLUSION: Oral administration of low-dose midazolam (0.049 +/- mg/kg) seems to be appropriate for premedication before ambulatory surgical procedures in elderly patients. In the interest of patient safety, standardised oral premedication with 3.75 mg midazolam may not be sufficient for some of the patients.