Douglas Mautz

Pharmacokinetics of oral triazolam in children

The purpose of this study was to determine the pharmacokinetic behavior of triazolam in children. Nine healthy children, aged 6 to 9 years, received oral triazolam (0.025 mg/kg suspended in Kool-Aid, Kraft General Foods, Chicago, IL) before dental treatment. Plasma triazolam concentrations were measured by gas chromatography/mass spectrophotometry at approximately 5, 15, 30, 45, 60, 90, 120, 180, and 240 minutes. A one-compartment model with first-order absorption and varying parameters was used, and estimated concentration curves were obtained for each subject. The observed peak plasma concentration was 8.5 +/- 3.0 ng/mL (mean +/- SD). The observed time to peak plasma concentration was 74 +/- 25 minutes. Elimination half-life was 213 +/- 144 minutes. Substantial recovery from signs and symptoms of clinical sedation required 180 to 240 minutes. The long duration of effect and relatively slow elimination should be noted by clinicians concerned with patient safety.

Epinephrine is metabolized by the spinal meninges of monkeys and pigs

Background Epinephrine commonly is added to epidural opioids and local anesthetics, however, little is known about the fate of epidurally administered epinephrine. Studies have identified the epinephrine metabolizing enzyme, catechol‐O‐methyl transferase (COMT), in the cranial meninges of several species. The purpose of this study was to determine whether the spinal meninges also contain COMT and are capable of metabolizing epinephrine. If so, then the spinal meninges may have an important impact in limiting the bioavailability of epinephrine in both the spinal cord and epidural space.

Posttreatment with propofol terminates lidocaine-induced epileptiform electroencephalogram activity in rabbits: effects on cerebrospinal fluid dynamics.

There are no controlled studies to determine whether propofol given after the onset of lidocaine-induced seizures (posttreatment) stops lidocaine-induced seizures. In this study, we determined whether posttreatment with propofol abolishes lidocaine-induced epileptiform electroencephalogram (EEG) activity as effectively as does midazolam, and cerebrospinal fluid (CSF) dynamics during lidocaine-induced epileptiform EEG activity and its treatment. EEG activity and CSF dynamics were determined in two groups of anesthetized rabbits at each of four experimental conditions: baseline, lidocaine-induced epileptiform activity, treatment with midazolam (n = 6) or propofol (n = 6), and return to baseline. The analog EEG signal was converted into a set of digital parameters using aperiodic analysis, and CSF dynamics were determined using ventriculocisternal perfusion. Propofol (3.8 +/- 1.3 mg/kg) stopped epileptiform activity, as did midazolam (2.0 +/- 1.7 mg/kg). The rates of CSF formation or reabsorption and resistances to CSF reabsorption or flow at the arachnoid villi did not differ among conditions or between groups. Our results indicate that propofol and midazolam both terminate epileptiform activity without changing CSF dynamics. Implications: Propofol may be an alternative to benzodiazepines for treating lidocaine-induced epileptiform electroencephalogram activity in patients. (Anesth Analg 1998;87:900-6)

Determination of alfentanil and noralfentanil in human plasma by gas chromatography—mass spectrometry

This report describes a simple gas chromatographic-mass spectrometric (GC-MS) assay for the simultaneous analysis of alfentanil and its major metabolite, noralfentanil, in human plasma. The method facilitates the processing of numerous samples for pharmacokinetic analysis. Alfentanil and noralfentanil are extracted from plasma under basic conditions and noralfentanil is converted to the pentafluoropropionyl derivative. The extraction efficiencies for noralfentanil and alfentanil were > 99% and 70%, respectively. Standard curves were linear (r2 = 0.99) over the ranges of 5-500 ng/ml for alfentanil and 0.4-10 ng/ml for noralfentanil. Inter-day coefficients significant improvement over existing HPLC assays which require radiolabelled significant improvement over existing HPLC assays which require radiolabelled alfentanil. The simultaneous disposition of alfentanil and noralfentanil in plasma after intravenous administration in humans is described.

Intravenous lidocaine decreases but cocaine does not alter the rate of cerebrospinal fluid formation in anesthetized rabbits

Considering that adrenergic stimulation was reported to decrease the rate of cerebrospinal fluid (CSF) formation (Vf), it was hypothesized that cocaine might exert a similar effect. Accordingly, the present study was designed to examine the effects of low, moderate, and high doses of cocaine on Vf and resistance to reabsorption of CSF (Ra). Because cocaine possesses both adrenergic-stimulating and local anesthetic properties, the present study examined the effects of lidocaine, a local anesthetic without adrenergic-stimulating properties, as a comparison treatment to cocaine. New Zealand white rabbits (n = 17) weighing 3.5-4.3 kg were anesthetized with halothane. A needle was inserted into the left lateral cerebral ventricle and a catheter was inserted into the cisterna magna to permit ventriculocisternal perfusion with mock CSF labeled with blue dextran. A1 each of four experimental conditions, control and three doses of cocaine or lidocaine, fluid volumes and concentrations of blue dextran in timed samples of cisternal outflow were used to determine Vf and the rate of reabsorption of CSF (Va). In turn, Va at normal and elevated CSF pressures (+6 cmH2O) were used to determine Ra. For both the cocaine group (n = 9) and the lidocaine group (n = 8) the three drug doses were 0.5 mg.kg-1 followed by 1.0 microgram.kg-1.min-1, 1.5 mg.kg-1 followed by 3.0 micrograms.kg-1.min-1, and 4.5 mg.kg-1 followed by 9.0 micrograms.kg-1.min-1 i.v. Cocaine caused no significant change of Vf or Ra. In the lidocaine group there was a dose/time-related decrease of Vf (although the slope relating Vf to dose/time was not significantly different from that in the cocaine group), but no significant change of Ra. It is concluded that during halothane anesthesia cocaine does not decrease Vf, a finding not consistent with previous reports that adrenergic stimulation decreases Vf. Decrease of Vf with lidocaine is consistent with previous reports of similar dose-related effects of thiopental, etomidate, midazolam, and fentanyl on Vf.

Acute Tolerance and Reversal of the Motor Control Effects of Midazolam

The purpose of this study was to determine whether acute tolerance develops to the motor control effects of the short-acting benzodiazepine, midazolam. Using a bolus and constant infusion scheme, 40 healthy adults received a 70-min intravenous infusion of either saline (n = 20) or 6.1 (SE = 0.2) mg midazolam (n = 20). Following the 70-min infusion period, half of the subjects in each group (n = 10) received a 25-min intravenous infusion of flumazenil (benzodiazepine antagonist); the remainder of the subjects (n = 10/group) received a 25-min infusion of saline. Drug administration during both infusion periods was double blind. Prior to the infusions, subjects were trained in a motor control assessment battery. Throughout both infusions, repeated motor control testing and blood sampling were performed. The initial (10 min) midazolam plasma concentration was 52.0 (SE = 2.2) ng/ml. Plasma midazolam concentration rose gradually to 60.7 (SE = 2.1) ng/ml at the end of the infusion (70 min). Midazolam initially impaired performance on the motor control tasks. However, performance improved in subjects receiving midazolam despite the gradual increase in midazolam concentrations. This suggests that the recovery of motor task performance may be attributable to the development of acute tolerance rather than to waning drug concentrations. Flumazenil immediately reversed midazolams effects on the visual tracking task. However, there was little evidence for precipitation of muscle force rebound, which has been hypothesized to result from the same underlying mechanism that is responsible for acute tolerance development.

Endotracheal flumazenil: A new route of administration for benzodiazepine antagonism

The purpose of this study was to determine if flumazenil is absorbed from broncho-pulmonary tissue after intratracheal administration and whether therapeutically significant plasma concentrations can be obtained. Six elective surgical patients received a dose of 1.0 mg flumazenil in 10 mL saline intratracheally during general anesthesia. Blood samples were drawn for 6 hours after administration and plasma concentrations were determined by gas chromatography-mass spectrometry (GC-MS). An average peak plasma flumazenil concentration of 65.9 +/- 43.1 ng/mL was attained within 1 minute after administration. No patients reported chest discomfort or dyspnea upon awakening and there were no other side effects noted. Administration of flumazenil via an endotracheal tube results in rapid attainment of therapeutic blood levels.

Concentrations of lidocaine and monoethylglycine xylidide in brain, cerebrospinal fluid, and plasma during lidocaine-induced epileptiform electroencephalogram activity in rabbits: the effects of epinephrine and hypocapnia.

UNLABELLED When injecting lidocaine into tissues, the mean toxic dose of lidocaine may be increased by adding epinephrine to lidocaine and by decreasing the PaCO(2). In contrast, when lidocaine is introduced directly into an artery or vein, adding epinephrine to lidocaine may decrease the mean toxic dose of lidocaine. Less is known about the effects of decreased PaCO(2) on intravascular lidocaine toxicity. We infused lidocaine in 24 rabbits at 4 mg. kg(-1). min(-1) with/without epinephrine and with/without hypocapnia. We measured the time to onset of lidocaine-induced seizures, total dose of lidocaine at the time of seizures, and concentrations of lidocaine and monoethylglycine xylidide (MEGX), a metabolite of lidocaine, in plasma, brain, and cerebrospinal fluid. Epinephrine decreased onset time by 11% with hypocapnia and by 21% with normocapnia, and it increased plasma MEGX by 1 microg/mL with hypocapnia and 2 microg/mL with normocapnia. Hypocapnia increased onset time by 18% without epinephrine and by 33% with epinephrine, and it increased whole-brain MEGX by 10 microg/mL without epinephrine and by 14 microg/mL with epinephrine. We conclude that, when lidocaine is given intravascularly, hypocapnia increases onset time and lidocaine dose required for seizures. These effects occur with no change in the concentration of lidocaine in plasma or the brain. IMPLICATIONS Hypocapnia increases the toxic dose of lidocaine given IV without altering lidocaine concentrations in blood, brain, or cerebrospinal fluid. Whole-brain monoethylglycine xylidide concentration is greater during hypocapnia than during normocapnia, and the addition of epinephrine to lidocaine increases the concentration of monoethylglycine xylidide in plasma.

Endotracheal lidocaine administration via an esophageal combitube

The purpose of this study was to test the hypothesis that lidocaine is systemically absorbed after administration via a Combitube placed in the esophagus, and that therapeutically significant plasma lidocaine concentrations can be attained using this route with standard endotracheal doses (2.0 mg/kg). During general anesthesia, 27 elective surgical patients received 2.0 mg/kg lidocaine (diluted as necessary with 0.9% saline to a minimum total volume of 10 mL) via a Combitube (study group, n = 13) or an endotracheal tube (control group, n = 14). Venous blood samples were drawn for 3 h after lidocaine administration and plasma concentrations determined by gas chromatography using a nitrogen-phosphorus detector (NPD). Overall, average lidocaine concentrations were maximal after 5 min, reaching 0.8+/-0.7 and 1.7+/-0.7 microg/mL in the Combitube and endotracheal tube groups, respectively. Individual patient peak concentrations averaged 1.0+/-0.7 and 2.2+/-1.1 microg/mL in the same two groups, 19+/-16 and 10+/-15 min after lidocaine administration, respectively. No patients reported chest discomfort or dyspnea upon awakening, and no other side effects were noted. In support of the hypothesis, administration of lidocaine via an esophageal Combitube results in systemic drug uptake; however, at conventional endotracheal doses, plasma concentrations are subtherapeutic. It remains to be determined whether higher doses of lidocaine administered via an esophageal Combitube will result in therapeutic plasma concentrations.