Martin Theisohn

Clinical experience with continuous intravenous sedation using midazolam and fentanyl in the paediatric intensive care unit

Twenty-four patients in a paediatric intensive care unit mostly undergoing cardiac surgery, received a midazolam dosage between 50–400 μg/kg per hour as a continuous intravenous infusion partly in combination with fentanyl [0,5–2,5 μg/kg per hour] for analgesia and sedation. The mean duration of midazolam infusion was 11.6 days (range 38h–40 days). Blood samples for the HPLC assay of serum midazolam concentration were taken and the clearance estimated. The efficiency of sedation in correlation to the midazolam concentration was evaluated by a clinical sedation score. Serum midazolam concentrations between 100–400 μg/l were sufficient for sedation. Dosage had to be increased during therapy according to an increased midazolam clearance. The evaluation of the sedation score showed that sedation of artifically ventilated infants and young children can be established by continuous intravenous infusion of midazolam.

HPLC analysis of the antifungal agent posaconazole in patients with haematological diseases

Posaconazole is a new antifungal drug used in prophylaxis and therapy of fungal infections in patients with immunodeficiency. In the clinical development, posaconazole exhibits variable oral bioavailability. Hence drug monitoring is recommended. For this purpose, a rapid and a convenient high‐performance liquid chromatography (HPLC) method has been developed. To 200 μl serum, 50 μl internal standard (itraconazole) was added. After precipitation of the proteins with acetonitrile, the clear supernatant was evaporated in a centrifugal evaporator, and the residue was dissolved in the HPLC elution. Separation was done on a chromatography performed by injecting a 50 μl aliquot of the resuspended sample onto a Multohyp C18 BDS column (250 × 4 mm). Column temperature was maintained at 50 °C. The flow rate was 1 ml min−1. Retention time of posaconazole was about 9 min and those of itraconazole was 17 min. The limit of quantification was 50 μg l−1 and the limit of detection about 10 μg l−1. Until now the concentration of posaconazole was measured in 14 patients (64 samples). After a daily dosage of 600–800 mg posaconazole the serum concentrations varied between 100 and 3000 μg l−1 (582 ± 579 μg l−1). Oral bioavailability was especially low in patients with cytostatic therapy and/or bone marrow transplantation. Further studies are needed to establish the therapeutic range of the posaconazole concentrations.

EEG changes in patients during the introduction of carbamazepine

This study evaluates the EEG changes during the standardized introduction of carbamazepine in 16 previously untreated neurological patients and their relationship to serum levels of carbamazepine and carbamazepine-10,11-epoxide. Therapy was started with a dosage of 400 mg carbamazepine b.i.d. and remained unchanged during the whole study period of 35 days. Frequency analysis of serial EEG records was performed by Fast Fourier Transformation. In comparison to the pretreatment period (1) the mean values of the total power and relative powers of the theta and delta bands increased and (2) the mean values of the relative power of the alpha band and the center frequency decreased. These changes were already established 3 days after the beginning of the treatment and remained constant during the observation period. There were marked interindividual differences. (3) There was no statistically significant correlation between serum levels of carbamazepine or carbamazepine-10,11-epoxide and the EEG parameters. Our results demonstrate that the degree of EEG change primarily reflects individual susceptibility to carbamazepine and its metabolite during the early stage of carbamazepine exposure and is not dose related.

Sensitive and convenient high-performance liquid chromatographic method for the determination of mitomycin C in human plasma

An improved high-performance liquid chromatographic assay for the cytostatic drug mitomycin C in plasma is presented. The principal steps are precipitation of plasma proteins with acetonitrile, lyophilization of the supernatant and reversed-phase chromatography on a Hypersil ODS 5 microm column with 0.01 M NaH2PO4 buffer (pH 6.5)-methanol (70:30, v/v) in isocratic mode. At a flow-rate of 1.3 ml/min a column pressure of 180-220 bar resulted. Porfiromycin served as internal standard. UV detection was performed at 365 nm. Quantitation limit based on a coefficient of variation <10% in intra- and inter-day assay was 5 microg/l mitomycin C, detection limit based on a signal-to-noise ratio of 3 was 1 microg/l. Recovery was 100% and linearity was shown for the whole range of concentration (1-500 microg/l). None of the five drugs used during chemoembolisation interfered with the assay in vitro. The assay meets the requirements for pharmacokinetic studies of mitomycin C in patients as regards sensitivity and ease of use.

Caffeine in saliva after peroral intake: early sample collection as a possible source of error.

The influence of collection time on the correlation of caffeine concentrations in saliva and serum was examined in six healthy adults after peroral administration of 5 mg/kg caffeine citrate. Saliva was obtained from three different salivary glands (sublingual, right parotid, and left parotid) and evaluated separately. Caffeine concentrations in saliva and serum samples were determined by high-performance liquid chromatography. There were no differences in the caffeine concentrations in saliva from the three investigated glands (alpha = 0.05). Saliva samples collected earlier than 2 hours after caffeine intake showed higher caffeine concentrations than could be expected from the corresponding serum samples. Gingiva contamination was shown to be responsible for the higher caffeine concentrations in saliva, and it was concluded that saliva is a feasible matrix for therapeutic drug monitoring of caffeine. If caffeine is administered orally, saliva samples should be taken at least 2 hours after caffeine intake. If caffeine-containing beverages are used as the source of caffeine or if subjects do not cooperate by rinsing the mouth of caffeine contamination, an additional 60 minutes should be added before saliva sampling.

Pseudocholinesterase-activity reduction during cardiopulmonary bypass : The role of dilutional processes and pharmacological agents

UNLABELLED 1. Pseudocholinesterase (ChE) activity is a determinant of the elimination kinetics of several drugs used in anesthesia. The time course of ChE activity was investigated in 16 patients undergoing cardiosurgery for a cardiopulmonary bypass (CPB) in normothermia or hypothermia. 2. The onset of the CPB was accompanied by a decrease in ChE activity (-37%) (P<0.05) and protein concentration (-24%) (P<0.05). The quotient ChE activity/protein concentration was numerically reduced to a smaller extent (-15%) (P>0.05). After the CPB was finished, ChE activity and the protein concentration remained low for the remaining operation time. 3. There was no difference in ChE activity, measured in vitro at 37 degrees C, between the normothermic and hypothermic group (P>0.05). 4. There was no correlation between heparin concentration in serum and reduction of ChE activity in vitro (P>0.05). In vitro, the ChE activity was not affected by either heparin in doses as high as 10,000 U/ml or aprotinin in doses as high as 10,000 U/ml (P>0.05). 5. CONCLUSIONS (1) ChE activity is reduced by CPB mainly by hemodilution and (2) the pharmacological agents used in the present anesthetic technique (heparin, aprotinin, midazolam, fentanyl, propofol and mivacurium) do not inhibit ChE activity at therapeutic serum concentrations.

Stereoselective high-performance liquid chromatographic assay with fluorometric detection of the three isomers of mivacurium and their cis- and trans-alcohol and ester metabolites in human plasma

An improved high-performance liquid chromatography assay for the three stereoisomers of the muscle relaxant mivacurium and its metabolites in plasma is presented. The principal steps in the assay are precipitation of plasma proteins by acetonitrile, lyophilization of the supernatant and ion-exchange chromatography on Spherisorb 5-SCX column, with gradient elution (acetonitrile from 32 to 68% v/v and ionic gradient from 7 to 56 nmol l-1 Na2SO4), a flow-rate of 2.0 ml min-1, D-tubocurarine as internal standard and fluorometric detection (excitation wavelength = 280 nm, emission wavelength = 320 nm). Quantitation limit of cis-cis, cis-trans, trans-trans isomers were 0.003, 0.002 and 0.005 mumol l-1, respectively. Quantitation limits for the monoestercis metabolite were 0.011 mumol l-1, for the monoestertrans metabolite 0.017 mumol l-1, for the amino-alcoholtrans 0.020 mumol l-1 and for the amino-alcoholcis 0.021 mumol l-1. None of eight drugs used during anaesthesia interfered with the assay in vitro. Satisfactory performance was demonstrated by the measurement of the isomers and their metabolites in plasma of two patients over a 6-h period after repeated injections of mivacurium.

Alcuronium : a pharmacodynamic and pharmacokinetic update

Alcuronium may be considered a muscle relaxant of historical rather than clinical significance.However, recent information from the manufacturer revealed its persisting clinical use in 26 countries worldwide. Thus, a pharmacodynamic-pharmacokinetic update appears mandatory. An intravenous (IV) single-bolus injection of alcuronium (0.25 mg/kg = ED95) was administered to 10 patients undergoing maxillofacial surgery during nitrous-oxide opioid anesthesia. Alcuronium neuromuscular block (evoked twitch tension), plasma concentration, and renal elimination (high-performance liquid chromatography [HPLC] assay) were measured during the 12-h after its administration. The time of onset, the time from end of injection to recovery to 25% of control twitch tension (DUR25%), and the recovery index were 2.2 +/- 1.2, 54 +/- 14, and 37 +/- 11 min, respectively (mean +/- SD). Two hours after the injection of alcuronium, partial recovery from the neuromuscular block had occurred from 100% to 26% +/- 24% depression of twitch tension, although less than 25% of the injected dose was recovered from the urine. The 12-h plasma concentration and urinary recovery were 0.1 +/- 0.08 mg/L (one-sixth of the 50% inhibitory concentration) and 61% +/- 20%, respectively. Recovery from neuromuscular block was dominated by intercompartmental distribution rather than by renal elimination. Since alcuronium does not undergo biodegradation, our data may serve as a reference for the complex pharmacokinetics of readily metabolized modern muscle relaxants. The long plasma half-life with slow excretion merits attention with respect to the erroneous original perception that alcuronium was an intermediate-acting muscle relaxant. (Anesth Analg 1995;80:373-7)

Simple and rapid high-performance liquid chromatography method for the determination of alcuronium in human plasma and urine

A simple and quick HPLC assay for alcuronium is presented. Its characteristics are: precipitation of plasma proteins by acetonitrile; Spherisorb 5-CN column; acetonitrile-water (46:54, v/v) as mobile phase; flow-rate 1 ml/min; laudanosine 0.06 mg/l as internal standard with plasma; external standard with urine; UV detection at 294 nm; retention time 5.4 min; detection limit 0.025 mg/l; documented linearity: 0.025-2.0 mg/l for plasma and 1.0-80 mg/l for urine; intra- and inter-assay variability below 4%. None of nine drugs used in perioperative pharmacotherapy interfered with the assay. Satisfactory performance was exemplified in a 12-h pharmacokinetic evaluation of two patients.

Pharmacokinetics and Pharmacodynamics of Atracurium and its Metabolite Laudanosine in Cardiac Surgery Involving Cardiopulmonary Bypass with Induced Hypothermia

SummaryThe infusion velocity of the short-acting muscle relaxant atracurium has to be reduced during hypothermic cardiopulmonary bypass to maintain a moderate degree of muscle relaxation. In the present study the extent of neuromuscular blockade and the plasma concentrations of atracurium and its main metabolite, laudanosine, were assayed by high-performance liquid chromatography in 10 patients undergoing open heart surgery for coronary artery bypass. Anaesthesia was induced by an intravenous bolus injection of midazolam (10 to 15mg) and fentanyl (0.75 to 1.5mg). Neuromuscular transmission was monitored at the adductor pollicis muscle after supramaximal stimulation of the ulnar nerve over the wrist (train-of-four). Muscle relaxation was initiated with an intravenous bolus injection of 460 µg/kg atracurium. Waning neuromuscular blockade was enhanced by intravenous injection of constant maintenance doses of atracurium (100 to 200 µg/kg) whenever the first twitch response of a train-of-four (T1) had attained 25% of its control.Plasma concentrations of atracurium and laudanosine were fitted to an open 2-compartment model where elimination of atracurium occurs from both the central and peripheral compartments. For the pharmacodynamic component of the model the Hill equation was assumed. Pharmacokinetic and pharmacodynamic parameters were estimated by means of the TOPFIT program and differences between normothermia and hypothermia were considered statistically significant.The increase in neuromuscular blockade during hypothermia was caused by a significantly (p < 0.05) decreased rate of the Hofmann-Elimination, the main metabolic pathway of atracurium, and by an increased sensitivity of neuromuscular junctions due to cooling.