Biomedical subjects
Publications and source records attributed to L E Mather.
Hypotension following peridural anesthesia with lidocaine was treated by intravenous injection of ephedrine. The ephedrine relieved the cardiovascular depression, but was associated with a concomitant increase in plasma lidocaine concentrations. This increase may push the plasma lidocaine concentration into the toxic region.
The plasma concentration-time profiles of meperidine following intravenous injection in surgical patients and volunteers were investigated by reference to a classical two-compartment open model. Physiologic characteristics of the subject and variables associated with the surgery and anesthesia were screened as determinants of the kinetic patterns observed. When meperidine administration preceded induction of anesthesia, induction was consistently followed by an increase in venous plasma concentrations that prevented classical kinetic analysis. To facilitate calculations in subsequent studies in patients, meperidine injections were made following induction of anesthesia. Type of anesthesia or premedication, patients' sex, or cigarette smoking did not appear to be important factors in this evaluation. Increasing alcohol consumption was associated with increasing volumes of distribution. Increasing age was associated with increasing fraction of drug unbound in plasma. These factors may relate directly to clinical observations that heavy alcohol consumers tend to be more refractory to central nervous system (CNS) depressants and that elderly patients are more susceptible to respiratory depression from narcotics.
Plasma concentrations of pethidine following i.m. gluteal injection were measured in surgical patients and volunteers. The mean plasma concentrations tended to be higher in the patients than in the volunteers; this may be a result of a slower initial absorption rate. At least 80% of the dose was absorbed from the injection site over the 6-hr period of the study. Fluctuations in plasma pethidine concentration were observed, probably caused by variations in local and systemic blood flow. This effect was more noticeable in the patient group. In general, the time-course of subjective effects in volunteers could be related to maximum plasma pethidine concentrations. However, patients appeared to be less sensitive to these effects at similar plasma drug concentrations, possibly because of catecholamine-mediated stimulus, suggesting that plasma concentrations may be a poor guide to the clinical response in patient-volunteer comparison.
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Information derived from measurements of blood concentrations of local anaesthetics can be extended by the application of pharmacokinetic anaylsis. A better understanding of quantitative aspects of the disposition and absorption of these drugs should assist the anaesthetist in deciding the optimal agent and dosage for regional block techniques.
Ten healthy, unpremedicated, male volunteers, aged 21-33 years, were given 20 ml 1 per cent etidocaine with 5 mug/ml epinephrine for peridural analgesia via a catheter placed L2. On a different occasion they were given 20 ml 2 per cent lidocaine with 5 mug/ml epinephrine in the same manner. Initial onset of sensory analgesia to pin prick was faster for etidocaine (7 min) than for lidocaine (9 min). Analgesia lasted significantly longer after etidocaine with respect to both two-segment regression (177 plus or minus SE min vs. 114 plus or minus 8 min) and total duration (379 plus or minus 22 min vs. 190 plus or minus 8 min). Onset of maximal motor blockade was significantly faster with etidocaine (15.4 plus or minus 2.5 min) than with lidocaine (31.7 plus or minus 3.3 min); blockade lasted longer with etidocaine (331 plus or minus 25 min vs. 167 plus or minus 13 min). Changes in mean arterial pressure cardiac output, central venous pressure, limb blood flows, total peripheral resistance, and stroke volume were similar with the two drugs, although those after etidocaine were more prolonged as a result of the longer blockade. Mean maximum arterial concentrations of etidocaine were 0.96 plus or minus 0.05 SE mug/ml (plasma) and 0.55 plus or minus 0.03 mug/ml (whold blood), achieved at 17 plus or minus 2 min. Mean maximum arterial concentrations of lidocaine were 2.22 plus or minus 0.09 mug/ml (plasma) and 1.85 plus or minus mug/ml (whold blood), achieved at 24 plus or minus 2 min. No sign of central toxicity was observed with either drug, although subjects receiving lidocaine tended to sleep, which was not the case with etidocaine. Hematologic screening, blood chemistries, and urinalyses performed 24 hours before and after each study showed no abnormality.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
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Computer techniques for numerical analysis are well known to pharmacokineticists. Powerful techniques for data file management have been developed by social scientists but have, in general, been ignored by pharmacokineticists because of their apparent lack of ability to interface with pharmacokinetic programs. Extensive use has been made of the Statistical Package for the Social Sciences (SPSS) for its data handling capabilities, but at the same time, techniques have been developed within SPSS to interface with pharmacokinetic programs of the users' choice and to carry out a variety of user-defined pharmacokinetic tasks within SPSS commands, apart from the expected variety of statistical tasks. Because it is based on a ubiquitous package, this methodology has all of the benefits of excellent documentation, interchangeability between different types and sizes of machines and true portability of techniques and data files. An example is given of the total management of a pharmacokinetic study previously reported in the literature by the authors.
Regional pharmacokinetics is the study of drug concentrations in specific regions of the body due to drug uptake and elution. Mathematical methods of interpreting regional pharmacokinetic data can vary greatly in their complexity depending on their intended use (i.e. to describe or predict), but must reinforce rather than replace experimental pharmacokinetics. 'Black box' analysis provides and empirical method for the study of complex pharmacokinetic systems using either statistical moment or linear systems analysis. However, these methods are only applicable to linear and time-invariant systems, and ignore the large body of information concerning the physiological and physiochemical basis of regional pharmacokinetics. Clearance concepts are suitable for describing linear drug uptake processes, but mass balance principles have wider applications in describing the rate and extent of both drug uptake and elution. Compartmental models of a region can vary from single compartment descriptions based on the concept of venous equilibrium to complex multi-compartmental models of the intravascular, interstitial, and intracellular spaces, in which drug transport between compartments is a function of drug binding and ionization. Ultimately, as more regional pharmacokinetic information is obtained, more complex three dimensional models may be necessary such as those used to describe the uptake of oxygen from capillaries.
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Local anaesthetic agents can cause central nervous system (CNS) and cardiovascular system toxicity. Whereas most previous work has described their behavioural CNS effects qualitatively (i.e., absence or presence of convulsions), we wished to describe their CNS effects more quantitatively. We hypothesised that early CNS excitatory or disinhibitory effects leading to convulsions represent a prodrome to the onset of chaotic dynamics in the form of a bifurcation in the chaotic map. We therefore used a chaotic map with a continuous scale to model their CNS effects. A Central Effects Index (CEI) was developed from our observation of behaviours before and after intravenous (iv) administration of local anaesthetic agents in graded doses to conscious sheep. These behaviours were ranked in severity, and modelled according to a logistic population growth equation using the onset of convulsive behaviour and death as point attractors. The behaviours, scaled to the maximum and area under the curve (AUC) CEI units, were then compared for intravenous doses of (+/-)-RS-bupivacaine and (-)-(S)-bupivacaine (or levobupivacaine), which is being evaluated as a substitute for (+/-)-RS-bupivacaine. (-)-(S)-bupivacaine produced smaller maximum and AUC CEI values at 75 and 100 mg doses, but equivalent values at 150 and 200 mg when the doses exceeded the convulsant threshold. It was concluded that the CEI provides a useful quantitative tool for evaluating these agents in subconvulsant doses, and that the CNS stimulatory potency of (-)-(S)-bupivacaine is less than that of (+/-)-RS-bupivacaine.
BACKGROUND AND OBJECTIVES: Whether patients titrate themselves to an individualized blood or plasma opioid concentration (the so-called minimum effective concentration or [MEC]) has been debated extensively. Nevertheless, there is consistent opinion that during patient controlled analgesia (PCA) patients balance acceptable pain relief against unacceptable side effects. This study sought to characterize fentanyl used by PCA with respect to MEC and factors influencing PCA use. METHODS: An intensive study of 25 patients with observations over the first 24 hours after orthopedic surgery was planned on the premise that this approach would provide a measure of the fentanyl MEC. This necessitated repeated measurements of pain scores and plasma fentanyl concentrations before and 10 minutes after every PCA demand. In addition, a battery of psychological tests was given before and approximately 48 hours after surgery. RESULTS: Logistic difficulties of maintaining a 24-hour study design resulted in its termination after 5 patients. The patients had convincingly distinct MECs (ranging from 0.23 to 0.99 ng/mL). The relationship between plasma fentanyl concentration and pain score was steep, such that small changes in concentration coincided with marked changes in pain relief. Despite preoperative expectations of achieving satisfaction in postoperative analgesia, not all patients titrated themselves to a pain-free state; all but one were satisfied with PCA. Surprisingly few side effects were reported. Unfortunately, the small sample size made systematic analysis of the psychological tests impossible. CONCLUSIONS: This study found evidence to support the concepts of an individual MEC and a therapeutic window of fentanyl used with PCA.