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PubMed1977

The age-dependence of intestinal absorption using d-xylose as an example.

In 40 infants the serum concentrations of D-xylose were measured from capillary blood samples up to 300 min after an oral dosage of 0.5 g of D-xylose per kg body weight. The parameters of the absorption kinetics, which are calculated by a digital computer program, showed an age-dependent behavior. Infants up to the age of 2 months have lower maximal serum concentrations compared to older ones because of a larger volume of distribution. The rate constant of invasion k1, which serves as a measure for the rate of intestinal absorption and the rate constant of elimination k2 were significantly lower in infants up to the age of 2 months compared to older ones. The quotient of k1:k2 was independent of age. The time it took to reach maximal serum concentration was significantly longer in young infants. By adding metoclopramide simultanously to the oral D-xylose doses it could be demonstrated that the slower motility of the gastrointestinal tract in newborns and young infants is not exclusively responsible for the slower rate of absorption of D-xylose. Comparing the absorption rates in 26 infants after different D-xylose dosages a saturation kinetics may be supposed.

Age Factors↗
PubMed1975

Cardiac muscle models for both isotonic and isometric contractions.

The choice of a suitable muscle model consistent with the mechanical behaviour of Rat papillary muscle at rest or during isotonic or isometric contraction has been considered. Three different preload levels within the ascending limb of the Frank-Starling curve have been used in five papillary muscles. Series elastic (SE) and parallel elastic (PE) length-tension relationships have been evaluated according to five mechanical muscle models using data from systolic and diastolic quick-release manoeuvres. For each preload level and muscle model, the time course of the force-velocity relationship of the contractile element (CE) has been calculated using a PDP 8/L digital computer. Several mechanical and biological characteristics are considered which exclude four of the five selected muscle models. The Maxwell model with a damper seems to be the most suitable mechanical model for Rat papillary muscle. According to the selected muscle model it seems that VCEmax is dependent on muscle length variation; the reliability of this parameter as an index of myocardial contractility is discussed.

Animals↗
PubMed1989

Evaluation of theophylline pharmacokinetics in a pediatric population using mixed effects models.

Routine clinical pharmacokinetic data collected prospectively from pediatric patients receiving theophylline were analyzed using the NONMEM (nonlinear mixed effects model) digital computer program. A total of 314 measured serum theophylline concentrations (STCs) were obtained from 84 hospitalized patients ranging in age from 4 months to 15.2 years with the majority of patients between the ages of 1 and 8 years. Fifty-six percent were male. The race/ethnicity distribution was 71.4% Latin, 15.5% black, 11.9% Caucasian, and 1.2% (one subject) Pakistani. Of the total number of observed STCs, 16.2% reflected some degree of outpatient dosing. The pharmacokinetic model used was a one-compartment open model with either zero-order or first-order absorption and first-order elimination. Age was the most important determinant of theophylline clearance (Cl); weight was inferior to age and did not statistically improve the model (p greater than 0.005) when combined with age. Total Cl increased by 10%/year over the age range of 1 to 15 years of age. Black race and male gender were associated with higher Cl values: for a given age, Cl was 34% higher for blacks than the reference population composed of the remaining patients, and Cl for males was 25% higher than that for females. The volume of distribution (Vd) for the population was estimated to be 0.62 L/kg. The interindividual variability in Cl and Vd expressed as coefficients of variation were 19 and 28%, respectively. The residual intraindividual error variance corresponded to a standard deviation of 2.8 micrograms/ml. The STCs that represented some degree of outpatient dosing were 21% lower than those reflecting only inpatient dosing. Alternate models that include weight as a determinant of theophylline clearance are also provided. The NONMEM method of determining population pharmacokinetics is well suited to the pediatric population since it does not require a large number of STCs per patient. In this study a mean of only 3.7 STCs per patient were utilized to provide information which should prove useful in the design and adjustment of theophylline dosage regimens in children.

Adolescent↗
PubMed1982

The effect of duration of intravenous infusion on maximum and threshold blood concentration for drugs exhibiting biexponential elimination kinetics.

The relationships among peak blood concentration (Cmax), the time (tD) during which blood concentrations are maintained above the minimum effective concentration (Cmin), and the duration of a constant-rate intravenous infusion (T) of a drug exhibiting biexponential pharmacokinetics were simulated by digital computer using Newton iterative procedures. These simulations showed that, in contrast with our previous findings for drugs with monoexponential pharmacokinetics, the relationships are more complex due to the larger number of variables. Therefore, investigation of these relationships for biexponential drugs should be done on a drug by drug basis. Accordingly, meperidine and sulfamethoxazole were chosen as examples of drugs which exhibit biexponential kinetics and were used to determine what errors were involved in using the simpler guidelines for drugs which exhibit monoexponential kinetics as an approximation. These simulations showed the following . (a) The effect of T on Cmax may be adequately estimated by using the guidelines for monoexponential kinetics with the elimination half-life (t1/2) taken as t1/2 lambda1, provided that lambda1 is 20 to 30 times lambda2 and that the AUC of the distribution phase (i.e., C1/lambda1) comprises greater than about 20% of the total AUC. (b) As with monoexponential drugs, it is possible to obtain a larger tD by infusing the dose compared to that obtained with a bolus, if the value of C(0)/Cmin less than 2.5. (c) Using th approximation of monoexponential pharmacokinetics to estimate the effect of T on tD will underestimate both tD and the maximum infusion time, which will just attain the Cmin unless the AUC of the distribution phase comprises only a very small proportion of the total AUC. (d) The simulations with meperidine also showed that the nature of the relationship between tD and T varies depending on whether Cmin is maintained in the distribution phase or in both the distribution and elimination phases.

Computers↗
PubMed1980

The effect of infusion time on the time course of drug concentration in blood.

We have studied by digital computer stimulation the relationship among the rate of intravenous infusion of the dose of a drug, the pharmacokinetic parameters of the drug, the maximum blood drug concentration achieved (Cmax) and the interval (TEff) during which the blood concentration of the drug is maintained above a selected minimum effective concentration (CEff) for the case of single dose administration of a drug with monoexponential pharmacokinetics. It was found that increasing the time during which the dose of the drug is infused results in a much smaller decrease in the maximum blood concentration attained. TEff, was found to be a fraction of the ratios infusion time/drug elimination half-life and zero-time intercept (Co)/CEff. The stimulations showed that TEff varies nonlinearly with increasing infusion time. However, the nature of the relationship between TEff and infusion time depends very much on the value of Co/CEff. At low values of Co/CEff, TEff decreased almost linearly with increasing infusion time, but at higher values of Co/CEff, TEff increased for a time with increasing infusion time. From these simulations, it should be possible to predict whether therapeutically effective blood concentrations of a drug may be achieved with the use of a slower infusion in situations where clinical considerations necessitate that the infusion time of the dose be increased.

Computers↗
PubMed1983

The pharmacokinetics of furazlocillin in healthy humans.

The pharmacokinetics of the novel acylureidopenicillin furazlocillin, 6-[D-2-(3-furfurylidenamino-2-oxo-imidazolidine-1-carboxamido)-2 -(4-hydroxyphenyl)-acetamido]-penicillanic acid and of its penicilloic acid derivative were investigated in five healthy male volunteers after intravenous administration of 2 and 4 g dosages. The volunteers were either in a lying or sitting position throughout the duration of the studies. The concentrations of the drug in plasma and urine were measured by two different methods in parallel: a microbiological assay and a newly developed high pressure liquid chromatography method. The latter method was also applicable for quantitation of the penicilloic acid derivative in these biological fluids. The drug's plasma protein binding (66%) and apparent red cell-plasma partition coefficient (0.055) were concentration independent. The pharmacokinetics of the drug were first order only at the lower dose level. The apparent half lives of three distinguishable phases were, respectively, 4(t1/21), 18 (t1/22), and 64 (t1/2z) min. The total and renal clearances of the drug were, respectively, 303 and 79 ml/min. The latter value implied tubular secretion of the drug. Graphical and digital computer analyses of the data were performed with a linear three compartment body model. Small but consistent deviations from linear kinetics caused by the nonrenal elimination route were observed after administration of the higher dose (4 g). In contrast, renal elimination showed no such dose dependency and was first order. The disposition kinetics of furazlocillin were body position independent. The penicilloic acid derivative of furazlocillin was found in plasma and urine in all the five subjects tested. The percentage of the dose excreted renally as the derivative amounted, respectively, to 5.2 and 7.0% after the lower and higher dosage of furazlocillin, with significant inter- and intrasubject variability. The renal clearance of the derivative was 41 ml/min.

Adult↗
PubMed1979

Accumulation kinetics of drugs with nonlinear plasma protein and tissue binding characteristics.

The purpose of this investigation was to study, by digital computer stimulation, the accumulation kinetics of drugs which exhibit concentration-dependent binding to tissues and either linear (constant free fraction) or concentration-dependent (increasing free action with increasing drug concentration) binding to plasma proteins. It was assumed that elimination rate is proportional to free drug concentration in plasma and that there occurs instantaneous equilibration of drug between vascular and nonvascular spaces. Nonlinear binding can yield, under certain conditions, apparently biexponential plasma concentration-time curves which may be misinterpreted as being representative of a linear and biexponential system. Such misinterpretation would cause the following errors in the prediction of drug accumulation and elimination kinetics during and after constant-rate infusion: (a) the time required to reach steady state may be overestimated, and (b) the prominence of the apparent distribution phase after cessation of infusion may be underestimated. Drugs with linear and nonlinear plasma protein binding characteristics differ with respect to the relaionship between infusion rate and steady-state concentration. This relationship is linear when plasma protein binding is linear. Steady-state concentration increases less than proportionally with increasing infusion rate if plasma protein binding is drug concentration dependent.

Blood Proteins↗
PubMed1980

A quantitative analysis of ultrastructural changes induced by electrical stimulation of identified spinal cord axons in the larval lamprey.

Microelectrodes filled with horseradish peroxidase (HRP) were used to label single identified giant axons in the isolated lamprey spinal cord. Subsequent to the iontophoretic injection of HRP, the spinal cord was stimulated at repetition rates of 20-30/s and the activity in labelled axons monitored. Immediately following failure of the action potential, the spinal cord was fixed by immersion and processed for light and electron microscopy. Electron micrographs were taken of synaptic contacts made by the labelled axons. Several quantitative measures were made from each synapse using a digitizing tablet interfaced with a digital computer. These measures included vesicle number (VN), vesicle area (VA), length of differentiated membrane (DM), vesicle density (VD = VN/VA), vesicle frequency (VF = VN/DM), and a relative measure of the amount of vesicle membrane added to the axolemma during the stimulation period, the curvature ratio (CR). Measures from 106 stimulated synapses were compared with 134 synapses from injected but unstimulated giant axons. The results from these experiments suggest that measurable ultrastructural changes occur during transmitter release at identified C.N.S. synapses, which are consistent with the hypothesis of synaptic vesicle recycling.

Action Potentials↗
PubMed1980

Clovoxamine and fluvoxamine-2 biogenic amine re-uptake inhibiting antidepressants: quantitative EEG, psychometric and pharmacokinetic studies in man.

In a double-blind placebo-controlled study, the encephalotropic, psychotropic, pharmacodynamic and pharmacokinetic properties of 2 new substances, clovoxamine (a 5-HT and NE re-uptake inhibitor) and fluvoxamine (a selective 5-HT inhibitor) were investigated utilizing quantitative pharmaco-EEG, psychometric and blood level analyses. Ten normal volunteers received randomized and in weekly intervals oral single doses 50 mg, 75 mg and 125 mg clovoxamine, 75 mg fluvoxamine, placebo and as reference drug 75 mg imipramine. Quantitative EEG, psychometric data, pulse, blood pressure, side effects and pharmacokinetic data were studied at the hours 0, 2, 4, 6 and 8. Plasma levels of both substances peaked in the 4th to 6th hour and declined slowly thereafter. Digital computer period analysis of the EEG demonstrated after clovoxamine only minor changes characterized by an increase of fast beta-activities suggesting slight activating qualities of the drug. On the other hand 75 mg fluvoxamine and especially 75 mg imipramine produced marked CNS changes characterized by a concomitant increase of slow and fast activities and a decrease of alpha-activity. However, 75 mg fluvoxamine induced less augmentation of slow activity than imipramine indicating less sedative properties of fluvoxamine than the standard reference drug. Psychometric tests demonstrated after 50 and 75 mg clovoxamine and 75 mg fluvoxamine an increase in attention, attention variability, concentration, CFF and after-effect in the Archimedean Spiral (indicating central activation), further an improvement in mood and affectivity as compared with placebo, while 125 mg clovoxamine and 75 mg imipramine produced an increase in reaction time, deterioration of mood and affect and psychomotor activity. The latter changes were observed also after other antidepressants in normals. Pharmacodynamic investigations regarding dose-efficacy and time-efficacy relations based on both EEG and psychometric parameters revealed that 75 mg imipramine was the most effective compound, followed by 75 mg fluvoxamine and 125 mg, 75 mg and 50 mg clovoxamine. The peak effect of clovoxamine and fluvoxamine was observed around the 6th hour, while 75 mg imipramine was maximally observed around the 6th hour, while 75 mg imipramine was maximally effective between the 2nd and the 4th hours. Side effects were minimal after clovoxamine (interestingly euphoria in 3 subjects), while tiredness was seen in 5 out of 10 subjects after 75 mg fluvoxamine and in 8 out of 10 subjects after 75 mg imipramine. There were no clinically relevant changes in pulse, systolic and diastolic blood pressure.

Adult↗
PubMed1995

An audio-video system for automated data acquisition in the clinical environment. LOTAS Group.

OBJECTIVE: Our objective was to develop an audiovideo data acquisition system that facilitates studying the activities of anesthesia care providers in the clinical environment. METHOD: Ceiling-mounted miniature video cameras, vital sign monitors, and videocassette recorders (VCRs) were interfaced to digital computers in two patient admitting areas and two operating rooms of a trauma center. This video data acquisition system network (VASNET) is simple to operate. Insertion of a videotape activates the system and begins video overlay of updated vital signs onto the video image every 5 sec. Recorded data is passed via a local area network, allowing remote monitoring of the data acquisition process. To facilitate analysis of the video at a later time, the image, soundtrack, and vital signs data are stamped with the same time code. Each tape is initialized by recording the data file name and wall clock time for 30 sec at the start of taping. This initialization enables comparison of the video recordings with anesthesia, surgical, and nursing records. RESULTS: During 2 years of operation, VASNET was used to record over 100 cases of acute trauma management. Vital signs overlaid onto the video image identified when patient monitors were in use and providing data. Participants found videotape review useful in assessing their own performance. VASNET was nonintrusive and acquired data with minimum user interaction. In one operating room, separate from the trauma center, VASNET was installed to function as a remote monitor, with the option of videotaping. Although users were aware of when videotaping occurred, once patient management was underway, the activities of the anesthesia care providers did not appear to be influenced by the videocassette recording. Equipment maintenance was not excessive. The most frequent problems were changes to the VCR control settings and disconnection of the power supply or interface connections. CONCLUSIONS: Videotapes of the process of anesthetizing and resuscitating trauma patients provided a record of the activities of anesthesia care providers. Video vignettes may be useful training tools. Excerpts from real scenarios can be incorporated into anesthesia stimulators. The soundtrack and timing of real events from such video acquisition may be useful in the development of multimedia simulations of trauma patient resuscitation. The data collection may be useful for research into human performance, ergonomics, training techniques, quality assurance, and certification of anesthesia care providers in trauma patient management. Potential additional applications of VASNET include remote monitoring of patients in the operating room, in the intensive care unit, during transportation, in hazardous environments, and in the field. Such VASNET telemetry may facilitate the availability of expert opinions during medical and other consultations.

Anesthesia↗
PubMed1977

Compartmental analysis of potassium efflux from growth-oriented heart cells.

Radioisotopic flux studies were initiated with a new preparation of growth-oriented heart cells to determine the contribution of heterogeneous cell types and the limitations of extracellular diffusion in quantitating the passive movement of potassium ions. The efflux of potassium-42 from contractile preparations, which contain two populations of cells, cardiac muscle and fibroblastlike, could be resolved into two components similar to that described for naturally occurring preparations of cardiac muscle. Compartmental analysis of the efflux data, using analog and digital computational methods, resolved the tracer kinetics into a slow compartment (k=0.015 min-1) associated with fibroblastlike cells and a fast compartment (k=0.067 min-1) associated with the cardiac muscle cells. The rate constants derived from compartmental analysis were independent of tracer equilibration and preparation dry weight. Analytical measurements of the preparations provided a quantitative basis for determing the transmembrane potassium fluxes from the tracer kinetics. Cardiac muscle cells stimulated at a rate of 150 min-1 in the presence of 5.4 mM external potassium were found to have a potassium efflux of 15.7 pmoles cm-2sec-1 whereas the value obtained for the fibroblastlike cells was 1.88 pmoles cm-2sec-1. Diffusional limitations of 42K efflux were analyzed for several important variables which can affect isotopic reflux, namely, transmembrane flux, cell volume-to-surface area and cell packing fraction.

Animals↗
PubMed1986

ICU monitoring of ventilation distribution.

The oxygen washin method has been shown to be a practical way to measure functional residual capacity (FRC) in the intensive care unit. The ventilator oxygen concentration is increased and measurements of respiratory flow and oxygen concentration at the mouth are made with the patient monitoring system. No additional personnel, bedside equipment or ventilator attachments are required. A feasibility study was performed to determine if this method could be used to estimate a continuous distribution of ventilation with respect to ventilation to volume ratio VA/V. Due to gas mixing in the ventilator, the inspired oxygen fraction does not increase instantaneously to its new value. An equation was derived which models the lung as 50 discrete compartments and accounts for the transient change in mean inspired oxygen fraction. A digital computer simulation demonstrated good distribution recovery for one and two mode ventilation distributions. Continuous distributions were computed for four post cardiac surgery patients at four levels of positive end expiratory pressure (PEEP). In these patients a linear increase in the amount of ventilation in the normal VA/V range occurred with increasing PEEP, i.e., slow and fast spaces tended to move centrally toward a more normal VA/V range. At zero PEEP 26% of the ventilation occurred in the normal range and this increased to 49% at 15 PEEP. Dead space fraction was poorly estimated and spurious modes occurred in the high VA/V range.

Cardiac Surgical Procedures↗
PubMedDate not supplied

[Principles of the genesis of pressure and flow pulse contours of the human carotid artery (author's transl)].

In order to clarify the genesis of the characteristic pressure and flow pulse contours of the common carotid artery of man, at first transcutaneous pulse recordings were carried out on healthy resting subjects during breathing of room air and of a mixture of 95% O2 and 5% CO2 (Carbogen). The latter was used to cause vasodilation of the cerebral resistance vessels and thus reducing the peripheral reflection coefficient. Secondly pulse constructions were performed by means of a theoretical inhomogeneous tube model using a digital computer. A side branch of this model represented the carotid artery. The pressure pulse of the aortic arch of the model was used as generating pulse for the carotid system. A satisfactory simulation of the carotid pressure and flow pulse contours under normal conditions and during peripheral vasodilation requires an intermediate reflection (positive for antegrade waves) at a site near the middle of the total transmission time of the carotid model system. The adequacy of the model is demonstrated by comparison of the recorded and constructed pulses.

Adult↗
PubMed1989

Analysis of human torso motion with muscle actuators.

A biomechanical model is devised to analyze the motion of the human torso and estimate the load on the lumbar spine, the contraction forces in the trunk muscles, and the sensory signals between the muscle and the nervous system. A state space formulation of three-dimensional (3D) equations of motion of the human torso is presented with muscle forces as input to the system. At least 3 pairs of skeletal muscles are considered to be necessary for 3D motion of human torso. Functional anatomy of these major muscles of the human trunk are discussed. These muscles as well as their feedback and feedforward sensory paths are modeled by linear viscoelastic components and force generators. Stability of the torso with three pairs of muscles is studied both with muscle spindles inactive (open loop) and active (closed loop). Voluntary point-to-point motion of the torso in three-dimensional space is simulated on a digital computer, employing a dynamic controller, where feedback gains are tuned (programmed) by higher centers of nervous system.

Biomechanical Phenomena↗
PubMed1992

Modeling the circulation with three-terminal electrical networks containing special nonlinear capacitors.

Development, first of analog and later of digital computers, as well as algorithms for analysis of electrical circuits, stimulated the use of electrical circuits for modeling the circulation. The networks used as building blocks for electrical models can provide accurate representation of the hydrodynamic equations relating the inflow and outflow of individual segments of the circulation. These networks, however, can contain connections in which voltages and currents have no analogues in the circulation. Problems arise because (a) electrical current must flow in closed loops, whereas no such constraints exist for hydraulic models; and (b) electrical capacitors have a number of characteristics that are not analogous to those of hydraulic compliant chambers. Disregarding these differences can lead to erroneous results and misinterpretation of phenomena. To ensure against these errors, we introduce an imaginary electrical element, the nonlinear residual-charge capacitor (NRCC), with characteristics equivalent to those of a compliant chamber. If one uses appropriate circuit connections and incorporates the residual-charge capacitor, then all voltages and currents in the model are proper analogues of pressures and flows in the circulation. It is shown that the capacitive current represents the rate of change of volume of blood inside the vessel, as well as the rate of the corresponding displacement of volume of the surrounding tissue.

Blood Circulation↗
PubMed1995

Use of a pattern recognition technique to control a multifunctional prosthesis.

Various kinds of command source can be used to control an above-elbow prosthesis. But none of them can be used to perform a specified task easily. The research is devoted to investigation of the potential effectiveness of applying the kinematic data of the shoulder joint to control an upper-limb prosthesis. Using these data as input signals, an appropriate signal processing technique, pattern recognition, is utilised to derive control commands. The purpose of the investigation is to use these commands to control a multifunctional prosthesis so that an amputee can perform a few tasks. For testing performance accuracy, a goniometer is worn by a subject with intact arm. It is also interfaced to a digital computer. Next, he is asked to do one of the predefined tasks for which the joint angle trajectories have already been derived and stored. Almost as soon as the shoulder joint angles are sampled and sent to the computer, the program calculates the elbow and wrist angles. These values are compared with actual elbow and wrist angles, which are monitored by the goniometer.

Arm↗
PubMed1985

Control of intraaortic balloon pumping: theory and guidelines for clinical applications.

The effectiveness of intraaortic balloon pumping was investigated by using a lumped parameter model of the cardiovascular/assist device system. The model consists of a time-varying elastance left ventricular simulation, a 2-element windkessel arterial simulation, and an RC venous return and pulmonary simulation. The four major hemodynamic variables, stroke volume (SV), aortic mean diastolic pressure (MDP), tension time index (TTI), and aortic end diastolic pressure (EDP), were divided into two categories related to system energy supply and demand: "external" and "internal" variables. The effects of balloon pumping on these variables can be described by closed-form equations that yield an optimal solution. The model prediction suggests that, in the ideal case, optimization of balloon pumping calls for instantaneous inflation of the balloon to maximum volume at end systole and instantaneous complete deflation at end diastole. For finite inflation/deflation rates, the optimal time for the start of inflation is end systole. Deflation timing, however, involves a tradeoff between maximizing the external variables and minimizing the internal variables. These predictions were tested using a nonlinear digital computer model. The results also suggest that when SV is not being monitored, optimal inflation timing can be controlled from the measurements of TTI or pulmonary venous pressure; optimal deflation timing can be controlled by a weighted combination of MDP and EDP.

Assisted Circulation↗