Preliminary results of simulations with an improved mathematical model of drug tolerance.
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Biomedical subjects
Publications and source records attributed to A Peper.
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A design for an amplifier for bioelectric events is presented that has fewer parts than conventional designs. The design allows the construction of amplifiers of a high quality in terms of noise and common mode rejection, with reduced dimensions and with a lower power consumption. Gain, bandwidth and number of channels are easily adapted to a wide range of biomedical applications. An application example is given in the form of a multichannel EEG amplifier (gain is 20,000), in which each channel consists of three operational amplifiers (one single and one dual), six resistors and two capacitors. The equivalent input noise voltage and current are 0.15 microVrms and 1 pArms, respectively, in a bandwidth of 0.2-40 Hz, and a common mode rejection ratio of 136 dB is achieved without trimming.
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A QRS onset and offset detection algorithm has been developed for use in body surface QRS integral mapping of ventricular tachycardia. To determine QRS intervals, the algorithm uses two computed signals: the sum of the absolute values of the first derivatives of all leads and the sum of the absolute values of all leads. The second order derivative of the latter parameter is used to detect the time instants of QRS onset and offset. Using the algorithm, QRS integral maps are subsequently computed, which are correlated with a database of QRS integral maps in order to localize the site of origin of ventricular tachycardia. Comparison of the performance of the algorithm with visual evaluation by a human expert in this procedure revealed, in 95% of the cases, an identical or adjacent localization of the site of origin.
The paper deals with the influence of mains interference on time coherent averaging using an internal trigger. The general distribution of the time jitter is derived and applied to a simplified signal. The authors prove that no amount of averaging can do away with this type of interference. Finally, the deformation this type of jitter has on a step signal is computed.
Since catheter or surgical techniques for ablating the arrhythmogenic substrate in patients with SVT due to accessory pathways or those with VT are now available, exact localization of the substrate is mandatory. We report preliminary results of two new non-invasive techniques for localizing either the site of earliest ventricular contraction using ISPECT, or the site of initial ventricular depolarization by magnetocardiography (MCG) in WPW syndrome and in VT patients. Thirteen patients with WPW syndrome and 8 patients with sustained VTs were studied with ISPECT. In 9/13, comparative catheter mapping data were available. Two patients had two Kent bundles. 13/15 Kent bundles could be localized by ISPECT. In 5/9 patients the area of Kent bundle insertion was identical with ISPECT and catheter mapping, in 3 correlation was fair, and in 2 patients with 2 Kent bundles ISPECT failed to localize their insertion. In 3/8 patients with VT catheter mapping could not be performed for hemodynamic reasons. In 2/5 patients the area of VT focus was identical with both methods, in one patient it was adjacent to each other, and in 2/5 patients a larger anatomic distance of the focus was found with both methods. In 3/7 patients with WPW the MCG showed the site of Kent bundle insertion, which was identical to that seen by catheter mapping. In one patient the area was adjacent, and in 3 more distant from the site determined by catheter mapping. In 1/2 patients with 2 Kent bundles, one of these could be detected by MCG. In 1/3 patients with VT, the site of VT focus was identical with both methods, but in the remaining two a distance of 3-4 cm was observed between the area seen with MCG and that with catheter mapping. In 4 further VT patients with stable and uniform ventricular late potentials, ventricular late magnetic activity was found with different QRS lengths within the single MCG channels. From our results we conclude that both ISPECT and MCG seem to become very promising non-invasive techniques for localizing ectopic ventricular depolarization in WPW syndrome and VT patients. However, these methods have to be refined, improved and validated by further systematical studies.
A multichannel instrumentation amplifier, developed to be used in a miniature universal eight-channel amplifier module, is described. After discussing the specific properties of a bioelectric recording, the difficulties of meeting the demanded specifications with a design based on operational amplifiers are reviewed. Because it proved impossible to achieve the demanded combination of low noise and low power consumption using commercially available operational amplifiers, an amplifier equipped with an input stage with discrete transistors was developed. A new design concept was used to expand the design to a multichannel version with an equivalent input noise voltage of 0.35 microV RMS in a bandwidth of 0.1-100 Hz and a power consumption of 0.6 mW per channel. The results of this study are applied to miniature, universal, eight-channel amplifier modules, manufactured with thick-film production techniques. The modules can be coupled to satisfy the demand for a multiple of eight channels. The low power consumption enables the modules to be used in all kinds of portable and telemetry measurement systems and simplifies the power supply in stationary measurement systems.
Galvanic isolation of a patient during a bioelectric recording is necessary to ensure the safety of the patient. In a typical measurement situation high interference voltages may be present across the isolation barrier. In this paper the necessity of a very high isolation mode rejection ratio--the ability of the amplifier to suppress feed-through from voltages across the isolation barrier to the output--is argued and a design of a multichannel amplifier with an isolation mode rejection ratio of 160 dB is described.
The effect of isoflurane 2.0 MAC on human atrioventricular conduction time was studied. A non-invasive recording system for the detection of His-Purkinje potentials based on signal averaging techniques was used. Recordings were made in 15 patients before and after induction with isoflurane. We were able to measure atrial (P-H) and His-Purkinje (HPS) conduction times in 11 patients. Mean (+/- SEM) P-H conduction time decreased from 101.8 +/- 5.3 to 89.3 +/- 3.3 ms (P less than 0.01). HPS conduction times did not change significantly. Heart rate increased significantly from 86.7 +/- 4.2 to 94.9 +/- 4.7 beats min-1 (P less than 0.05). Systolic blood pressure decreased from 117.3 +/- 4.6 to 94.1 +/- 4.7 mmHg (P less than 0.05). It is concluded that the effects of isoflurane on supraventricular conduction time in humans depend on interactions of several different mechanisms.
When the instantaneous magnitude of an electrical signal is to be determined, a reference has to be known against which the signal value should be measured. In electrocardiology, this reference is commonly derived from the isoelectrical period in the ECG. However, this period is not a clearly defined part of the ECG, and its use can be problematic. The signal level obtained from it is often not sufficiently unambiguous and in the case of a high heart rate this period is too short to be used or not present at all. In the paper a method is developed to compute a reference value, independent of the isoelectrical period and of heart rate. The method is derived from a method published before, which we developed for the separation of the surface His-Purkinje signal from the P-wave in the case of overlap. In the present application of the method, two successive heartbeats are separated in an analogous manner, revealing the signal level at zero heart activity. In applications described in the paper, this signal level is used as zero reference in nonlinear techniques. The method proved to work well and accurately.
In the first part of the review the various mechanisms that could be the cause of interference in bioelectric recordings are considered. It is demonstrated that the performance of a good amplifier can be seriously degraded in its functioning if the whole measurement situation is not taken into account. Several techniques used to reduce interference, of which guarding and driven right leg circuits are the most important, are analysed. In the second part of the review some examples of the application of the theory in practical situations are presented. The instrumentation amplifier circuit normally used in bioelectric recordings is improved for measurements under difficult circumstances. Another application is a low-cost 64-channel amplifier for multichannel ECG recordings. The third application is a device that can be added to bioelectric measurement systems and will provide a major reduction in interference.
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Sudden cardiac death occurs in the Federal Republic of Germany with an incidence of 60,000 to 90,000 per year. Ambulatory ECG monitoring has demonstrated that in about 80% of such events, the heart rhythm before and during sudden cardiac death shows ventricular tachycardia leading to ventricular fibrillation and circulatory standstill. From experimental studies it is known that the substrate for precipitation of the ventricular arrhythmia is localized injury in myocardial tissue with conduction delays and conduction blocks resulting in inhomogeneous spread of the impulse between normal and injured myocardium enabling the existence of an electrical re-entry circuit. Anisotrophy, that is differing velocities of conduction parallel and perpendicular to fiber direction as well as dispersion of repolarization appears responsible for propagation of the circuit. Because of the delayed impulse spread, the late depolarization after the end of the QRS complex can be detected in the ECG as ventricular late potentials by means of high resolution systems. Ventricular late potentials may be regarded as indicative of increased electrical vulnerability of the ventricles. Prevalence of ventricular late potentials: In our own studies using the signal-averaged ECG technique, ventricular late potentials were found most frequently in patients with coronary artery disease and only in 6/100 healthy subjects, in 5/30 patients with dilated cardiomyopathy, in none of 30 patients with aortic stenosis or ten with "small vessel disease". With continuously-registered high resolution electrocardiography but not with the signal-averaged ECG, patients with dilated cardiomyopathy or QT-syndrome can be found to have labile, intermittent ventricular late potentials. In patients with coronary artery disease, the number of those in whom ventricular late potentials can only be detected with continuously-registered high resolution ECG in addition to signal-averaged technique lies between 6 and nearly 30%. With respect to frequency analysis of the ST-segment, which is based on the hypothesis that the fractionated signals in arrhythmogenic areas are of higher frequency than the normal low frequency signals of the ST-segment in normal myocardial areas, there is only limited experience and no data from larger collectives.(ABSTRACT TRUNCATED AT 400 WORDS)
The effects of 2.0 MAC halothane on atrioventricular conduction times in humans were studied. A real-time recording system for the detection of surface His-Purkinje potentials based on signal averaging techniques was used. Recordings were made in 23 patients before and after the administration of halothane. In 18 patients we were able to measure atrial (P-H) and His-Purkinje (H-V) conduction times (78%). A small but statistically significant decrease in P-H conduction times from 115.3 +/- 3.9 (SEM) to 110.8 +/- 4.2 ms was found (P less than or equal to 0.01). H-V conduction times did not change significantly. Heart rates decreased significantly from 87.6 +/- 2.6 to 74.8 +/- 2.5 beats/min (P less than or equal to 0.01). Systolic blood pressures decreased from 118.9 +/- 3.7 to 103.6 +/- 4.2 mm Hg. It is concluded that the decrease in heart rate and the decrease in atrial conduction time caused by halothane can be explained by interactions of several different mechanisms. The specific combination of slowing heart rate and a decrease of atrial conduction time provides a possible explanation for atrial arrhythmias during the administration of halothane.
In the previous paper (Peper et al., 1987: J. theor. Biol. 127, 413), a model of drug tolerance was developed based on the assumption that the decrease of drug effect after repeated administration of a drug is caused by the involved regulations in the organism adapting themselves to the presence of the drug. In the present paper, the behaviour of the model is studied with respect to the dose-response relation, the drug effect in dependent and non-dependent subjects and withdrawal symptoms. Computer simulations demonstrate the model to be highly sensitive to sudden changes of drug dose. Dependent on the open loop gain of the adaptive mechanism, a sudden decrease of drug dose might result in an effect opposite to the common drug effect. In the model, the rate of decrease of drug dose necessary for optimal drug withdrawal appears to be determined by the same mechanism as the rate of increase of dose necessary for a constant effect at the commencement of treatment. The behaviour of the model suggests the degree of drug dependence in an addicted subject to depend on the extent to which non-somatic factors are involved in the process of initiation of the adaptive mechanisms.
In this paper the disturbing effect of drugs upon regulation in the organism is argued to be an important factor in the total drug effect. It is made plausible that the decrease of the drug effect after prolonged or repeated administration of the drug is caused by the adaptation of the involved regulations to the presence of the drug, the adaptive process being selective for the drug in question. A model based on these assumptions is developed taking into account the specific behaviour of regulated processes. The functioning of the model is investigated by means of computer simulations. The behaviour of the model appears to be well in accordance with the phenomenon of drug tolerance as described in literature.
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