Characterization of highly multiplexed monolithic PET / gamma camera detector modules.

PET detectors use signal multiplexing to reduce the total number of electronics channels needed to cover a given area. Using measured thin-beam calibration data, we tested a principal component based multiplexing scheme for scintillation detectors. The highly-multiplexed detector signal is no longer amenable to standard calibration methodologies. In this study we report results of a prototype multiplexing circuit, and present a new method for calibrating the detector module with multiplexed data. A [Formula: see text] mm3 LYSO scintillation crystal was affixed to a position-sensitive photomultiplier tube with [Formula: see text] position-outputs and one channel that is the sum of the other 64. The 65-channel signal was multiplexed in a resistive circuit, with 65:5 or 65:7 multiplexing. A 0.9 mm beam of 511 keV photons was scanned across the face of the crystal in a 1.52 mm grid pattern in order to characterize the detector response. New methods are developed to reject scattered events and perform depth-estimation to characterize the detector response of the calibration data. Photon interaction position estimation of the testing data was performed using a Gaussian Maximum Likelihood estimator and the resolution and scatter-rejection capabilities of the detector were analyzed. We found that using a 7-channel multiplexing scheme (65:7 compression ratio) with 1.67 mm depth bins had the best performance with a beam-contour of 1.2 mm FWHM (from the 0.9 mm beam) near the center of the crystal and 1.9 mm FWHM near the edge of the crystal. The positioned events followed the expected Beer-Lambert depth distribution. The proposed calibration and positioning method exhibited a scattered photon rejection rate that was a 55% improvement over the summed signal energy-windowing method.

Evaluation of event position reconstruction in monolithic crystals that are optically coupled.

A PET detector featuring a pseudo-monolithic crystal is being developed as a more cost-effective alternative to a full monolithic crystal PET detector. This work evaluates different methods to localize the scintillation events in quartered monolithic crystals that are optically coupled. A semi-monolithic crystal assembly was formed using four 26 × 26 × 10 mm3 LYSO crystals optically coupled together using optical adhesive, to mimic a 52 × 52 × 10 mm3 monolithic crystal detector. The crystal assembly was coupled to a 64-channel multi-anode photomultiplier tube using silicon grease. The detector was calibrated using a 34 × 34 scan grid. Events were first filtered and depth separated using a multi-Lorentzian fit to the collected light distribution. Next, three different techniques were explored to generate the look up tables for the event positioning. The first technique was 'standard interpolation' across the interface. The second technique was 'central extrapolation', where a bin was placed at the midpoint of the interface and events positioned within the interface region were discarded. The third technique used a 'central overlap' method where an extended region was extrapolated at each interface. Events were then positioned using least-squares minimization and maximum likelihood methods. The least-squares minimization applied to the look up table generated with the standard interpolation technique had the best full width at half maximum (FWHM) intrinsic spatial resolution and the lowest bias. However, there were discontinuities in the event positioning that would most likely lead to artifacts in the reconstructed image. The central extrapolation technique also had discontinuities and a 30% sensitivity loss near the crystal-crystal interfaces. The central overlap technique had slightly degraded performance metrics, but it still provided ~2.1 mm intrinsic spatial resolution at the crystal-crystal interface and had a symmetric and continuously varying response function. Results using maximum likelihood positioning were similar to least-squares minimization for the central overlap data.

Multiplexing strategies for monolithic crystal PET detector modules.

To reduce the number of output channels and associated cost in PET detectors, strategies to multiplex the signal channels have been investigated by several researchers. This work aims to find an optimal multiplexing strategy for detector modules consisting of a monolithic LYSO scintillator coupled to a 64-channel PMT. We apply simulated multiplexing strategies to measured data from two continuous miniature crystal element (cMiCE) detector modules. The strategies tested include standard methods such as row column summation and its variants, as well as new data-driven methods involving the principal components of measured data and variants of those components. The detector positioning resolution and bias are measured for each multiplexing strategy and the results are compared. The mean FWHM over the entire detector was 1.23 mm for no multiplexing (64 channels). Using 16 principal component channels yielded a mean FWHM resolution of 1.21 mm, while traditional row/column summation (16 channels) yielded 1.28 mm. Using 8 principal component output channels resulted in a resolution of 1.30 mm. Using the principal components of the calibration data to guide the multiplexing scheme appears to be a viable method for reducing the number of output data channels. Further study is needed to determine if the depth-of-interaction resolution can be preserved with this multiplexing scheme.

Effective count rates for PET scanners with reduced and extended axial field of view.

We investigated the relationship between noise equivalent count (NEC) and axial field of view (AFOV) for PET scanners with AFOVs ranging from one-half to twice those of current clinical scanners. PET scanners with longer or shorter AFOVs could fulfill different clinical needs depending on exam volumes and site economics. Using previously validated Monte Carlo simulations, we modeled true, scattered and random coincidence counting rates for a PET ring diameter of 88 cm with 2, 4, 6, and 8 rings of detector blocks (AFOV 7.8, 15.5, 23.3, and 31.0 cm). Fully 3D acquisition mode was compared to full collimation (2D) and partial collimation (2.5D) modes. Counting rates were estimated for a 200 cm long version of the 20 cm diameter NEMA count-rate phantom and for an anthropomorphic object based on a patient scan. We estimated the live-time characteristics of the scanner from measured count-rate data and applied that estimate to the simulated results to obtain NEC as a function of object activity. We found NEC increased as a quadratic function of AFOV for 3D mode, and linearly in 2D mode. Partial collimation provided the highest overall NEC on the 2-block system and fully 3D mode provided the highest NEC on the 8-block system for clinically relevant activities. On the 4-, and 6-block systems 3D mode NEC was highest up to ∼300 MBq in the anthropomorphic phantom, above which 3D NEC dropped rapidly, and 2.5D NEC was highest. Projected total scan time to achieve NEC-density that matches current clinical practice in a typical oncology exam averaged 9, 15, 24, and 61 min for the 8-, 6-, 4-, and 2-block ring systems, when using optimal collimation. Increasing the AFOV should provide a greater than proportional increase in NEC, potentially benefiting patient throughput-to-cost ratio. Conversely, by using appropriate collimation, a two-ring (7.8 cm AFOV) system could acquire whole-body scans achieving NEC-density levels comparable to current standards within long, but feasible, scan times.

Maximum-likelihood Estimation of 3D Event Position in Monolithic Scintillation Crystals: Experimental Results.

We present a simple 3D event position-estimation method using raw list-mode acquisition and maximum-likelihood estimation in a modular gamma camera with a thick (25mm) monolithic scintillation crystal. This method involves measuring 2D calibration scans with a well-collimated 511 keV source and fitting each point to a simple depth-dependent light distribution model. Preliminary results show that angled collimated beams appear properly reconstructed.

Role of myofilaments and calcium handling in left ventricular relaxation.

Myocardial relaxation is governed by the interplay of two macromolecular systems: (1) myofilaments and (2) calcium extruding pumps/exchangers. In myocardium from failing hearts, both systems act more slowly than normal, and cause relaxation to decelerate, which may impede early rapid filling and can often limit cardiac pumping ability--especially during exercise. Gene-based therapy to augment sluggish SERCA pumps is a possibility being currently investigated in research laboratories. In normal myocardium, the rate of dissociation of myosin crossbridges sets the rate of relaxation. In this case, relaxation is characterized by two features: (1) load-dependence and (2) displacement-dependence. Load-dependence derives from cooperative mechanisms acting among ensembles of crossbridges and myofilament regulatory proteins (troponin, tropomyosin); it allows contraction to be prolonged when more crossbridges are attached and mutually support each other. The rate of relaxation can still be rapid, however, as this cooperative system begins to collapse. Displacement-dependence is more important later in contraction, because tenuous crossbridge attachments cannot easily re-form after being disrupted when myofilaments slide along each other. Myofilaments control normal relaxation because the calcium extruding systems reduce calcium to near diastolic levels relatively early; however, when the relative timing of crossbridge dissociation versus calcium sequestration is altered, and calcium uptake is slowed (relative to crossbridges), then removal of calcium can become rate limiting instead. In this case, load- and displacement-dependence are less marked. Both the timing of calcium removal and the sensitivity of the myofilaments to calcium affect relaxation timing.

Mapping of regional myocardial strain and work during ventricular pacing: experimental study using magnetic resonance imaging tagging.

OBJECTIVES: The purpose of this study was to determine the spatial distribution of myocardial function (myofiber shortening and work) within the left ventricular (LV) wall during ventricular pacing. BACKGROUND: Asynchronous electrical activation, as induced by ventricular pacing, causes various abnormalities in LV function, perfusion and structure. These derangements may be caused by abnormalities in regional contraction patterns. However, insight into these patterns during pacing is as yet limited. METHODS: In seven anesthetized dogs, high spatial and temporal resolution magnetic resonance-tagged images were acquired in three orthogonal planes. Three-dimensional deformation data and LV cavity pressure and volume were used to determine midwall circumferential strain and external and total mechanical work at 192 sites around the left ventricle. RESULTS: During ventricular pacing, systolic fiber strain and external work were approximately zero in regions near the pacing site, and gradually increased to more than twice the normal value in the most remote regions. Total mechanical work, normalized to the value during right atrial pacing, was 38 +/- 13% (right ventricular apex [RVapex] pacing) and 61 +/- 23% (left ventricular base [LVbase] pacing) close to the pacing site, and 125 +/- 48% and 171 +/- 60% in remote regions, respectively (p < 0.05 between RVapex and LVbase pacing). The number of regions with reduced work was significantly larger during RVapex than during LVbase pacing. This was associated with a reduction of global LV pump function during RVapex pacing. CONCLUSIONS: Ventricular pacing causes a threefold difference in myofiber work within the LV wall. This difference appears large enough to regard local myocardial function as an important determinant for abnormalities in perfusion, metabolism, structure and pump function during asynchronous electrical activation. Pacing at sites that cause more synchronous activation may limit the occurrence of such derangements.

Comparison of putative cooperative mechanisms in cardiac muscle: length dependence and dynamic responses.

Length-dependent steady-state and dynamic responses of five models of isometric force generation in cardiac myofilaments were compared with similar experimental data from the literature. The models were constructed by assuming different subsets of three putative cooperative mechanisms. Cooperative mechanism 1 holds that cross-bridge binding increases the affinity of troponin for Ca2+. In the models, cooperative mechanism 1 can produce steep force-Ca2+ (F-Ca) relations, but apparent cooperativity is highest at midlevel Ca2+ concentrations. During twitches, cooperative mechanism 1 has the effect of increasing latency to peak as the magnitude of force increases, an effect not seen experimentally. Cooperative mechanism 2 holds that the binding of a cross bridge increases the rate of formation of neighboring cross bridges and that multiple cross bridges can maintain activation of the thin filament in the absence of Ca2+. Only cooperative mechanism 2 can produce sarcomere length (SL)-dependent prolongation of twitches, but this mechanism has little effect on steady-state F-Ca relations. Cooperativity mechanism 3 is designed to simulate end-to-end interactions between adjacent troponin and tropomyosin. This mechanism can produce steep F-Ca relations with appropriate SL-dependent changes in Ca2+ sensitivity. With the assumption that tropomyosin shifting is faster than cross-bridge cycling, cooperative mechanism 3 produces twitches where latency to peak is independent of the magnitude of force, as seen experimentally.

Mechanical contribution of endocardium during finite extension and torsion experiments on papillary muscles.

Finite extension and torsion tests on cardiac papillary muscles are presently the best way to directly measure the response to shear along myocardial fibers. Quantifying this response is necessary for determining the complete three-dimensional constitutive behavior of myocardium as a transversely isotropic material. Analysis of such tests is complicated, however, since papillary muscles are materially inhomogeneous, consisting of a myocardial core surrounded by an endocardial sheath that is rich in collagen. In this article, we show that the papillary muscle response to extension and torsion additively decouples into the response of the bare myocardial core plus the response of an endocardial sheath filled with fluid (assuming the muscle is a radially inhomogeneous and incompressible continuum with cylindrical symmetry). This result allows the endocardial response to be subtracted from the intact papillary muscle response to obtain the response of the bare myocardial core. An initial estimate suggests that the endocardial sheath affects the axial moment significantly (50% of torque for all twists at low stretch) but affects the axial force only slightly (<10% at moderate twists).

Mapping propagation of mechanical activation in the paced heart with MRI tagging.

The temporal evolution of three-dimensional (3-D) strain maps derived from magnetic resonance imaging (MRI) tagging were used to noninvasively evaluate mechanical activation in the left ventricle (LV) while seven canine hearts were paced in situ from three different sites: the base of the LV free wall (LVb), the right ventricular apex (RVa), and the right atrium (RA). Strain maps plotted against time showed the evolution of shortening over the entire LV midwall and were used to generate mechanical activation maps showing the onset of circumferential shortening. RA pacing showed rapid synchronous shortening; LVb pacing showed a wave front of mechanical activation propagating slowly and steadily from the pacing site, whereas RVa pacing showed regions of rapid and slower propagation. The mechanical (M) activation times correlated linearly with the electrical (E) activation (M = 1.06E + 8.4 ms, R = 0.95). The time for 90% activation of the LV was 63.1 +/- 24.3 ms for RA pacing, 130.2 +/- 9.8 ms for LVb pacing, and 121.3 +/- 17.9 ms for RVa pacing. The velocity of mechanical activation was calculated for LVb and RVa pacing and was similar to values reported for electrical conduction in myocardium. The propagation of mechanical activation for RVa pacing showed regional variations, whereas LVb pacing did not.

Imaging asynchronous mechanical activation of the paced heart with tagged MRI.

A method for imaging the rapid temporal-spatial evolution of myocardial deformations in the paced heart is proposed. High time resolution-tagged MR images were obtained after stimulation of the myocardium with an MR-compatible pacing system. The images were analyzed to reconstruct dynamic models of local 3D strains over the entire left ventricle during systole. Normal canine hearts were studied in vivo with pacing sites on the right atrium, left ventricular free wall and right ventricular apex. This method clearly resolved local variations in myocardial contraction patterns caused by ventricular pacing. Potential applications are noninvasive determination of electrical conduction abnormalities and the evaluation of new pacing therapies.

Measurements of active myocardial tension under a wide range of physiological loading conditions.

Active tension developed while cardiac muscle shortens has been studied extensively under afterloaded isotonic or isovelocity conditions. However, these are not true in vivo loading conditions. To obtain more physiological loading, we controlled sarcomere length to follow the time courses that we observed previously in a beating canine left ventricle. Sarcomere length was measured by laser diffraction in 12 rat cardiac trabeculae, superfused with Krebs-Henseleit solution (25 degrees C; [Ca] = 1.5 mM). Force was measured by a silicon strain gauge. Sarcomere length time courses were scaled slightly in time to account for temperature and species differences. We examined the relationships between active tension and sarcomere length under loading observed over a wide range of left ventricular preloads and afterloads, and at two sites. Under all loading conditions, active tension was not isotonic but declined steadily throughout the ejection period. While there were major differences in peak tension dependent on loading conditions and the incidence of 'pre-ejection' sarcomere shortening, these factors did not influence the relationship between sarcomere length and peak active tension. This study provides excellent illustrations of the potential differences in stress (1) within a ventricular wall, and (2) under different operating conditions. Moreover, it provides data for developing models of fiber contraction to be synthesized into a whole heart for predicting potential differences in stress at all sites and under all loading conditions.

Anterior and posterior left ventricular sarcomere lengths behave similarly during ejection.

Previous studies of regional differences in myocardial deformation between the anterior and posterior walls of the canine left ventricle were based on strain, which is not an absolute measure of deformation. We thus compared sarcomere lengths at anterior and posterior sites during ejection in isolated dog hearts. Cineradiographic imaging of regional deformation with radiopaque markers implanted near the midwall in five hearts and just below the epicardium in six hearts, combined with postmortem histology, allowed sarcomere length reconstruction throughout the cardiac cycle. The amount of sarcomere shortening accompanying left ventricular ejection was similar in both walls of the left ventricle for sarcomeres located at epicardial and midwall sites. The mean sarcomere length (taken at the middle of the ejecting range) was also similar between the anterior and posterior sites when averaged over all hearts. The similarity of sarcomere function held not only at end systole but throughout ejection and over wide ranges of ventricular pre- and afterloads. Hence functional measurements of relative myocardial shortening may not be indicative of regional sarcomere length heterogeneity.

Force, not sarcomere length, correlates with prolongation of isosarcometric contraction.

Recent studies have emphasized the importance of the late systolic phase for understanding ventricular ejection. To examine the myocardial factors controlling this phase, we studied the timing of twitch contraction in nine excised rat trabeculae contracting isosarcometrically. By varying both sarcomere length (SL) and extracellular Ca2+ concentration ([Ca2+]) we determined which of these factors or the developed peak twitch force correlated better with the prolongation of contraction. We focused on the period from just before the peak of force to the time of half relaxation. SL was measured by laser diffraction and kept constant using adaptive control. Peak twitch force was the factor most tightly correlated with prolongation of contraction: as force rose from 10 to 100 mN/mm2, duration tripled from 100 to 300 ms. When the trend with force was removed, however, no separate influence of SL remained. Increase in [Ca2+]o abbreviated contraction equally at all force levels. Prolongation of late systolic contraction was also highly correlated with prolongation of the time constant for late relaxation, suggesting a common mechanism by which peak twitch force lengthens the entire subsequent time course of a twitch. We hypothesize that 1) increased force correlates with prolonged Ca2+ binding to troponin-C, and/or 2) attached cross bridges act cooperatively to oppose the inhibiting effects of tropomyosin as Ca2+ is lost from the thin filaments.(ABSTRACT TRUNCATED AT 250 WORDS)

Three-dimensional myocardial deformations: calculation with displacement field fitting to tagged MR images.

PURPOSE: To reconstruct three-dimensional (3D) myocardial deformations from orthogonal sets of parallel-tagged magnetic resonance (MR) images. MATERIALS AND METHODS: Displacement information in the direction normal to the undeformed tag planes was obtained at points along tag lines. Three independent sets of one-dimensional displacement data were used to fit an analytical series expression to describe 3D displacement as a function of deformed position. The technique was demonstrated with computer-generated models of the deformed left ventricle with data from healthy human volunteers. RESULTS: Model deformations were reconstructed with a 3D tracking error of less than 0.3 mm. Error between estimated and observed one-dimensional displacements along the tags in 10 human subjects was 0.00 mm +/- 0.36 (mean +/- standard deviation). Robustness to noise in the tag displacement data was demonstrated by using a Monte Carlo simulation. CONCLUSION: The combination of rapidly acquired parallel-tagged MR images and field-fitting analysis is a valuable tool in cardiac mechanics research and in the clinical assessment of cardiac mechanical function.

Impact of ejection on magnitude and time course of ventricular pressure-generating capacity.

This study focuses on elucidating how ventricular afterloading conditions affect the time course of change of left ventricular pressure (LVP) throughout the cardiac cycle, with particular emphasis on revealing specific limitations in the time-varying elastance model of ventricular dynamics. Studies were performed in eight isolated canine hearts ejecting into a simulated windkessel afterload. LVP waves measured (LVPm) during ejection were compared with those predicted (LVPpred) according to the elastance theory. LVPm exceeded LVPpred from a time point shortly after the onset of ejection to the end of the beat. The instantaneous difference between LVPm and LVPpred increased steadily as ejection proceeded and reached between 45 and 65 mmHg near end ejection. This was in large part due to an average 35-ms prolongation of the time to end systole (tes) in ejecting compared with isovolumic beats. The time constant of relaxation was decreased on ejecting beats so that, despite the marked prolongation of tes, the overall duration of ejecting contractions was not greater than that of isovolumic beats. The results demonstrate a marked ejection-mediated enhancement and prolongation of ventricular pressure-generating capacity during the ejection phase of the cardiac cycle with concomitant acceleration of relaxation. None of these factors are accounted for by the time-varying elastance theory.

Ventricular stroke work and efficiency both remain nearly optimal despite altered vascular loading.

Recent clinical and animal studies have suggested that ventricular-vascular coupling normally operates at either optimal ventricular efficiency (EFF = stroke work/myocardial oxygen consumption) or stroke work (SW) and that efficiency in particular is compromised by cardiac dysfunction. These distinctions between coupling states at maximal work vs. efficiency are largely based on theoretical models. To date, there are few direct experimental data defining optimal conditions for each parameter, respectively, in the same heart or tests of whether changes from these conditions must produce significant declines in both parameters. Therefore, 10 isolated blood-perfused canine hearts were studied at varying contractilities, with the heart ejecting into a simulated three-element Windkessel model of arterial impedance. For a given inotropic state [indexed by the slope of the end-systolic pressure-volume relationship (Ees)], myocardial oxygen consumption and SW were measured over a broad range of afterload resistances. The latter was indexed by the effective arterial elastance (Ea) and ventricular-vascular interaction expressed by the ratio of Ea to Ees (Ea/Ees). On average, maximal SW occurred at Ea/Ees = 0.80 +/- 0.16, whereas EFF was maximal at Ea/Ees = 0.70 +/- 0.15 (P < 0.01). However, these differences were small, and both SW and EFF were > or = 90% of their respective optima over a broad overlapping range of Ea-to-Ees ratios (0.3-1.3, corresponds with ejection fractions ranging from approximately 40 to 80%). These data show that both SW and efficiency are nearly maximal under many conditions of ventricular-vascular interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Similarities between dynamic elastance of left ventricular chamber and papillary muscle of rabbit heart.

The frequency-dependent dynamic elastance of the left ventricle (LV) of isolated rabbit heart was determined and compared with dynamic stiffness of excised rabbit papillary muscle. Comparison was made in three states: 1) relaxed, 2) BaCl2 contracture, and 3) rigor. Dynamic chamber elastance was determined by pressure-to-volume ratio at 12 frequencies of sinusoidal volume variation between 0.1 and 30 Hz. Dynamic elastance during BaCl2 contracture was distinctly different from that during either relaxed or rigor states. Characteristics of BaCl2 contracture were 1) as frequency increased, polar plot of real and imaginary elastance showed a progressively opening clockwise spiral that tended eventually to become tangent to the apogee of a semi-circle by 30 Hz; 2) modulus spectrum exhibited asymptotes at low and high frequencies with an intervening dip to a minimum at 1.25 Hz; and 3) phase showed a sharp transition at dip frequency from small negative values at lower frequencies to large positive values at intermediate frequencies and then declined at highest frequencies. There was little dependence of dynamic elastance on frequency in both relaxed and rigor states. Dynamic muscle stiffness exhibited all features of dynamic chamber elastance in all three states. We concluded that dynamic elements responsible for myofiber stiffness were also responsible for LV chamber elastance. Furthermore, it was possible to describe and interpret dynamic chamber elastance and muscle stiffness with a common model based on muscle cross-bridge theory. This model did a reasonable job of reproducing all important features of experimentally observed LV chamber elastance and muscle stiffness. Thus dynamic homologies between chamber and muscle were established in experimental data and in the fact that a single interpretive model served equally well for both chamber elastance and muscle stiffness.

Macroscopic three-dimensional motion patterns of the left ventricle.

The pattern of displacements in the left ventricle (LV) can be described by 13 modes of motion and deformation. Three functional modes of deformation are essential for ejection: a decrease in cavity volume, torsion, and ellipticalization. Four additional modes are used to describe asymmetric deformation. Six modes of rigid body motion describe rotation and translation. In the LV 14-20 radiopaque markers were inserted in the wall of the LV. They were distributed more or less evenly from base to apex and around the circumference. Torsion and volume changes require the definition of a cardiac coordinate system. The point at which ejection focuses is used as the origin, and the torsion axis is used as the z-axis. In the present study the coordinate system was positioned objectively by a least squares fit of the kinematic model to the measured motion of markers. In five dogs in the control state the kinematic parameters were determined as a function of time for all 13 modes. The torsion axis was displaced 4 +/- 2 mm (mean +/- sd) from the center of the cross-section of the LV towards the lateral free wall. The direction of the torsion axis closely coincided with anatomical landmarks at the apex and base. During systole, a unique relation was found between the ratio of cavity volume to wall volume and torsion. This relation was universal to all LVs, the cylinder-symmetric mathematical model of cardiac mechanics inclusive. In diastole the patterns of deformation seem less universal and reproducible.

Effects of pentobarbital on inotropic state of isolated canine left ventricle.

Although pentobarbital has been found to depress myocardial function, the magnitude of its direct effects on ventricular contraction at anesthetic concentrations has not been well quantified. The direct effects of pentobarbital on left ventricular function were measured by employing an isolated canine heart preparation with a blood oxygenator. Seven hearts were perfused with blood, dextran, and perfluorochemical artificial blood. Ventricular function was evaluated using the slope of the end-systolic pressure-volume relationship (Ees) and the maximal rate of pressure development (dP/dtmax) in ventricles contracting isovolumically in control, after a low dose (13 micrograms/ml), and after a high dose (48 micrograms/ml) of pentobarbital. These concentrations represent one-half and two times the typical value (25 micrograms/ml) found to produce anesthesia in canines (assessed by tail clamp or blink reflex). The low dose of pentobarbital did not produce clear-cut depression in contractile function. The high dose of pentobarbital produced significant reductions of Ees, and dP/dtmax: Ees decreased 29%, from a control of 4.30 +/- 0.84 to 3.05 +/- 0.49 mmHg/ml and dP/dtmax decreased 24%, from a control of 909 +/- 148 to 695 +/- 173 mmHg/s. Thus, the threshold for the direct depressant effect of pentobarbital on ventricular function falls within the range of half to double the typically-reported anesthetic concentrations.