Alterations in Canine Left Ventricular-arterial Coupling and Mechanical Efficiency Produced by Propofol 

All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care and Use Committee of the Medical College of Wisconsin. All procedures conformed to the Guiding Principles in the Care and Use of Animals of the American Physiological Society and were performed according to the Guide for the Care and Use of Laboratory Animals, [DHEW(DHHS) publication (NIH) no. 85–23, revised 1996].

The experimental preparation used in this investigation has been described previously in detail. [11] Briefly, dogs (n = 8) were fasted overnight and anesthetized with sodium pentobarbital (25 mg/kg) and sodium barbital (200 mg/kg). Fluid deficits were replaced before experimentation with saline, 0.9%(500 ml), which was continued at 3 ml [center dot] kg sup -1 [center dot] h sup -1 for the duration of each experiment. A pilot study demonstrated that this fluid replacement regimen maintained constant left ventricular end diastolic pressure during administration of propofol in barbiturate-anesthetized dogs. After tracheal intubation, each dog's lungs were ventilated via positive pressure with 100% oxygen. Respiratory rate and tidal volume were adjusted to maintain acid-base status and carbon dioxide partial pressure within physiologic limits. The right femoral vein was cannulated for fluid administration. A 7-French, dual micromanometer-tipped catheter was placed across the aortic valve for measurement of continuous left ventricular and arterial pressures and the peak rate of increase of left ventricular pressure (dP/dt^max). A left fifth space thoracotamy was performed, and the lungs were gently retracted. A 7-French, eight-electrode conductance catheter was inserted into the left ventricular cavity through the apex. A hydraulic vascular occluder was placed around the inferior vena cava for abrupt alteration of preload. A fluid-filled catheter was placed in the left atrial appendage for administration of hypertonic saline (20%; 5 ml) used to determine parallel conductance volume (V^p). The experimental preparation was allowed to stabilize for 30 min after instrumentation had been completed.

Left ventricular volume was measured using the conductance technique. [12] Briefly, a multielectrode conductance catheter was interfaced to a module that drove a constant current between the two outermost electrodes and measured the resultant voltage difference between each of the five remaining adjacent remaining electrode pairs. Time-dependent left ventricular volume [V(t)] was determined using the equation: V(t)= G(t)[center dot] L²[center dot](alpha [center dot] sigma) sup -1 - V^p, where G(t)= the sum of time-dependent conductances from each intraventricular electrode pair, L = the intraelectrode distance (1.0 cm), alpha = a slope correction factor relating the measured conductance volume to actual left ventricular volume, and sigma = the blood conductivity. The parallel conductance volume (V^p) is a constant offset error volume that results from current leakage into surrounding tissue and was determined using the hypertonic saline technique. [12,13] No changes in V^pwere observed during the administration of propofol. Blood conductivity (sigma) was determined at each intervention from a 5-ml blood sample using a cuvette that was precalibrated with solutions of known conductivity. No changes in sigma were observed during the course of each experiment. End systolic and end diastolic volumes (ESV and EDV, respectively) were measured at left ventricular maximum elastance [14] and immediately before the onset of left ventricular isovolumic contraction, respectively. Hemodynamic variables were determined at steady-state and averaged for 10 consecutive beats just before caval occlusion. Ejection fraction (EF) was determined using the equation: EF =(EDV - ESV)[center dot] 100 [center dot] EDV sup -1. Hemodynamic data were continuously recorded on a polygraph and simultaneously digitized (200 Hz) by a computer interfaced with an analog to digital converter for recording and subsequent analysis of left ventricular pressure-volume diagrams.

Left ventricular pressure-volume diagrams used to assess myocardial contractility were obtained at end expiration by abruptly decreasing left ventricular preload via inflation of the inferior vena caval balloon cuff occluder (Figure 1). Using linear regression analysis, the end systolic pressure (P^es) and volume (V^es) of each left ventricular pressure-volume diagram were fit to the equation: P^es= E^es[center dot](V^es- V⁰), where E^es= left ventricular end systolic elastance and V⁰= the extrapolated volume intercept of the relation. Myocardial contractility also was evaluated with the slope (M^SW) of the preload recruitable stroke work relation derived from the same left ventricular pressure-volume diagrams. [15] Effective arterial elastance (E^a) was calculated as the ratio of end systolic arterial pressure and stroke volume. [1,2]Figure 1shows representations of E^esand E^ain the pressure-volume plane. Left ventricular-arterial coupling was described by the ratio of E^esand E^a. [1] PVA (total mechanical energy) was determined as the sum of SW and potential energy (PE), where PE = 0.5 [center dot] P^es[center dot](V^es- V⁰). [16] PE represents left ventricular energy that does not contribute to ejection. The ratio of SW to PVA was used to determine left ventricular mechanical efficiency. [5]

Baseline systemic hemodynamics and left ventricular pressure-volume diagrams were recorded during steady-state conditions 30 min after instrumentation was completed. Propofol then was administered as an intravenous infusion at 5, 10, 20, and 40 mg [center dot] kg sup -1 [center dot] hr sup -1 in escalating dosages. Hemodynamics were recorded, and left ventricular pressure-volume diagrams were obtained using the techniques described previously after 15 min equilibration at each dose. At the end of each experiment, the heart was electrically fibrillated, and the positions of the fluid-filled, conductance, and micro-manometer-tipped catheters were confirmed.

Statistical analysis of the data before and during administration of propofol was performed by analysis of variance (ANOVA) with repeated measures followed by Student's t test with Duncan's adjustment for multiplicity. Changes between interventions were considered statistically significant when the probability (P) value was less than 0.05. All data are expressed as mean +/- SEM.

The hemodynamic effects of propofol are summarized in Table 1. Propofol caused significant (P < 0.05) decreases in heart rate, mean arterial pressure, and left ventricular systolic pressure. Increases in EDV and ESV also were observed at higher dosages. Left ventricular end diastolic pressure remained unchanged. Reductions in E^es(4.7 +/- 0.9 during control to 2.7 +/- 0.5 mmHg/ml during the high dose) and M sub SW (66 +/- 6 during control to 43 +/- 5 mmHg during the high dose) were observed during administration of propofol, indicating a direct negative inotropic effect. Concomitant reductions in dP/dt^maxand ejection fraction also occurred. The volume intercepts of the end systolic pressure-volume (V^O) and preload recruitable stroke work (V^SW) relations were unchanged. Propofol caused reductions in SW and PVA at the 40 mg [center dot] kg sup -1 [center dot] h sup -1 dose. An increase followed by a decrease in E^awas observed at the 10 and 40 mg [center dot] kg sup -1 [center dot] h sup -1 doses of propofol, respectively. The ratio of E^esto E^awas decreased by propofol (0.88 +/- 0.13 during control to 0.56 +/- 0.10 during the high dose;Figure 2(A)), indicating that this intravenous anesthetic impairs the mechanical interaction between the left ventricle and the arterial circulation. Propofol also reduced the ratio of SW to PVA (0.54 +/- 0.03 during control to 0.45 +/- 0.03 during the 20 mg [center dot] kg sup -1 [center dot] h sup -1 dose;Figure 2(B)), consistent with a decline in the conversion of total left ventricular energy to external stroke work. However, SW and PVA increased toward control values at the highest dosage of propofol, suggesting that partial restoration of left ventricular mechanical efficiency had occurred.

The present results indicate that propofol reduces myocardial contractility as evaluated by E^esand M^SWderived from left ventricular pressure-volume diagrams generated using the conductance catheter. The present findings confirm and extend the findings from a previous investigation from our laboratory, [8] in which regional preload recruitable SW derived from subendocardial segment length was used as a relatively heart rate- and load-independent index of contractile state before and during propofol anesthesia in chronically instrumented dogs. E^aincreased slightly at the 10 mg [center dot] kg sup -1 [center dot] h sup -1 dose and then decreased with higher dosages of propofol. E^ais closely related to left ventricular afterload because this coupling variable directly depends on systemic vascular resistance and inversely depends on total arterial compliance. The present results are consistent with previous findings from this [8,10] and other laboratories, [17–19] indicating that propofol does not alter indices of left ventricular afterload (e.g., systemic vascular resistance and aortic input impedance) in dogs despite producing dose-related depression of myocardial contractility at very low dosages of propofol similar to those used in the present study. In contrast, propofol reduces afterload at higher dosages concomitant with additional negative inotropic effects. [8,10,17] These observations have important implications for left ventricular-arterial coupling relations.

The present investigation examined the effects of propofol on left ventricular-arterial coupling using a series elastic chamber model quantified by the ratio of E^esto E^a. [1,2] It has been shown that SW is maximized when E^ais equal to E^es. [1] The results indicate that propofol decreases E^es/E^a, indicating that this intravenous anesthetic impairs mechanical coupling of the left ventricle to the arterial vasculature. These propofol-induced reductions in E^es/E^aresult from primary decreases in E^es. At higher dosages of propofol (20 and 40 mg [center dot] kg sup -1 [center dot] h sup -1), E^es/E^aplateaus and does not decrease further because modest reductions in E^aoffset further declines in contractility. This finding indicates that left ventricular-arterial coupling is not restricted at higher doses of propofol despite dose-related decreases in E^es. The present results with propofol contrast with a previous investigation examining the influence of desflurane, isoflurane, and sevoflurane on left ventricular-arterial coupling in barbiturate-anesthetized dogs. [11] These volatile anesthetics decreased E^esand E^ain a dose-related manner. However, because volatile anesthetic-induced declines in E^eswere proportionally greater than E^a, the ratio of E^esto E^aalso declined in a dose-dependent manner.

The effects of propofol on the efficiency of energy transfer from the left ventricle to the arterial system also were quantified in the present investigation using the ratio of SW to PVA. PVA represents the amount of work performed by the left ventricle and is defined as the sum of SW (kinetic energy that contributes to ejection) and potential energy (energy used to overcome the viscoelastic and inertial properties of the myocardium itself). [5,20] Decreases in SW and PVA imply less efficient energy transfer from the left ventricle to the arterial system. The present results indicate the propofol reduces SW and PVA at the intermediate dosages, although these declines in SW and PVA were reversed to some degree at the 40 mg [center dot] kg sup -1 [center dot] h sup -1 dose. This finding parallels the observations with E^esand E^aand suggests that modest reductions in afterload produced by propofol also may limit declines in left ventricular mechanical efficiency at higher dosages. The predominant hemodynamic effect of lower dosages of propofol is a reduction in myocardial contractile function with little change in afterload, resulting in deleterious declines in left ventricular-arterial coupling. This was not the case in our previous study, in which desflurane, isoflurane, and sevoflurane caused dose-related reductions in SW and PVA. [11] Maintenance of stroke volume may be one of the important benefits of preserving left ventricular-arterial coupling relationships. Stroke volume remained constant at all dosages of propofol.

The present results require interpretation within the constraints of several potential limitations. The cardiovascular depression associated with barbiturate anesthesia and acute surgical instrumentation may prevent direct comparison of the present results with those obtained in conscious, chronically instrumented dogs. The negative inotropic effects of sodium barbital and sodium pentobarbital may have resulted in greater decreases in contractility with propofol in the present study than observed previously. [8] However, reductions in M^SWduring the 40 mg [center dot] kg sup -1 [center dot] h sup -1 dose of propofol in the present study (approximately 65% of control) were similar to those observed with 30 and 60 mg [center dot] kg sup -1 [center dot] h sup -1 doses (approximately 68% and 60%, respectively) in a previous investigation, in which chronically instrumented dogs were used. [8] These data indicate that the baseline barbiturate anesthetic did not substantially alter the effects of propofol on myocardial contractility. The value of E^esand E^aobserved during control steady-state hemodynamic conditions also was similar to that observed in conscious dogs, [4] suggesting the barbiturate-induced alterations in left ventricular-arterial coupling did not adversely influence the effects of propofol on this relation. Nevertheless, the possibility of drug interactions between the barbiturate anesthetics and propofol in this investigation cannot be completely excluded from interpretation of the results. Lack of a conscious control state also impairs direct comparison of the present and previous results.

The slope of the end systolic pressure-volume relation has been shown to be curvilinear for a range of pressures. [21] However, this relation has been established to be linear [22] for the relatively narrow range of left ventricular pressures observed during interior vena caval occlusion in the present investigation. E^esand V⁰may be underestimated using the conductance catheter technique to measure left ventricular volume, [23] but alterations in E^esin response to vasoactive drugs were appropriately quantified with the conductance technique when compared with three-dimensional sonomicrometry. [23] Thus, it is likely that propofol-induced negative inotropic effects were accurately measured using conductance catheter-derived left ventricular volume data. The determination of stroke volume required for the calculation of E^ausing the conductance technique also has been validated previously. [12,13]

The dosages of propofol used in the present investigation were chosen because these doses produce corresponding plasma concentrations that fall within the anesthetic range in humans. The 20 and 40 mg [center dot] kg sup -1 [center dot] h sup -1 doses of propofol produce plasma concentrations between 2 and 13 micro gram/ml in dogs [17] that correlate with clinically relevant concentrations. Nevertheless, comparison of the effects of propofol on systemic hemodynamics, myocardial contractility, and left ventricular-arterial coupling relations between barbiturate-anesthetized dogs and humans can be inferred only indirectly.

In summary, the present investigation demonstrated that propofol reduces optimal left ventricular-arterial coupling and mechanical efficiency as evaluated by E^esand E^aand SW and PVA, respectively. These detrimental effects plateau at higher doses of propofol because declines in afterload occur that partially offset depression of myocardial contractility. Propofol-induced impairment in left ventricular-arterial coupling may contribute to declines in overall cardiovascular performance observed with this anesthetic in vivo.

The authors thank Rich Rys for the design, construction, and maintenance of the conductance module; Dave Schwabe for technical assistance; and Angela M. Barnes for preparation of the manuscript.