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Anesth Analg 2003;96:1589-1597 © 2003 International Anesthesia Research Society
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Abstract |
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Linking physiological pharmacokinetic models to models of the cardiovascular system requires knowledge of the sites in the body that mediate a drug’s cardiovascular effects. We examined the role of the coronary concentrations of propofol. Nine sheep anesthetized with isoflurane (2%) were instrumented acutely for cardiovascular measurements. In a random crossover design, they were administered ramped coronary artery (CA) infusions of propofol to selectively enrich the myocardium (as indicated by the coronary sinus blood concentration) or IV infusions to achieve the same concentration range in all sites of the body. Reductions in left ventricular myocardial contractility (LV dP/dtmax) and mean arterial blood pressure were linearly related to the propofol concentration. For the CA route, LV dP/dtmax was reduced by 52 mm Hg/s for each milligram per liter increase in coronary sinus propofol concentration. For the IV route, the reduction in LV dP/dtmax was equivalent to that with the CA route, showing that the coronary propofol concentration was the major contribution to this effect. For the CA route, mean arterial blood pressure was reduced by 0.6 mm Hg for each milligram per liter. There was a larger reduction (2.5 mm Hg · mg-1 · L-1) for the IV route. Therefore, this effect was predominantly mediated by propofol concentrations elsewhere in the body.
IMPLICATIONS:With use of selective coronary artery infusions in sheep, the coronary concentrations of propofol were shown to be the major contributor to the cardiac depression caused by propofol but were a less significant contributor to the hypotension caused by this drug. Models of the cardiovascular effects of propofol should account for these relationships.
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Introduction |
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Physiological pharmacokinetic models of a number of anesthetic-related drugs have been reported (1–3). These models can predict the concentrations of drugs in specific organs such as the heart or brain. The literature also contains many models of the cardiovascular system of varying complexity (4–6). However, there have been relatively few reports (7,8) in which these two types of models have been linked so that the combined model can describe and predict the cardiovascular effects of an anesthetic. A major difficulty (particularly for acute administration, in which anesthetic concentrations throughout the body are heterogeneous and rapidly changing) is choosing the effect site or organ in the body where drug concentration can be linked with a particular cardiovascular effect. There are several candidate effect sites or organs for the cardiovascular effects of drugs, and these are not exclusive. They may be mediated by the concentration of the drug (a) directly in the myocardium, (b) in key parts of the central nervous system responsible for autonomic control of the cardiovascular system, or (c) in key parts of the peripheral cardiovascular system, such as vessel walls or baroreceptors.
To begin addressing this problem for propofol, this article reports a study in which the contribution of the coronary concentrations of propofol to its cardiovascular effects was examined in anesthetized acutely instrumented sheep. The cardiovascular effects of propofol have been studied extensively and are complex (9,10). The hypotension caused by propofol appears to be caused to differing extents by a combination of reduction in myocardial contractility, sympathoinhibition, and reductions in arterial resistance and venous capacitance, depending on circumstances (10,11). However, cardiovascular studies in which propofol was administered systemically in progressively increasing doses provide no information about the sites of action of propofol, because propofol concentrations would have increased in proportion in all the potential effect sites of the body discussed above.
The general strategy used in this study was to enrich the myocardium with propofol via a direct coronary artery (CA) infusion while keeping propofol concentrations in the remaining organs of the body relatively small. Thus, any cardiovascular effects present for the CA infusion were a function of the concurrent coronary concentrations of propofol. The hypothesis examined was that the coronary concentrations of propofol can be attributed to reductions in myocardial contractility caused by propofol, whereas reductions in mean arterial blood pressure (MAP) can be attributed to the actions of propofol elsewhere in the body.
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Methods |
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The study design was approved by the institutional Animal Ethics Committee. Sheep were prepared by using a modification of the method reported previously (12). Briefly, sheep (approximately 50 kg) were anesthetized with thiopental and maintained with 2% isoflurane and 100% oxygen with mechanical ventilation. By using the Seldinger technique (13), two 7F catheters were placed in the right carotid artery and jugular vein. A 7.5F multilumen thermodilution catheter was placed into the pulmonary artery. The position of the catheter was confirmed by monitoring the pressure wave pattern (14). A 7F catheter was placed into the coronary sinus. Its position was confirmed under direct vision by using a fluoroscope with the injection of radioopaque contrast (Conray Angiorafin 420; May and Baker Ltd., Dagenham, UK) into the coronary sinus. The hemiazygos vein was ligated to ensure that the coronary sinus catheter sampled pure effluent blood from the myocardium. The coronary sinus concentrations are in direct equilibrium with the myocardial tissue concentrations for diffusible drugs such as propofol.
A left thoracotomy (fourth intercostal space) and a pericardiotomy were performed to expose the left main CA. The apex of the heart was stitched with a 2-O silk suture, and a micropressure transducer (Codman MicroSensor; Johnson & Johnson Professional, Inc., Raynham, Miami, FL) was placed 3 cm into the left ventricle (LV) through a 5-gauge needle via the apex of the heart and fixed securely with suture. The leads of the probes and the microtransducer were exteriorized though the chest incision. A Doppler flowprobe was placed around the left main CA for measurement of an index of left coronary blood flow. For the CA infusion, a 3F catheter was placed into the main CA, approximately 0.2 cm proximal to the flowprobe, with its tip facing toward the probe but not under the crystal of the probe. The catheter was fixed securely to minimize any tension or occlusion that distorted the natural shape of the CA.
The CA catheter was infused with heparinized (2 IU/mL) 0.9% saline at speed of 10 mL/h to ensure patency. All other catheters were flushed at regular intervals with the same heparinized saline. Once the instrumentation was placed, the chest was loosely closed, and the sheep were kept warm by passive insulation. Saline (0.9%) was infused IV at a rate of approximately 250 mL/h. Once experimentation was completed, the sheep were killed with a pentobarbitone overdose (9.75 g).
During the experiments, the following cardiovascular measurements were recorded continuously. Data were acquired at a sampling rate of 1 Hz (150 Hz for LV pressure [LVP]) by using an analog-to-digital card (MetraByte Corp., Taunton, MA) in a personal computer.
The Doppler frequency shifts from the CA Doppler flowprobe were measured with a four-channel pulsed Doppler flowmeter (Bioengineering Department, University of Iowa, Iowa City, IA), to give myocardial blood velocity. MAP was measured with a pressure transducer on an arterial catheter. LVP was recorded from the intraventricular transducer-tipped catheter. The peak value of the rate of increase of LVP (LV dP/dtmax) was calculated and used as an index of myocardial contractility. LV end-diastolic pressure (LVEDP) and heart rate (HR) were also calculated from the pressure wave form of the LV. Before every study, the transducers were calibrated with a sphygmomanometer over the range 0 to 160 mm Hg.
Cardiac output (CO) was determined in triplicate at given time points by using the pulmonary artery catheter and a CO computer (Abbott Laboratories, North Chicago, IL) with injections of 10 mL of ice cold 0.9% saline. Stroke volume was calculated as CO divided by HR.
Studies were conducted in nine sheep prepared as described above. Studies were not commenced until at least 30 min after the end of surgery and placement of the cardiovascular measurement devices. The sheep were placed in a right lateral position and were allocated randomly to receive either an IV or CA infusions of propofol in a cross-over design, with the limbs of the cross-over separated by 40 min (Fig. 1). Five of the nine sheep received the CA infusion first. For each route, cardiovascular measurements were recorded during a control period (designated "control"), a period in which vehicle alone was infused ("vehicle-prepropofol"), during three ramped infusions of propofol ("propofol 1, 2, and 3"), and a final period during which vehicle alone was again infused ("vehicle-postpropofol"). The duration of each infusion period was 15 min and was 10 min for the IV and CA infusions, respectively. To achieve a wide range of concentrations suitable for regression analysis, the propofol infusions were divided into overlapping small (three sheep), medium (three sheep), and large (three sheep) dose ranges. The IV infusions used 1% propofol (10 mg/mL) as an emulsion formulation (Diprivan; Zeneca, Macclesfield, UK), with 10% Intralipid as vehicle (Baxter, Kista, Sweden). The range of doses used was between 5 and 30 mg/min.
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For the CA infusions, the doses were 10% of the matching IV doses, on the basis of pilot data, and both propofol and vehicle solutions were diluted fivefold (i.e., to 2 mg/mL) with 5% dextrose in accordance with the manufacturer’s recommendations. The resultant larger infused volume minimized errors in drug delivery.
The values of the cardiovascular variables during the last 30 s of each infusion for each dose rate were averaged and used for subsequent analysis. Paired carotid arterial and coronary sinus blood samples (1 mL) were also taken at the end of each period for propofol and blood gas determinations. CO was determined 2 min before the end of each infusion. The body temperature of each sheep was maintained in the range 36°C–37.5°C by passive insulation.
Propofol concentrations in whole blood were assayed by using a modification of the technique of Mather et al. (15), as used previously in our laboratory (16). In brief, blood samples were taken and stored in plastic tubes with heparin (25 IU) and then stored at -5°C. Propofol concentrations in whole blood were assayed by using high-performance liquid chromatography with fluorescence detection. Standard curves were prepared by adding known amounts of propofol to blood taken before propofol administration. The limit of sensitivity was 0.02 µg/mL.
A blood gas analyzer (ABL Model 625; Radiometer Medical A/S, Copenhagen, Denmark) was used to determine oxygen tension (PO2), pH, carbon dioxide tension, and oxygen saturation (SaO2) for both the arterial and coronary sinus blood samples. These abbreviations were appended with an "art" or "cs" suffix to indicate arterial or coronary sinus blood, respectively.
Data were analyzed with the "R" data analysis and graphing language (17). Analysis of variance, paired Student’s t-tests, and multiple linear regression were used as indicated in Results. P < 0.05 was considered significant.
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Results |
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In one sheep, the MAP trace for the IV infusions was found to be heavily damped, and the data were not used. Analysis of variance showed significant differences between sheep for some cardiovascular measurements. This reflected differences in the baseline cardiovascular state of the animal after surgical preparation and is typical for open-chested studies. Data were therefore analyzed on a sheep-by-sheep basis. LVEDP is of particular interest because it is known to affect LV dp/dtmax. LVEDP differed between sheep (P < 0.001) and between infusion type (e.g., vehicle or propofol) (P = 0.01), but not between route of administration (P = 0.22). However, the total increase in LVEDP with propofol was <3 mm Hg (Fig. 2, Table 1).
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There were no significant differences in any measurement between the two control periods (P values ranged between 0.20 and 0.91). Furthermore, there were no significant effects of the vehicle (control versus vehicle [prepropofol]) on any cardiovascular measurements for the IV and CA infusions (P values ranged between 0.06 and 1). An exception was the pH of arterial blood, which increased slightly with vehicle for the CA infusion group. Cardiovascular changes after the administration of propofol were therefore expressed as a percentage of those measured for the vehicle (prepropofol) infusions.
The baseline cardiovascular and blood gas measurements are shown in Table 1 and were consistent with expected values. In particular, the pH and PO2 of coronary sinus blood were in the normal range (7.36, SD 0.025, and 41.9 mm Hg, SD 9.6, respectively), confirming that initial flowprobe and catheter placement in the CA was not associated with myocardial ischemia.
Paired Student’s t-tests were used to compare the cardiovascular and blood gas measurements between the "vehicle-prepropofol" and "propofol 3" infusion periods for each infusion route (Table 1). The following changes were statistically significant. LV dP/dtmax and MAP decreased, whereas the PO2 and SaO2 in coronary sinus blood increased. LVEDP increased for the CA route by 2.4 mm Hg (Table 1). HR and CO did not change with propofol for either route.
The increase in PO2 and SaO2 in coronary sinus blood is consistent with a slight vasodilatory effect of the largest dose of propofol on the heart, rather than a direct reduction in myocardial oxygen consumption. This is supported by the fact that myocardial blood velocity was increased, albeit not significantly, by propofol to 120% and 124% of baseline for the IV and CA routes, respectively. On the basis of these findings, reductions in LV dP/dtmax and MAP were considered to be the major cardiovascular effects of propofol in this experimental paradigm, and these were therefore subjected to further kinetic/dynamic analysis.
All cardiovascular measurements had returned to within 10% of baseline values at the end of the vehicle (postpropofol) infusion period after the washout of propofol. The exceptions were CO, which was 15% above baseline in this period for the IV route, and LVEDP, which was 24% and 29% above baseline for the IV and CA routes, respectively. No measurements were affected by the order in which the crossover was conducted (P ranged from 0.13 to 0.88), with the exception of LVEDP (P < 0.01). The slight increase in LVEDP (<3 mm Hg) during the study was consistent with fluid-loading due to CO measurements during the study, and its effect was minimized by the use of a random crossover design.
Plots of the observed arterial and coronary sinus blood concentrations of propofol against dose for the IV and CA infusions are shown in Figure 3. The propofol concentrations achieved were within the clinical range and were comparable to the peak arterial concentrations measured in sheep after bolus doses of approximately 4 mg/kg—a dose sufficient for the induction of anesthesia (18).
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) blood concentrations plotted against the infusion rate of propofol for the IV and coronary artery (CA) infusions. Each point represents the individual arterial or coronary sinus propofol concentration observed at the end of each of three increasing propofol infusion rates in nine sheep. The lines of best fit by linear regression for the arterial (solid line) and coronary sinus (dashed line) concentrations are also shown.For the IV infusions, there was a linear concentration/dose relationship for the arterial concentrations (r2 = 0.94; P < 0.001); the coronary sinus concentration/dose relationship was also linear (r2 = 0.90; P < 0.001). The slopes of the two lines were similar (0.47, SEM 0.02, and 0.42, SEM 0.03, respectively), suggesting that the heart was close to complete equilibration with the arterial blood by the end of each 15-min infusion period.
For the CA infusions, the coronary sinus concentrations were linear with dose (r2 = 0.66; P < 0.001; slope, 3.31; SEM, 0.47) and covered a concentration range similar to those observed for the IV dose. In comparison, the slope of the line for arterial propofol concentrations against dose was small (0.29, SEM 0.66). This shows that significant coronary concentrations of propofol were achieved, but with small concentrations in the remaining organs of the body (because these would be perfused with arterial blood not enriched with propofol). Thus, any cardiovascular effects manifest for the CA infusion can be attributed largely to a direct effect of propofol on the myocardium.
Figures 4 and 5 show the measured LV dP/dtmax and MAP, respectively, as a percentage of their baseline values plotted against the simultaneous coronary sinus propofol concentrations for the IV and CA propofol infusions for each sheep in the study. In general, there was a consistent linear concentration-response relationship for each individual sheep. The slopes for each individual regression line are shown in Tables 2 and 3.
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In summary, for the CA route, LV dP/dtmax was reduced by 2.31% (52 mm Hg/s) for each milligram per liter increase in coronary sinus propofol concentration. For the IV route, the reduction in LV dP/dtmax was not statistically different from the CA route, showing that the coronary propofol concentrations were the major contribution to this cardiovascular effect. Thus, changes in LV dP/dtmax were mediated in a concentration-dependent manner by the presence of propofol in the myocardium.
For the CA route, MAP was reduced by 0.58% (0.6 mm Hg) for each milligram per liter increase in the coronary sinus propofol concentration. MAP was reduced significantly more (an additional 2.18% for each milligram per liter) for the IV route to give a total reduction of 2.5 mm Hg · mg-1 · L-1. Therefore, this blood pressure effect was predominantly mediated by propofol concentrations elsewhere in the body.
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Discussion |
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In summary, IV propofol caused a relatively modest reduction in myocardial contractility. Because the same effect could be achieved by infusing propofol directly into the heart, this effect was a direct effect of propofol on the heart. In contrast, only one-third of the hypotensive effect of propofol could be attributed to a direct effect of propofol on the heart.
LV dP/dtmax has been used extensively as an index of myocardial contractility but is inversely related to LVEDP in open-chested, anesthetized preparations (19). However, the range of change in LVEDP (<3 mm Hg) during this study was small compared with that studied in previous work. Importantly, the usefulness of LV dP/dtmax as an index of myocardial contractility in the presence of propofol is shown by studies in which it was measured concurrently with alternative measures of contractility based on pressure-volume loops (preload recruitable stroke work slope). These data can be used to show that in both closed-chested (10) and open-chested animals (20), the two measures of contractility showed a strong linear relationship (R2 = 0.98 and 0.97, respectively). Taken together, this evidence suggests that the reductions in LV dP/dtmax observed in this study reflect a true reduction in myocardial contractility.
By necessity, this study was conducted in anesthetized animals. Isoflurane was chosen as the basal volatile anesthetic because it causes less cardiovascular depression than halothane (21), which we confirmed in a pilot study. IV anesthesia was not used because opioids are unproven for this role in sheep, and barbiturates cause substantial myocardial depression. As a result, the baseline LV dP/dtmax in this study (Table 1) was comparable to that reported for conscious sheep (12). Furthermore, the relative changes in contractility during the administration of propofol were comparable to those measured in initially conscious sheep (18). The fact that contractility decreased in a linear manner with propofol concentration suggests that concentration-effect mechanisms were not saturated (i.e., the concentrations achieved were on the linear part of a concentration-effect curve that eventually becomes nonlinear as the maximum [physically possible] drug effect is approached).
Another limitation of this study was the use of an open-chest preparation. As in previous studies (19), this caused baseline variability in contractility and filling pressures. However, the effect of this was minimized by the crossover design and by expressing changes as a function of their baseline value.
This study confirms that propofol caused depression of myocardial contractility. Myocardial depression is evident in studies in which propofol was administered systemically at relatively large doses (9,10,20). The concept of direct CA infusion has been used previously (22,23). As in this study, Ismail et al. (22) used this approach to differentiate direct myocardial effects from those mediated elsewhere in the body. They found that propofol had a direct negative inotropic effect but that this was minimal at calculated blood concentrations in the clinically relevant range. This study added a kinetic component to the study design (i.e., coronary concentrations were measured rather than calculated) and infused propofol via the left main CA rather than the left anterior descending CA. This approach may have increased the proportion of LV enriched with propofol and thereby accounts for the relatively greater depression of contractility observed in this study. Nevertheless, these data are consistent with the notion that the magnitude of the direct effect of propofol on the heart, although concentration dependent, is small to moderate compared with that for thiopental (23,24). It is therefore not unexpected that it has not been detected in some experimental paradigms.
In contrast, the fact that propofol reduces MAP is a consistent finding in the literature. This work excludes significant reductions in myocardial contractility as a mechanism for this hypotension, because reductions in MAP were minor (approximately one third of the total) for the CA infusion despite reductions in myocardial contractility. The most likely cause is the dilatory effect of propofol on the smooth muscle of peripheral (venous more than arterial) blood vessels, but there is conflicting evidence whether this effect is mediated directly (25,26) or via sympathoinhibition (11).
A relatively simple method to establish a direct myocardial effect of a drug is the use of isolated heart or heart tissue preparations in which there can be no doubt that the observed effect is due to a drug acting directly in the myocardium. The data for propofol generally show a depressant effect (27–29). All but one of these studies (27) considered the effect to occur at concentrations larger than the clinical range. This relative insensitivity to propofol may be a property of in vitro preparations, because a number of in vivo studies have shown myocardial depression (9,10,20). Interestingly, one in vitro study showed myocardial depression with propofol in hearts perfused with buffer, but not in hearts perfused with whole blood (30). This shows the importance of achieving clinically relevant free fractions of drug in such studies.
The data suggest that for kinetic-dynamic models linking propofol concentrations to cardiovascular effects, changes in myocardial contractility should be linked to the coronary concentration of propofol, whereas MAP changes are better linked to concentrations elsewhere in the body. This is likely to be particularly important at the induction of anesthesia, when both anesthetic concentrations and cardiovascular effects can change rapidly. One outstanding issue is that MAP and myocardial contractility in vivo are governed, to various extents, by endogenous cardiovascular control systems. This study allowed 10–15 minutes for the cardiovascular control systems to accommodate to relatively slow changes in propofol concentration. It may be that rapid bolus administration of propofol produces greater transient changes in MAP and contractility for a given effect-site concentration than those of this study, because the control systems temporarily lag behind the perturbations caused by propofol (18). The importance of this phenomenon will become evident as kinetic-dynamic models of propofol and the cardiovascular system evolve.
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Acknowledgments |
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Supported by the National Health and Medical Research Council of Australia, Project Grant No. 157952.
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References |
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