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Complications during vascular surgery: basic principles and management of cardiac ischaemia
BaillieÁre's Clinical Anaesthesiology Vol. 14, No. 1, pp. 97±108, 2000
doi:10.1053/bean.2000.0064, available online at http://www.idealibrary.com on
5 Complications during vascular surgery: basic principles and management of cardiac ischaemia Richard Teplick Department of Anesthesia, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA
Systematic management of cardiac ischaemia requires an understanding of both the determinants of myocardial oxygen consumption, MVO2 and coronary perfusion. This chapter discusses the mechanical and pharmacological determinants of MVO2 using primarily end-systolic pressure±volume relation, ESPVR, and the relation of the pressure±volume area, which is based upon the ESPVR to MVO2. First, the mechanical determinants of cardiac performance are discussed, followed by their interaction with MVO2. Emphasis is placed upon the eects of heart rate, changes in cardiac loading, and in contractility on MVO2 using the PVA as a basis for analysis. It will be shown that the eects of blood pressure on MVO2 depend mostly on the contractile state of the heart, whereas when considered per beat heart rate probably does not aect MVO2. The concept of increasing contractility causing oxygen wasting and the controversy surrounding this concept is also discussed. Key words: myocardial oxygen consumption; end-systolic pressure±volume relation; stroke volume; inotropes; pressure±volume area; heart rate.
CARDIAC MECHANICS The terms pre-load, afterload and contractility are often used to describe the determinants of ventricular performance. Contractility can be de®ned in dierent ways depending on what aspect of performance is being studied. Pre-load and afterload have precise de®nitions in papillary muscle experiments. Pre-load is de®ned as a force (or weight) applied to a papillary muscle that stretches it to a given length during diastole. Afterload is the constant force that a papillary muscle develops during shortening. However, because the geometry and dynamics of a functioning ventricle dier so radically from those of a papillary muscle, these terms are not directly applicable to an intact ventricle. Although an analogous de®nition of pre-load in an intact ventricle might be possible, functionally it is more useful to de®ne ventricular pre-load as the volume at end-diastole (Ved). In contrast, because the force developed by a ventricle changes constantly during ejection (which is analogous to shortening in a papillary muscle), the term afterload cannot be applied directly to intact ventricles. However, rather than struggling to apply such terms to an intact ventricle, it seems more sensible to determine the factors that have a major in¯uence on the stroke volume (SV) of the 1521±6896/00/01009+13 $35.00/00
c 2000 Harcourt Publishers Ltd. *
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ventricles. Because SV is, by de®nition, the dierence between Ved and the end-systolic volume (Ves), the question becomes what determines these two volumes. End-diastolic volume Ved is related to the pressure at end-diastole (Ped) by the end-diastolic pressure± volume relationship (EDPVR), which is often referred to as the ventricular compliance curve. However, it is actually an elastance curve because the slope is the change in pressure per unit change in volume, not the change in volume with pressure. End-systolic volume An elastance curve can also be de®ned at end-systole. This curve, the end-systolic pressure±volume relationship (ESPVR), shown in Figure 1, relates the end-systolic pressure (Pes) and volume (Ves). It diers from the EDPVR in that it is approximately linear and therefore can be described by a slope and intercept. As discussed below, the ESPVR can be used to de®ne contractility in a load-independent manner. Thus, the determinants of Ves are analogous to those of Ved, Pes and the ESPVR, a pressure and 200 180
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VR
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Volume (ml) Figure 1. Left ventricular ejection and the ESPVR. See text for detailed description. The ejection occurs in a counterclockwise direction. a, onset of systole; b, end of isovolumic systole and onset of ejection (diastolic blood pressure); c, systolic pressure; d, end of ejection and onset of isovolumic relaxation (end-systolic pressure); e, end of isovolumic relaxation and onset of diastolic ®lling; f, onset of atrial ejection. Vertical broken lines 1 and 2 indicate pressures that would be developed if the further ejection were prevented at the corresponding volumes.
Principles and management of cardiac ischaemia 99
an elastance. To understand the ESPVR more completely, it is helpful to digress into some basic mechanical principles of ventricular performance. The isovolumic peak pressure volume line If the out¯ow of the left ventricle (LV) or right ventricle (RV) were occluded so that the ventricle could not eject, as the end-diastolic volume (EDV) was increased, the peak pressure attained during systole would also increase. Although such beats are usually depicted by plotting ventricular pressure against time, they may also be characterized by plotting ventricular pressure on the Y-axis against ventricular volume on the X-axis. In such a plot, isovolumic beats with dierent Ves would appear as vertical lines with dierent heights because volume, by de®nition, would not change during the cardiac cycle. The height of each vertical line would re¯ect the peak pressure developed during the beat. The base of each vertical pressure±volume line would lie on the EDPVR. When beats at dierent Ved are plotted in this way, keeping contractile state constant, the relation between peak pressure and volume has been observed to be approximately linear. The line connecting the peak pressures to the corresponding Ves is termed the ESPVR shown in Figure 1. If the ESPVR were known, Ves could be determined from the peak pressure of an isovolumic beat. This is analogous to the relation between pressure and volume at end-diastole except that the EDPVR is markedly non-linear. The ESPVR intersects the volume axis at a point known as V0, which is the volume at which the ventricle does not develop any pressure. An inotrope causes peak pressure to increase at any volume. The overall eect is to rotate the ESPVR counterclockwise around V0. Thus, for isovolumic contractions, an increase in contractility is re¯ected by a steeper slope of the ESPVR and a decrease in contractility by a ¯atter slope. This line, therefore, provides a Ved-independent measure of contractility for isovolumic beats. End-systolic pressure±volume line in ejections1 The ESPVR can be extended to describe ejecting beats as shown in Figure 1. The utility of this description is that it provides a load-independent de®nition of contractility and uses the ESPVR to relate Ves to Pes in a simple manner. For an ejecting LV, as soon as the pressure within the ventricle exceeds that in the aorta, the aortic valve opens and ejection begins (point b). The period of systole preceding the ejection (points a±b) is isovolumic because both valves are closed. Therefore this appears on a pressure±volume diagram as a vertical line positioned at Ved. The onset of ejection is marked by an abrupt change from a vertical line to a curve with a decreasing volume and increasing pressure. The rise in pressure depends on a complex interaction between the properties of the arterial tree and the LV. Systolic pressure corresponds to point c. If the ejection is allowed to proceed to completion, the pressure at end-ejection will fall on the ESPVR (point d). That is, at the end of ejection, the pressure (i.e. Pes) is determined by the volume at that point (by de®nition Ves) and the contractile state of the ventricle (i.e. the ESPVR). Following the completion of ejection, the aortic valve closes and isovolumic relaxation ensues (points d±e). When the pressure in the LV decreases to less than the left atrial pressure, the mitral valve opens, the ventricle again ®lls to its Ved (point e). Atrial contraction is marked by point f after which ejection begins again (point a). Overall, this model is referred to as the time-varying elastance model of ventricular contraction because, during systole, the relation between ventricular pressure and volume can be described by a line that becomes progressively stier (less elastic,
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steeper) with time. Maximum stiness corresponds to the ESPVR. Thereafter, the ventricle becomes less sti (more elastic). Minimum stiness corresponds to the EDPVR (compliance curve). If ejections are repeated with dierent vascular properties or starting from dierent Ves, the end of ejection will still always fall approximately on the ESPVR. Therefore, from the values of Pes corresponding to dierent Ves, strong inferences can be made about the contractile state of the ventricle. In fact, Pes yields considerably more information than using vascular properties such as resistance or compliance to try to describe ventricular load. It is certainly true that these vascular properties aect pressures and therefore Pes. However, given the resistance and compliance of the vasculature (in themselves greatly simpli®ed concepts) and the contractility of the ventricle, it is dicult, if not impossible, to calculate Ves without additional information. Moreover, the only way that arterial properties can be `sensed' by a ventricle is by their eect on the ease of ejection via the eects of pressure development. In other words, vascular properties such as resistance and compliance are not measures of ventricular afterload but only modi®ers of load as measured by pressure. Using these principles, the SV can be speci®ed by only two pressures and two elastances as depicted in Figure 2. Ved is determined by Ped and the EDPVR, the enddiastolic elastance curve, and Ves is determined by Pes and the ESPVR, the end-systolic elastance curve. This model has important implications in predicting myocardial oxygen consumption. MYOCARDIAL OXYGEN CONSUMPTION Enormous research has been devoted to trying to determine the mechanical factors that in¯uence myocardial oxygen consumption (MVO2). The result has been a myriad of indices such as the rate±pressure product, which is the product of heart rate and systolic pressure, which combine dierent measured parameters to predict MVO2. However, many of these indices have been derived either empirically or from mechanical factors that are statistically closely associated with MVO2. Among the former are indices such as the rate±pressure product, the triple product and the tension±time index. Among the latter are the pressure work index or the multi-parameter index derived by Brutsaert.2 There is, however, a third class of indices derived from basic physical principles. Two examples are the force±time integral (FTI) and the pressure± volume area (PVA), the latter of which is probably the most widely tested and validated of all predictors of MVO2. Consequently, it will be used below in considering the balance between MVO2 and coronary perfusion. For the heart, energy consumption per beat and oxygen consumption per beat are essentially equivalent because the heart has very little anaerobic capacity. That is, all the energy utilized by the beating heart is re¯ected in the oxygen consumed. For this reason, energy utilization in joules is often used interchangeably with MVO2. The energy yield of 1 ml of oxygen consumed by the heart is equivalent to 19.7 J. Pressure±volume area In accordance with the ®rst law of thermodynamics, the amount of energy consumed by the heart must equal the work performed plus the heat produced. The PVA incorporates these principles using stroke work (SW) and the end-systolic potential energy.3
Principles and management of cardiac ischaemia 101
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Figure 2. Determinants of SV. SV is determined by the dierence between EDV and end-systolic volume (ESV). EDV is determined by the EDPVR, also termed the compliance curve, and the end-diastolic pressure (EDP). ESV is determined by the end-systolic pressure (ESP) and the ESPVR, which is also a measure of the contractile state or maximum elastance. Because the slopes of both the EDPVR and ESPVR are dV/dP, both curves are actually elastances. Therefore, the SV is determined by two elastance curves, EDPVR and ESPVR, and two pressures, EDP and ESP.
Stroke work If an object is pushed with a constant force, the work done is de®ned as the force multiplied by the distance moved. However, for the heart it is equivalent but more convenient to describe the work as pressure multiplied by the change in volume. The problem is, however, more complicated because ventricular pressure during systole is constantly changing. Consequently, SW should be calculated as Z
Ves Ved
P VdV
where Ved and Ves are the end-diastolic and end-systolic volumes respectively. The pressure, P(V), used in this calculation is the developed pressure at a given volume, V, which is the dierence between the intraventricular pressure measured at each instant
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during systole and the pressure that would exist if the ventricle were completely relaxed at the ventricular volume at that instant. Therefore the SW of a ventricle is simply the area enclosed by the pressure±volume loop, bounded on the right by Ved, on the left by Ves, above by the pressure during ejection and below by the EDPVR (Figure 1). Frequently, the SW is approximated by the product of the SV and the mean arterial pressure minus Ped. In essence, this is simply a rectangle bounded above by the mean arterial pressure and below by Ped with the right and left sides bounded by Ved and Ves respectively. Under some conditions this approximation may yield an accurate estimate of SW, despite underestimating some of the area of the pressure±volume loop and overestimating other areas. Under other conditions, however, the approximation may not be very accurate. Heat production During an isovolumic beat the ventricle does no work because there is no volume change. However, experimentally for a given contractile state and Ved, an isovolumic contraction consumes the greatest energy per beat. Because there is no work done, all of the energy utilized must be dissipated as heat. The time-varying elastic model of pressure development is also useful in predicting the heat produced during a single beat. Because at the time of peak systolic pressure in an isovolumic contraction the ventricular stiness is maximal, it should be possible to recover some work during the subsequent decrease in stiness if the ventricle were allowed to eject after peak systole was reached. Moreover, if this ejection were controlled in such a way that the maximum possible pressure was developed as the volume decreased, then as shown in Figure 3, the ejection would follow the ESPVR as this line de®nes the maximum pressure that can be developed at any volume. If such an ejection could be achieved, the ventricle would perform the maximum possible work. This work would equal the area of the triangle shown in Figure 3. Because this would be the maximum work that is theoretically possible, all the energy utilized would be expended in doing this work so that no heat would be produced. This triangular area is termed the end-systolic potential energy (PEes) by Suga et al because it represents the maximum potential work that could be performed at the end of systole if the heart were forced to eject along the ESPVR rather than relaxing isovolumically. Because the ventricle actually does not do any work after end-systole (the RV may be an exception) all this potential work is dissipated as heat. Consequently, PEes is predicted to be proportional to the heat produced during an isovolumic contraction and therefore also proportional to the MVO2 used during such a beat. This was studied extensively in the isolated canine LV and found to be correct. This principle is easily extended to ejections. At the end of ejection, the pressure developed at Ves is the same as if the ventricle had contracted isovolumically with volume ®xed at Ves. Therefore, as shown in Figure 3, PEes for an ejection is the area to the left of the isovolumic relaxation line. Because the ®rst law of thermodynamics states that the energy consumed should equal the heat dissipated plus the work done, Suga et al predicted that the MVO2 of ejecting ventricles should be proportional to the stroke work plus PEes. He termed this sum the PVA. To recap, from the ®rst law of thermodynamics DE dQ dW
1
where DE is the change in energy of a system, dQ is the heat produced and dW is the work done by the system. By analogy, MVO2 is proportional to the PVA which equals
MVO2/beat (ml/min)
Principles and management of cardiac ischaemia 103
e
rop
Inot
Activation energy Basal energy Pressurevolume area (mmHg ml3) Figure 3. Relation between PVA and MVO2 (per beat). See text for details. PVA and MVO2 are, as shown, related linearly. That is, MVO2 b PVA a. At a PVA of 0, MVO2 equals a which is thought to be the energy required for two processes that are not related directly to force development. One process is the basal energy (coloured region) which is energy required to keep the cells viable. The other much larger energy is that required for activation (hatched region) which is used for subcellular processes that are needed for force development but do not directly generate force. Examples are calcium mobilization and re-uptake, ion pumps and various phosphorylations. Inotropic stimulation causes a parallel upward shift in the line (labelled `Inotrope').
PEes SW. It is important to note that this equation predicts MVO2 per beat and must be multiplied by heart rate to calculate MVO2 per minute. However, in this chapter MVO2 will always be used to refer to oxygen consumption per beat. This model has been extensively tested in isolated hearts, and a linear relation between MVO2 and the PVA has consistently been found as shown in Figure 3. That is, whether a given PVA is generated by an isovolumic beat or by ejections with dierent Ved and Ves, for a constant contractile state, the MOV2 will be constant. This model is very powerful because it allows the mechanical properties of a ventricle, described using the ESPVR and EDPVR, also to be used to predict its MVO2. The appeal of this model is then several-fold. First, it has the correct units, i.e. the units of the PVA are in fact energy. Second, it is easy to relate MVO2 to mechanical parameters such as contractility and ejection patterns using the concepts introduced above. Third, it is thermodynamically correct. That is, it is consistent with the ®rst law of thermodynamics. Notice in Figure 3 that if the PVA is extrapolated to zero, that is, at a volume where no pressure is developed, MVO2 is not zero. This is thought to be due to two factors. The ®rst, as shown by the coloured rectangle, is the basal oxygen consumption that is required to keep the cell alive. The second factor is the activation energy, depicted as the hatched area, which is thought to be the energy required for the biochemical
104 R. Teplick
processes needed for contraction to occur, such as calcium release and re-uptake from the sarcoplasmic reticulum. Eects of inotropic state on oxygen consumption The contractile state of a ventricle is usually cited as an important determinant of MVO2. This concept is based on the observation that, for a ®xed value of most indices of ventricular performance such as the PVA, inotropic drugs increase MVO2. This is illustrated for the PVA in Figure 3 in which an inotrope causes a parallel upward shift in the MVO2±PVA line so that, for any PVA, MVO2 is increased by the inotrope.4 This parallel upward shift is thought to be due to an increase in activation energy so that, as shown in the ®gure, for any PVA, the increase in MVO2 is equal to the increase in activation energy. Thus, based on indices such as the PVA, inotropes are said to increase MVO2, that is they are oxygen wasting. The reason that indices are used to normalize performance to compare MVO2 at dierent contractile states is that, by de®nition, as contractility changes, haemodynamics must also change. Consequently, it is impossible to compare MVO2 for beats with identical haemodynamic characteristics and dierent inotropic states. For example, if the inotropic state is increased (corresponding to an increase in the slope of the ESPVR) and Ves is held constant, then, for the same Pes, the SV must increase. Conversely, if the SV is ®xed, then Pes must increase. Thus, there is no way to keep all haemodynamic factors constant, e.g. SV, Ved and Pes, so that beats at dierent contractile states can never be directly compared. Consequently, it could always be argued that any change in MVO2 observed with an inotrope is a result of haemodynamic changes rather than a direct eect of the inotrope. Understanding the direct eects of inotropes is particularly important in managing ischaemia because haemodynamic eects of inotropes can both negate and enhance their direct eects on MVO2. To surmount this problem, performance indices such as the PVA have been used to compensate for changes in cardiac mechanics caused by inotropes so that MVO2 can be compared at the same value of the index at dierent contractile states despite dierences in haemodynamics. However, this approach is limited because the increment in MVO2 observed with, for example, the PVA could be a true eect of the inotrope or it could be an artifact due to inadequacies in the PVA as an index of MVO2. This problem was underscored in a study by Rook and Figel5, in which they compared the change in MVO2 with various interventions, including inotropes in canine hearts using two dierent indices to normalize performance. Their results, using a measure of performance known as the pressure±work index (PWI), did not show a direct eect of inotropes on MVO2. That is, the linear relationship that they observed between MVO2 and the PWI was not shifted by inotropes. Thus, based on the PWI, inotropes do not appear to have any direct eect on MVO2, i.e. they are not oxygen wasting, so that their only eect on MVO2 is via the changes induced in haemodynamics. Evidently, then, whether or not inotropes are oxygen wasting depends on the index used to characterize performance. Consequently, the direct eects of inotropes on MVO2 is, at this moment, actually unknown. However, biochemical considerations would suggest that inotropes that act via adenyl cyclase should be oxygen wasting because in the process of increasing contractility they also activate processes that either have no eect on performance or may actually inhibit performance. For example, b agonists cause the phosphorylation of tropinin I, which inhibits the binding of calcium to the regulatory protein, tropinin C. As a result, it should take higher cytosolic calcium concentrations to cause the same increment in developed pressure
Principles and management of cardiac ischaemia 105
after b-receptor stimulation. It seems logical that this increase in cytosolic calcium would require additional energy which should increase MVO2 for a given level of performance. That is, such phosphorylations should cause oxygen wasting. There are numerous other phosphorylations that occur, such as the phosphorylation of phospholambin, the sarcoplasmic reticulum calcium transport protein, or of myosin light chain, that also would not be expected to lead directly to an increase in performance. Therefore, biochemical considerations suggest that inotropes should be oxygen wasting; at least for those inotropes that alter biochemical processes by phosphorylations, which include all drugs now in use except digoxin. In contrast, the enhanced contractility seen with cooling an isolated LV is not associated with any increment in MVO2 as judged by the PVA. Thus, it is likely that whether or not all increments in contractility are associated with oxygen wasting depends very much on the mechanism of inotropic stimulation. It should also be noted that the same arguments that suggest inotropes are oxygen wasting show that depressants are oxygen conserving. Heart rate and oxygen consumption Because increases in heart rate also increase MVO2 per minute, heart rate is usually considered to be a major determinant of MVO2. However, although an increase in heart rate increases cardiac contractile state, there is no shift in the MVO2±PVA line. This suggests that, apart from eects on haemodynamics, heart rate has no eect on MVO2 per beat. The question then is whether MVO2 should be considered per beat or per minute. The answer depends on the reason for measuring MVO2. However, it seems reasonable to consider MVO2 over a time frame during which limitations in supply would lead to dysfunction. Thus, for example, type 2 skeletal muscle can incur an oxygen debt for a relatively long time period, e.g. function anaerobically, during a sprint. However, in the heart, there are data to suggest that, within one or two beats of low ¯ow, mechanical dysfunction occurs.6 Therefore, it seems reasonable to think about MVO2 per beat, rather than per minute, and as available data suggest that MVO2 per beat is not directly aected by heart rate, other than as expected with any associated haemodynamic changes, MVO2 is not aected by heart rate. Rate-related ischaemia then occurs because of limited supply, not because of increased demand. In normal ventricles, the small coronary arteries dilate with an increase in heart rate to keep ¯ow per beat approximately constant even though the time for ¯ow is diminished. However, post-stenotic coronary vessels are already dilated and therefore have limited reserve. Consequently, they cannot dilate suciently with increases in heart rate to preserve ¯ow. Therefore, the myocardial regions supplied by such coronary arteries become ischaemic at high heart rates. Similar mechanisms, i.e. limited coronary reserve, account for the eects of heart rate in producing ischaemia in patients with hypertrophy or aortic stenosis without signi®cant coronary disease. Clinical applications Pressure work versus volume work It is generally taught that, for a given SW, a ventricle that develops high pressures and relatively low SV consumes more oxygen than one that develops a high SV and relatively low pressures. The explanation for this phenomenon is readily apparent by examining PVA diagrams as shown in Figure 4 which is adapted from a study conducted by Suga et al.7 In this study an isolated LV was made to eject from a ®xed EDV at a ®xed
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2
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PEes2
Pressure (mmHg)
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100 PEes1
80 60 40 20 0
EDPVR 0
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Volume (ml) Figure 4. SW and MVO2. Two beats with identical SW can still have very dierent MVO2 if PEes diers. In this experiment, LVEDV was kept constant. The SV of beat 1 (full ejection curve) was large relative to beat 2 (broken ejection curve) but the SW was the same for both beats. Because of the higher ESP developed by beat 2, its PEes (coloured plus hatched regions) was considerably greater than that of beat 1 (coloured region only). Consequently, MVO2 was greater for beat 2. This is the reason that `pressure work' is said to consume more O2 than `volume work'.
contractile state developing high pressures and low SV or low pressures and high SV, but with identical SW in both cases. As can be seen from Figure 4, the ventricle developing high pressures, i.e. doing pressure work, should consume more oxygen than the ventricle doing volume work because the former has a much larger PEes. This theoretical explanation has been validated in the experiment cited above. Intuitively, what is occurring is that at the end of ejection a ventricle developing high pressure dissipates relatively large amounts of heat because, given the high Pes, it potentially could do considerably more work but instead dissipates this potential as heat. This analysis also shows that the reason that pressure work consumes more oxygen than volume work is unrelated to the SW itself, as it is equal in both instances, but rather to the much larger PEes associated with the development of high pressures. Loading in normal and depressed ventricles Because the ESPVR is, by de®nition, ¯atter in a depressed ventricle, for a given increment in Pes a depressed ventricle will have a much larger increment in Ves than a normal ventricle (Figure 5). Because of the resultant loading of the RV, it is likely that the SV will also decrease and thus the SW may not increase as much as it would in a
Principles and management of cardiac ischaemia 107
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Volume (mmHg) Figure 5. Eects of increasing blood pressure on ventricular volumes and PVAs. (A) The ventricle has a normal contractile state as indicated by the steep ESPVR. Consequently, an increase in blood pressure has relatively little eect on end-systolic volume. Ves, and therefore end-diastolic volume, Ved, also changes minimally. The result is that SW and end-systolic potential energy, Pes, are increased only slightly. Consequently, the PVA and therefore MVO2 also increase relatively little. (B) In contrast, for a depressed ventricle, the same increase in blood pressure causes a relatively large increase in Pes (coloured area) thereby causing PVA and MVO2 to increase substantially.
108 R. Teplick
MVO2/beat (ml/min)
normal ventricle or it may actually decrease. Nonetheless, as shown in Figure 5, PEes would increase considerably more in a depressed than in a normal LV because of the greater increase in Ves. Consequently, the relative increment in MVO2 would also be much greater in the depressed than in the normal LV. This explains why the use of a agonists can be deleterious in a depressed ventricle. Not only will Ves and Ved increase much more in a depressed than in a normal ventricle, with the resultant increase in Ped potentially leading to pulmonary oedema, but the increment in MVO2 would also be substantially greater. This relative increase in MVO2 plus the high endocardial pressures impeding coronary blood ¯ow produce conditions conducive to ischaemia. For these reasons it seems reasonable to conclude that if one uses an a agonist in a ventricle where the contractile state is not known, and observes a marked increase in LVEDP associated with a decline in SV, an inotropic drug should probably be used in its place. The caveat is that the heart rate should not be allowed to increase. It also seems likely from the electrophysiology and anecdotal experience that b-blockers can be used in small doses to blunt increases in heart rate without aecting appreciably the inotropic eects of b agonists. Regardless of whether oxygen consumption is directly increased by inotropes, the decrement in size associated with the increased inotropic state is likely to lead to a decrease in MVO2. That is, as shown in Figure 6, even if the MVO2±PVA line is shifted upward by the inotrope, the PVA would decrease suciently because of the reduction in Ves and thus PEes is suciently large that MOV2 would still decrease. This phenomenon has been demonstrated for a variety of inotropes including digoxin.
B
e
rop
Inot
a
b A
2 1
Activation energy Basal energy
Pressurevolume area (mmHg ml3) Figure 6. Inotropes and MVO2. Inotropes have been shown to cause a parallel upward shift in the PVA± MVO2 line (line A to line B). This is thought to be due to an increase in activation energy (from hatched region 1 to hatched plus grey region) and is the basis of the concept that inotropes are O2 wasting (see text for details). If the LV is very large it will usually have a high PVA (point a). However, despite the upward shift in the PVA±MVO2 line caused by the inotrope, if ventricular size and thus PVA decrease suciently (point b), MVO2 can still decrease.
Principles and management of cardiac ischaemia 109
REFERENCES 1. Sugawa K. End-systolic pressure±volume relationship in retrospect and prospect. Federation Proceedings 1984; 43: 2399±2401. 2. Futaki S, Goto Y, Ohgoshi Y et al. Comparison between Bretschneider's total myocardial energy demand (Et) and our total mechanical energy (PVA) as a predictor of cardiac oxygen consumption in dogs. Japanese Journal of Physiology 1990; 40: 809±825. 3. Suga H, Yamada O & Goto Y. Energetics of ventricular contraction as traced in the pressure±volume diagram. Federation Proceedings 1984; 43: 2411±2413. 4. Sagawa K, Maughan L, Suga H & Sunagawa K. Cardiac Contraction and the Pressure-Volume Relationship. New York: Oxford University Press, 1988. 5. Rooke GA & Feigl EO. Work as a correlate of canine left ventricular oxygen consumption, and the problem of catecholamine oxygen wasting. Circulation Research 1982; 50: 273±286. 6. Arai AE, Pantley GA, Thoma WJ et al. Energy metabolism and contractile function after 15 beats of moderate myocardial ischaemia. Circulation Research 1992; 70: 1137±1145. 7. Suga H, Hisano R, Hirata S et al. Mechanism of higher oxygen consumption rate: pressure-loaded vs. volume-loaded heart. American Journal of Physiology 1982; 242: H942±H948.
doi:10.1053/bean.2000.0064, available online at http://www.idealibrary.com on
5 Complications during vascular surgery: basic principles and management of cardiac ischaemia Richard Teplick Department of Anesthesia, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA
Systematic management of cardiac ischaemia requires an understanding of both the determinants of myocardial oxygen consumption, MVO2 and coronary perfusion. This chapter discusses the mechanical and pharmacological determinants of MVO2 using primarily end-systolic pressure±volume relation, ESPVR, and the relation of the pressure±volume area, which is based upon the ESPVR to MVO2. First, the mechanical determinants of cardiac performance are discussed, followed by their interaction with MVO2. Emphasis is placed upon the eects of heart rate, changes in cardiac loading, and in contractility on MVO2 using the PVA as a basis for analysis. It will be shown that the eects of blood pressure on MVO2 depend mostly on the contractile state of the heart, whereas when considered per beat heart rate probably does not aect MVO2. The concept of increasing contractility causing oxygen wasting and the controversy surrounding this concept is also discussed. Key words: myocardial oxygen consumption; end-systolic pressure±volume relation; stroke volume; inotropes; pressure±volume area; heart rate.
CARDIAC MECHANICS The terms pre-load, afterload and contractility are often used to describe the determinants of ventricular performance. Contractility can be de®ned in dierent ways depending on what aspect of performance is being studied. Pre-load and afterload have precise de®nitions in papillary muscle experiments. Pre-load is de®ned as a force (or weight) applied to a papillary muscle that stretches it to a given length during diastole. Afterload is the constant force that a papillary muscle develops during shortening. However, because the geometry and dynamics of a functioning ventricle dier so radically from those of a papillary muscle, these terms are not directly applicable to an intact ventricle. Although an analogous de®nition of pre-load in an intact ventricle might be possible, functionally it is more useful to de®ne ventricular pre-load as the volume at end-diastole (Ved). In contrast, because the force developed by a ventricle changes constantly during ejection (which is analogous to shortening in a papillary muscle), the term afterload cannot be applied directly to intact ventricles. However, rather than struggling to apply such terms to an intact ventricle, it seems more sensible to determine the factors that have a major in¯uence on the stroke volume (SV) of the 1521±6896/00/01009+13 $35.00/00
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ventricles. Because SV is, by de®nition, the dierence between Ved and the end-systolic volume (Ves), the question becomes what determines these two volumes. End-diastolic volume Ved is related to the pressure at end-diastole (Ped) by the end-diastolic pressure± volume relationship (EDPVR), which is often referred to as the ventricular compliance curve. However, it is actually an elastance curve because the slope is the change in pressure per unit change in volume, not the change in volume with pressure. End-systolic volume An elastance curve can also be de®ned at end-systole. This curve, the end-systolic pressure±volume relationship (ESPVR), shown in Figure 1, relates the end-systolic pressure (Pes) and volume (Ves). It diers from the EDPVR in that it is approximately linear and therefore can be described by a slope and intercept. As discussed below, the ESPVR can be used to de®ne contractility in a load-independent manner. Thus, the determinants of Ves are analogous to those of Ved, Pes and the ESPVR, a pressure and 200 180
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Volume (ml) Figure 1. Left ventricular ejection and the ESPVR. See text for detailed description. The ejection occurs in a counterclockwise direction. a, onset of systole; b, end of isovolumic systole and onset of ejection (diastolic blood pressure); c, systolic pressure; d, end of ejection and onset of isovolumic relaxation (end-systolic pressure); e, end of isovolumic relaxation and onset of diastolic ®lling; f, onset of atrial ejection. Vertical broken lines 1 and 2 indicate pressures that would be developed if the further ejection were prevented at the corresponding volumes.
Principles and management of cardiac ischaemia 99
an elastance. To understand the ESPVR more completely, it is helpful to digress into some basic mechanical principles of ventricular performance. The isovolumic peak pressure volume line If the out¯ow of the left ventricle (LV) or right ventricle (RV) were occluded so that the ventricle could not eject, as the end-diastolic volume (EDV) was increased, the peak pressure attained during systole would also increase. Although such beats are usually depicted by plotting ventricular pressure against time, they may also be characterized by plotting ventricular pressure on the Y-axis against ventricular volume on the X-axis. In such a plot, isovolumic beats with dierent Ves would appear as vertical lines with dierent heights because volume, by de®nition, would not change during the cardiac cycle. The height of each vertical line would re¯ect the peak pressure developed during the beat. The base of each vertical pressure±volume line would lie on the EDPVR. When beats at dierent Ved are plotted in this way, keeping contractile state constant, the relation between peak pressure and volume has been observed to be approximately linear. The line connecting the peak pressures to the corresponding Ves is termed the ESPVR shown in Figure 1. If the ESPVR were known, Ves could be determined from the peak pressure of an isovolumic beat. This is analogous to the relation between pressure and volume at end-diastole except that the EDPVR is markedly non-linear. The ESPVR intersects the volume axis at a point known as V0, which is the volume at which the ventricle does not develop any pressure. An inotrope causes peak pressure to increase at any volume. The overall eect is to rotate the ESPVR counterclockwise around V0. Thus, for isovolumic contractions, an increase in contractility is re¯ected by a steeper slope of the ESPVR and a decrease in contractility by a ¯atter slope. This line, therefore, provides a Ved-independent measure of contractility for isovolumic beats. End-systolic pressure±volume line in ejections1 The ESPVR can be extended to describe ejecting beats as shown in Figure 1. The utility of this description is that it provides a load-independent de®nition of contractility and uses the ESPVR to relate Ves to Pes in a simple manner. For an ejecting LV, as soon as the pressure within the ventricle exceeds that in the aorta, the aortic valve opens and ejection begins (point b). The period of systole preceding the ejection (points a±b) is isovolumic because both valves are closed. Therefore this appears on a pressure±volume diagram as a vertical line positioned at Ved. The onset of ejection is marked by an abrupt change from a vertical line to a curve with a decreasing volume and increasing pressure. The rise in pressure depends on a complex interaction between the properties of the arterial tree and the LV. Systolic pressure corresponds to point c. If the ejection is allowed to proceed to completion, the pressure at end-ejection will fall on the ESPVR (point d). That is, at the end of ejection, the pressure (i.e. Pes) is determined by the volume at that point (by de®nition Ves) and the contractile state of the ventricle (i.e. the ESPVR). Following the completion of ejection, the aortic valve closes and isovolumic relaxation ensues (points d±e). When the pressure in the LV decreases to less than the left atrial pressure, the mitral valve opens, the ventricle again ®lls to its Ved (point e). Atrial contraction is marked by point f after which ejection begins again (point a). Overall, this model is referred to as the time-varying elastance model of ventricular contraction because, during systole, the relation between ventricular pressure and volume can be described by a line that becomes progressively stier (less elastic,
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steeper) with time. Maximum stiness corresponds to the ESPVR. Thereafter, the ventricle becomes less sti (more elastic). Minimum stiness corresponds to the EDPVR (compliance curve). If ejections are repeated with dierent vascular properties or starting from dierent Ves, the end of ejection will still always fall approximately on the ESPVR. Therefore, from the values of Pes corresponding to dierent Ves, strong inferences can be made about the contractile state of the ventricle. In fact, Pes yields considerably more information than using vascular properties such as resistance or compliance to try to describe ventricular load. It is certainly true that these vascular properties aect pressures and therefore Pes. However, given the resistance and compliance of the vasculature (in themselves greatly simpli®ed concepts) and the contractility of the ventricle, it is dicult, if not impossible, to calculate Ves without additional information. Moreover, the only way that arterial properties can be `sensed' by a ventricle is by their eect on the ease of ejection via the eects of pressure development. In other words, vascular properties such as resistance and compliance are not measures of ventricular afterload but only modi®ers of load as measured by pressure. Using these principles, the SV can be speci®ed by only two pressures and two elastances as depicted in Figure 2. Ved is determined by Ped and the EDPVR, the enddiastolic elastance curve, and Ves is determined by Pes and the ESPVR, the end-systolic elastance curve. This model has important implications in predicting myocardial oxygen consumption. MYOCARDIAL OXYGEN CONSUMPTION Enormous research has been devoted to trying to determine the mechanical factors that in¯uence myocardial oxygen consumption (MVO2). The result has been a myriad of indices such as the rate±pressure product, which is the product of heart rate and systolic pressure, which combine dierent measured parameters to predict MVO2. However, many of these indices have been derived either empirically or from mechanical factors that are statistically closely associated with MVO2. Among the former are indices such as the rate±pressure product, the triple product and the tension±time index. Among the latter are the pressure work index or the multi-parameter index derived by Brutsaert.2 There is, however, a third class of indices derived from basic physical principles. Two examples are the force±time integral (FTI) and the pressure± volume area (PVA), the latter of which is probably the most widely tested and validated of all predictors of MVO2. Consequently, it will be used below in considering the balance between MVO2 and coronary perfusion. For the heart, energy consumption per beat and oxygen consumption per beat are essentially equivalent because the heart has very little anaerobic capacity. That is, all the energy utilized by the beating heart is re¯ected in the oxygen consumed. For this reason, energy utilization in joules is often used interchangeably with MVO2. The energy yield of 1 ml of oxygen consumed by the heart is equivalent to 19.7 J. Pressure±volume area In accordance with the ®rst law of thermodynamics, the amount of energy consumed by the heart must equal the work performed plus the heat produced. The PVA incorporates these principles using stroke work (SW) and the end-systolic potential energy.3
Principles and management of cardiac ischaemia 101
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Figure 2. Determinants of SV. SV is determined by the dierence between EDV and end-systolic volume (ESV). EDV is determined by the EDPVR, also termed the compliance curve, and the end-diastolic pressure (EDP). ESV is determined by the end-systolic pressure (ESP) and the ESPVR, which is also a measure of the contractile state or maximum elastance. Because the slopes of both the EDPVR and ESPVR are dV/dP, both curves are actually elastances. Therefore, the SV is determined by two elastance curves, EDPVR and ESPVR, and two pressures, EDP and ESP.
Stroke work If an object is pushed with a constant force, the work done is de®ned as the force multiplied by the distance moved. However, for the heart it is equivalent but more convenient to describe the work as pressure multiplied by the change in volume. The problem is, however, more complicated because ventricular pressure during systole is constantly changing. Consequently, SW should be calculated as Z
Ves Ved
P VdV
where Ved and Ves are the end-diastolic and end-systolic volumes respectively. The pressure, P(V), used in this calculation is the developed pressure at a given volume, V, which is the dierence between the intraventricular pressure measured at each instant
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during systole and the pressure that would exist if the ventricle were completely relaxed at the ventricular volume at that instant. Therefore the SW of a ventricle is simply the area enclosed by the pressure±volume loop, bounded on the right by Ved, on the left by Ves, above by the pressure during ejection and below by the EDPVR (Figure 1). Frequently, the SW is approximated by the product of the SV and the mean arterial pressure minus Ped. In essence, this is simply a rectangle bounded above by the mean arterial pressure and below by Ped with the right and left sides bounded by Ved and Ves respectively. Under some conditions this approximation may yield an accurate estimate of SW, despite underestimating some of the area of the pressure±volume loop and overestimating other areas. Under other conditions, however, the approximation may not be very accurate. Heat production During an isovolumic beat the ventricle does no work because there is no volume change. However, experimentally for a given contractile state and Ved, an isovolumic contraction consumes the greatest energy per beat. Because there is no work done, all of the energy utilized must be dissipated as heat. The time-varying elastic model of pressure development is also useful in predicting the heat produced during a single beat. Because at the time of peak systolic pressure in an isovolumic contraction the ventricular stiness is maximal, it should be possible to recover some work during the subsequent decrease in stiness if the ventricle were allowed to eject after peak systole was reached. Moreover, if this ejection were controlled in such a way that the maximum possible pressure was developed as the volume decreased, then as shown in Figure 3, the ejection would follow the ESPVR as this line de®nes the maximum pressure that can be developed at any volume. If such an ejection could be achieved, the ventricle would perform the maximum possible work. This work would equal the area of the triangle shown in Figure 3. Because this would be the maximum work that is theoretically possible, all the energy utilized would be expended in doing this work so that no heat would be produced. This triangular area is termed the end-systolic potential energy (PEes) by Suga et al because it represents the maximum potential work that could be performed at the end of systole if the heart were forced to eject along the ESPVR rather than relaxing isovolumically. Because the ventricle actually does not do any work after end-systole (the RV may be an exception) all this potential work is dissipated as heat. Consequently, PEes is predicted to be proportional to the heat produced during an isovolumic contraction and therefore also proportional to the MVO2 used during such a beat. This was studied extensively in the isolated canine LV and found to be correct. This principle is easily extended to ejections. At the end of ejection, the pressure developed at Ves is the same as if the ventricle had contracted isovolumically with volume ®xed at Ves. Therefore, as shown in Figure 3, PEes for an ejection is the area to the left of the isovolumic relaxation line. Because the ®rst law of thermodynamics states that the energy consumed should equal the heat dissipated plus the work done, Suga et al predicted that the MVO2 of ejecting ventricles should be proportional to the stroke work plus PEes. He termed this sum the PVA. To recap, from the ®rst law of thermodynamics DE dQ dW
1
where DE is the change in energy of a system, dQ is the heat produced and dW is the work done by the system. By analogy, MVO2 is proportional to the PVA which equals
MVO2/beat (ml/min)
Principles and management of cardiac ischaemia 103
e
rop
Inot
Activation energy Basal energy Pressurevolume area (mmHg ml3) Figure 3. Relation between PVA and MVO2 (per beat). See text for details. PVA and MVO2 are, as shown, related linearly. That is, MVO2 b PVA a. At a PVA of 0, MVO2 equals a which is thought to be the energy required for two processes that are not related directly to force development. One process is the basal energy (coloured region) which is energy required to keep the cells viable. The other much larger energy is that required for activation (hatched region) which is used for subcellular processes that are needed for force development but do not directly generate force. Examples are calcium mobilization and re-uptake, ion pumps and various phosphorylations. Inotropic stimulation causes a parallel upward shift in the line (labelled `Inotrope').
PEes SW. It is important to note that this equation predicts MVO2 per beat and must be multiplied by heart rate to calculate MVO2 per minute. However, in this chapter MVO2 will always be used to refer to oxygen consumption per beat. This model has been extensively tested in isolated hearts, and a linear relation between MVO2 and the PVA has consistently been found as shown in Figure 3. That is, whether a given PVA is generated by an isovolumic beat or by ejections with dierent Ved and Ves, for a constant contractile state, the MOV2 will be constant. This model is very powerful because it allows the mechanical properties of a ventricle, described using the ESPVR and EDPVR, also to be used to predict its MVO2. The appeal of this model is then several-fold. First, it has the correct units, i.e. the units of the PVA are in fact energy. Second, it is easy to relate MVO2 to mechanical parameters such as contractility and ejection patterns using the concepts introduced above. Third, it is thermodynamically correct. That is, it is consistent with the ®rst law of thermodynamics. Notice in Figure 3 that if the PVA is extrapolated to zero, that is, at a volume where no pressure is developed, MVO2 is not zero. This is thought to be due to two factors. The ®rst, as shown by the coloured rectangle, is the basal oxygen consumption that is required to keep the cell alive. The second factor is the activation energy, depicted as the hatched area, which is thought to be the energy required for the biochemical
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processes needed for contraction to occur, such as calcium release and re-uptake from the sarcoplasmic reticulum. Eects of inotropic state on oxygen consumption The contractile state of a ventricle is usually cited as an important determinant of MVO2. This concept is based on the observation that, for a ®xed value of most indices of ventricular performance such as the PVA, inotropic drugs increase MVO2. This is illustrated for the PVA in Figure 3 in which an inotrope causes a parallel upward shift in the MVO2±PVA line so that, for any PVA, MVO2 is increased by the inotrope.4 This parallel upward shift is thought to be due to an increase in activation energy so that, as shown in the ®gure, for any PVA, the increase in MVO2 is equal to the increase in activation energy. Thus, based on indices such as the PVA, inotropes are said to increase MVO2, that is they are oxygen wasting. The reason that indices are used to normalize performance to compare MVO2 at dierent contractile states is that, by de®nition, as contractility changes, haemodynamics must also change. Consequently, it is impossible to compare MVO2 for beats with identical haemodynamic characteristics and dierent inotropic states. For example, if the inotropic state is increased (corresponding to an increase in the slope of the ESPVR) and Ves is held constant, then, for the same Pes, the SV must increase. Conversely, if the SV is ®xed, then Pes must increase. Thus, there is no way to keep all haemodynamic factors constant, e.g. SV, Ved and Pes, so that beats at dierent contractile states can never be directly compared. Consequently, it could always be argued that any change in MVO2 observed with an inotrope is a result of haemodynamic changes rather than a direct eect of the inotrope. Understanding the direct eects of inotropes is particularly important in managing ischaemia because haemodynamic eects of inotropes can both negate and enhance their direct eects on MVO2. To surmount this problem, performance indices such as the PVA have been used to compensate for changes in cardiac mechanics caused by inotropes so that MVO2 can be compared at the same value of the index at dierent contractile states despite dierences in haemodynamics. However, this approach is limited because the increment in MVO2 observed with, for example, the PVA could be a true eect of the inotrope or it could be an artifact due to inadequacies in the PVA as an index of MVO2. This problem was underscored in a study by Rook and Figel5, in which they compared the change in MVO2 with various interventions, including inotropes in canine hearts using two dierent indices to normalize performance. Their results, using a measure of performance known as the pressure±work index (PWI), did not show a direct eect of inotropes on MVO2. That is, the linear relationship that they observed between MVO2 and the PWI was not shifted by inotropes. Thus, based on the PWI, inotropes do not appear to have any direct eect on MVO2, i.e. they are not oxygen wasting, so that their only eect on MVO2 is via the changes induced in haemodynamics. Evidently, then, whether or not inotropes are oxygen wasting depends on the index used to characterize performance. Consequently, the direct eects of inotropes on MVO2 is, at this moment, actually unknown. However, biochemical considerations would suggest that inotropes that act via adenyl cyclase should be oxygen wasting because in the process of increasing contractility they also activate processes that either have no eect on performance or may actually inhibit performance. For example, b agonists cause the phosphorylation of tropinin I, which inhibits the binding of calcium to the regulatory protein, tropinin C. As a result, it should take higher cytosolic calcium concentrations to cause the same increment in developed pressure
Principles and management of cardiac ischaemia 105
after b-receptor stimulation. It seems logical that this increase in cytosolic calcium would require additional energy which should increase MVO2 for a given level of performance. That is, such phosphorylations should cause oxygen wasting. There are numerous other phosphorylations that occur, such as the phosphorylation of phospholambin, the sarcoplasmic reticulum calcium transport protein, or of myosin light chain, that also would not be expected to lead directly to an increase in performance. Therefore, biochemical considerations suggest that inotropes should be oxygen wasting; at least for those inotropes that alter biochemical processes by phosphorylations, which include all drugs now in use except digoxin. In contrast, the enhanced contractility seen with cooling an isolated LV is not associated with any increment in MVO2 as judged by the PVA. Thus, it is likely that whether or not all increments in contractility are associated with oxygen wasting depends very much on the mechanism of inotropic stimulation. It should also be noted that the same arguments that suggest inotropes are oxygen wasting show that depressants are oxygen conserving. Heart rate and oxygen consumption Because increases in heart rate also increase MVO2 per minute, heart rate is usually considered to be a major determinant of MVO2. However, although an increase in heart rate increases cardiac contractile state, there is no shift in the MVO2±PVA line. This suggests that, apart from eects on haemodynamics, heart rate has no eect on MVO2 per beat. The question then is whether MVO2 should be considered per beat or per minute. The answer depends on the reason for measuring MVO2. However, it seems reasonable to consider MVO2 over a time frame during which limitations in supply would lead to dysfunction. Thus, for example, type 2 skeletal muscle can incur an oxygen debt for a relatively long time period, e.g. function anaerobically, during a sprint. However, in the heart, there are data to suggest that, within one or two beats of low ¯ow, mechanical dysfunction occurs.6 Therefore, it seems reasonable to think about MVO2 per beat, rather than per minute, and as available data suggest that MVO2 per beat is not directly aected by heart rate, other than as expected with any associated haemodynamic changes, MVO2 is not aected by heart rate. Rate-related ischaemia then occurs because of limited supply, not because of increased demand. In normal ventricles, the small coronary arteries dilate with an increase in heart rate to keep ¯ow per beat approximately constant even though the time for ¯ow is diminished. However, post-stenotic coronary vessels are already dilated and therefore have limited reserve. Consequently, they cannot dilate suciently with increases in heart rate to preserve ¯ow. Therefore, the myocardial regions supplied by such coronary arteries become ischaemic at high heart rates. Similar mechanisms, i.e. limited coronary reserve, account for the eects of heart rate in producing ischaemia in patients with hypertrophy or aortic stenosis without signi®cant coronary disease. Clinical applications Pressure work versus volume work It is generally taught that, for a given SW, a ventricle that develops high pressures and relatively low SV consumes more oxygen than one that develops a high SV and relatively low pressures. The explanation for this phenomenon is readily apparent by examining PVA diagrams as shown in Figure 4 which is adapted from a study conducted by Suga et al.7 In this study an isolated LV was made to eject from a ®xed EDV at a ®xed
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Volume (ml) Figure 4. SW and MVO2. Two beats with identical SW can still have very dierent MVO2 if PEes diers. In this experiment, LVEDV was kept constant. The SV of beat 1 (full ejection curve) was large relative to beat 2 (broken ejection curve) but the SW was the same for both beats. Because of the higher ESP developed by beat 2, its PEes (coloured plus hatched regions) was considerably greater than that of beat 1 (coloured region only). Consequently, MVO2 was greater for beat 2. This is the reason that `pressure work' is said to consume more O2 than `volume work'.
contractile state developing high pressures and low SV or low pressures and high SV, but with identical SW in both cases. As can be seen from Figure 4, the ventricle developing high pressures, i.e. doing pressure work, should consume more oxygen than the ventricle doing volume work because the former has a much larger PEes. This theoretical explanation has been validated in the experiment cited above. Intuitively, what is occurring is that at the end of ejection a ventricle developing high pressure dissipates relatively large amounts of heat because, given the high Pes, it potentially could do considerably more work but instead dissipates this potential as heat. This analysis also shows that the reason that pressure work consumes more oxygen than volume work is unrelated to the SW itself, as it is equal in both instances, but rather to the much larger PEes associated with the development of high pressures. Loading in normal and depressed ventricles Because the ESPVR is, by de®nition, ¯atter in a depressed ventricle, for a given increment in Pes a depressed ventricle will have a much larger increment in Ves than a normal ventricle (Figure 5). Because of the resultant loading of the RV, it is likely that the SV will also decrease and thus the SW may not increase as much as it would in a
Principles and management of cardiac ischaemia 107
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Volume (mmHg) Figure 5. Eects of increasing blood pressure on ventricular volumes and PVAs. (A) The ventricle has a normal contractile state as indicated by the steep ESPVR. Consequently, an increase in blood pressure has relatively little eect on end-systolic volume. Ves, and therefore end-diastolic volume, Ved, also changes minimally. The result is that SW and end-systolic potential energy, Pes, are increased only slightly. Consequently, the PVA and therefore MVO2 also increase relatively little. (B) In contrast, for a depressed ventricle, the same increase in blood pressure causes a relatively large increase in Pes (coloured area) thereby causing PVA and MVO2 to increase substantially.
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MVO2/beat (ml/min)
normal ventricle or it may actually decrease. Nonetheless, as shown in Figure 5, PEes would increase considerably more in a depressed than in a normal LV because of the greater increase in Ves. Consequently, the relative increment in MVO2 would also be much greater in the depressed than in the normal LV. This explains why the use of a agonists can be deleterious in a depressed ventricle. Not only will Ves and Ved increase much more in a depressed than in a normal ventricle, with the resultant increase in Ped potentially leading to pulmonary oedema, but the increment in MVO2 would also be substantially greater. This relative increase in MVO2 plus the high endocardial pressures impeding coronary blood ¯ow produce conditions conducive to ischaemia. For these reasons it seems reasonable to conclude that if one uses an a agonist in a ventricle where the contractile state is not known, and observes a marked increase in LVEDP associated with a decline in SV, an inotropic drug should probably be used in its place. The caveat is that the heart rate should not be allowed to increase. It also seems likely from the electrophysiology and anecdotal experience that b-blockers can be used in small doses to blunt increases in heart rate without aecting appreciably the inotropic eects of b agonists. Regardless of whether oxygen consumption is directly increased by inotropes, the decrement in size associated with the increased inotropic state is likely to lead to a decrease in MVO2. That is, as shown in Figure 6, even if the MVO2±PVA line is shifted upward by the inotrope, the PVA would decrease suciently because of the reduction in Ves and thus PEes is suciently large that MOV2 would still decrease. This phenomenon has been demonstrated for a variety of inotropes including digoxin.
B
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Pressurevolume area (mmHg ml3) Figure 6. Inotropes and MVO2. Inotropes have been shown to cause a parallel upward shift in the PVA± MVO2 line (line A to line B). This is thought to be due to an increase in activation energy (from hatched region 1 to hatched plus grey region) and is the basis of the concept that inotropes are O2 wasting (see text for details). If the LV is very large it will usually have a high PVA (point a). However, despite the upward shift in the PVA±MVO2 line caused by the inotrope, if ventricular size and thus PVA decrease suciently (point b), MVO2 can still decrease.
Principles and management of cardiac ischaemia 109
REFERENCES 1. Sugawa K. End-systolic pressure±volume relationship in retrospect and prospect. Federation Proceedings 1984; 43: 2399±2401. 2. Futaki S, Goto Y, Ohgoshi Y et al. Comparison between Bretschneider's total myocardial energy demand (Et) and our total mechanical energy (PVA) as a predictor of cardiac oxygen consumption in dogs. Japanese Journal of Physiology 1990; 40: 809±825. 3. Suga H, Yamada O & Goto Y. Energetics of ventricular contraction as traced in the pressure±volume diagram. Federation Proceedings 1984; 43: 2411±2413. 4. Sagawa K, Maughan L, Suga H & Sunagawa K. Cardiac Contraction and the Pressure-Volume Relationship. New York: Oxford University Press, 1988. 5. Rooke GA & Feigl EO. Work as a correlate of canine left ventricular oxygen consumption, and the problem of catecholamine oxygen wasting. Circulation Research 1982; 50: 273±286. 6. Arai AE, Pantley GA, Thoma WJ et al. Energy metabolism and contractile function after 15 beats of moderate myocardial ischaemia. Circulation Research 1992; 70: 1137±1145. 7. Suga H, Hisano R, Hirata S et al. Mechanism of higher oxygen consumption rate: pressure-loaded vs. volume-loaded heart. American Journal of Physiology 1982; 242: H942±H948.