Medial Pharmacology: Cardiac Anesthesiology

Cardiac Anesthesiology

Research Article #1: Thoracic Epidural Anesthesia Attenuates Halothane-induced Myocardial Sensitization to Dysrhythmogenic Effect of Epinephrine in Dogs
Research Article #2: Inhalational Agents and Baroreflex Control and the Sympathetic System
Research Article #3: Differential Effects of Propofol and Sevoflurane on Heart Rate Variability
Research Article #4: Effect of Sevoflurane on QT Interval in a Patient with Congenital Long QT Syndrome
Research Article #5: "Thoracic Epidural Anesthesia Attenuates Halothane-induced Myocardial Sensitization to Dysrhythmogenic Effect of Epinephrine in Dogs"

¹Introduction:
- Most inhalational anesthetics are myocardial depressants. Depression in myocardial contractility may be well-tolerated and even beneficial in some circumstances.
  - Assessment of effects of inhalational agents on myocardial and cardiovascular performance depends on initially evaluating different means of assessing myocardial contractility.
  - Isolated papillary muscle preparations have been historically used to provide information about contractility with specified pre and afterload conditions; however, in the intact heart it becomes much more difficult to measure contractility.
  - Representation of contractility and has been inferred following determination (invasively) of some myocardial functional parameters.
    - These parameters include circumferential fiber shortening velocity (Vcf), isovolumic phase indices, maximal rates of ventricular pressurize (dP/dt), maximal ratio of dP/dt at a given ventricular pressure (Vpm) and the ratio of dP/dt relative to a given isometric pressure, usually 40 mm Hg.
  - Ejection indices tend to be afterload-dependent; isovolumic phase indices usually are preload-dependent as well as dependent on myocardial inotropic state (myocardial contractility)
  - Echocardiography-determined measurements of left ventricular inotropic state (contractility) tend to be load-dependent. These measurements include: circumferential fiber shortening velocity heart-rate corrected (Vcfc), stroke volume, fractional shortening, ejection fraction, and dP/dt.
    - A preload-independent measure of systolic function is left ventricular end-systolic wall tension.
    - The relationship between left ventricular end-systolic wall stress and Vcfc appears to be a load-independent, sensitive measure of contractility. Electrocardiographic-based systolic functional assessment uses ejection fraction measurements.
  - Frank-Starling curve analysis as an index of contractility is generally appreciated.
    - Cardiac performance could be estimated as a point on the Frank-Starling curve using measurement techniques relating flow (cardiac output) and associated left ventricular filling pressures.
      - Cardiac output might be estimated from thermal dilution methods and left ventricular filling pressures estimated using pulmonary artery catheters.
      - Frank-Starling curves do not define contractile status as such but relate pumping efficacy to load dependency.
    - ¹Frank-Starling Relationship (Figure 16-2 from Ref. 1)

The Frank-Starling relationship is indicated above. Application to the clinical environment dependent on the use of balloon-guided pulmonary artery catheters with thermistors allowing cardiac output measurement by thermal dilution with the occlusive balloon permitting estimation of pulmonary capillary wedge pressure. The lack of the linear relationship between ventricular end diastolic volume and pressure has been viewed as a limitation, at least in terms of quantifying pump function in terms of a specific number.

Linearity is associated with relationships between ventricular pressure and ventricular volume, as noted by graphing upper left corners of pressure-volume loops of ejecting contractions. As a result, the end-systolic pressure-volume relationship can be viewed as representing a given contractile state. This linearity in the end-systolic pressure-volume relationship shifts left and upward with a enhancement in the inotropic state and conversely to the right and downward with negative intropism. Furthermore, these changes appear independent of preload or afterload

^1,2Changes in contractile state and their effects on pressure-volume lops, end-systolic pressure-volume lines and the volume axis intercept V_d (Figure 16-3 from Ref. 1)

Pressure-volume loop cycle:

Volume Pressure Loop Annimation attribution: D. Penny, Ph.D. Wayne State University, School of Medicine Virtual Classroom "My Physiology"

The Cardiac Cycle-Wiggers' Diagram--Superimposition of Wiggers' Diagram onto Pressure-Volume Curve⁴

"⁴The cardiac cycle refers to all of the events associated with beat-to-beat activity of the heart including electrical and contractile events, ventricular volume changes and heart sounds.

The graphical representation of these events as a function of time, is referred to as the Wiggers Diagram.... The events illustrated in the Wiggers Diagram are causally related and thus can be derived from "first principles".

The parameters of function measured and displayed in the Wiggers Diagram include:

aortic pressure (obtained by placing a catheter and associated pressure transducer in the aorta);

left ventricular pressure (obtained by placing a catheter and associated pressure transducer in the left ventricular chamber - through the aortic valve);

left atrial pressure (obtained as a "wedge pressure" from a catheter inserted into the pulmonary artery from the right side of the heart);

aortic blood flow (obtained by one of a variety of techniques including doppler); ventricular volume (obtained from indicator dilution techniques); heart sounds (obtained by auscultation);

venous pulse (obtained by placement of a catheter and associated pressure transducer in the inferior or superior vena cava); and

electrocardiogram (obtained from placement of surface electrodes)."

³Cardiac Pressure Volume Curves

³Cardiac work can be defined in terms of ventricular volume x ventricular pressure or alternatively the area of the pressure-volume curve, shown above.
- Examining this left ventricular pressure-line curve for a single cardiac cycle, we note that the line segment D-A would represent diastolic ventricular filling. Considering the pressure axis, (D + A) /2 would represent the left ventricular or left atrial mean diastolic pressure.
  - ⁴During ventricular filling, beginning with mitral valve opening, atrial pressure exceeds ventricular pressure (the pressure differential sometimes is very small).
    - The three stages of ventricular filling includes a rapid filling phase that is passive and occurs first. During this phase and there would be a fairly large pressure differential and at resting heart rates for about 60% to about 75% of stroke volume will be accounted for during this rapid phase (duration = about 150 milliseconds-200 milliseconds).
    - The second phase is also passive and characterized by a significantly reduced filling rate with 0% to 20% added to ventricular volume; however, this period also corresponds to the SA nodal excitation triggering next heartbeat.
    - Atrial contraction (electrically corresponding to P-wave) results in additional injection of blood into the ventricle-defining the final phase of ventricular filling. At rest, this phase may account for only 5%-15% of end diastolic ventricular volume; however, atrial kick (this final phase) is more important at higher heart rates. In that case (i.e. high heart rate) phase 3 corresponds to the addition of 25% to 40% of ventricular filling. During ventricular filling process atrial pressure is decreasing.
- ³The initiation of ventricular contraction begins at point A at some particular end-diastolic pressure which represents preload (initial ventricular load).
  - With ventricular myocardial muscle tension development, ventricular pressure increases causing mitral valve closure (point A).
  - Isovolumic contraction lasts until the aortic valve opens (point B);therefore, ventricular ejection starts at B and ventricular pressure at this point is equal to aortic pressure and corresponds to afterload.
  - Eventually, ventricular pressure falls below the aortic pressure (point C).
  - Total volume ejected during this time frame defines the stroke volume (SV).
  - The initial part of ventricular relaxation is isovolumic, represented in the diagram as the line segment C-D. Finally, pressure in the left ventricle drops below that in the left atrium (point D), thus initiating blood flow into the ventricle (diastolic filling, line segment D-A). Inflow causes ventricular wall stretching defining the preload for the next contractile cycle.

³Effects of Changing Preloads on Ventricular Work

³The curve above can be compared to figure 16 -- 3 from Ref. 1, also above. These curves represent changes in preload and resultant effects on the left ventricular pressure-volume curves.

Recall also that that the area of less ventricular pressure-volume curves corresponds to ventricular work.

With mean left atrial pressure increasing, diastolic filling will increase and therefore preload increases-note that point a' continues to slide to the right. Assuming afterload is constant, then ejection begins at the same ventricular pressure which is represented as b' points. The ventricular relaxation begins at point c', with successive c' values, when plotted, corresponds to a straight line. The slope of this line is an index then of contractility since the factor that initiates changes in the c' position is one that effects intropism. This line could be called the end-systolic pressure-volume curve and is sometimes called the pressure-diameter curve.

³Effects of Changing Afterload on Ventricular Work

³As a follow-on to the previous figure, this figure above describes changes in the ventricular pressure-volume curve due to afterload changes.

Curve 1 illustrates what happens if the only change is an afterload increase. In that case, contractility is not altered and the initial relaxation phase is moves up the end-systolic pressure-volume curve. The stroke volume decreases with an accompanying increase in cardiac work.

Curve 2 illustrates cardiac compensation for afterload increases through a preload increase. The effect is maintenance of a constant stroke volume. With increased afterloads, a larger pressure-volume curve area results and with that, an increase in ventricular work.

³Relationships between Altered Contractility on Ventricular Work

³The curve above represents changes in contractility; increased contractility is shown by the increased slope of the end-systolic pressure-volume curve (curve 1) . Reduced contractility would then be illustrated by a reduction in curve slope. Therefore, for any given end-systolic pressure, the corresponding volume would be reduced with an attendant increased contractility. Reduced intropism (reduced contractility; reduced slope) results in increased end systolic volume for any given end systolic pressure.

Questions and Answers Concerning Cardiac Pressure-Volume Curves⁶ (Some of these curves are similar to the curves above, but with additional explanations in some cases)

⁶Brandis, K., Anesthesia Self-Education Modules, Queensland Anaesthesia, Chapter 3)

⁶Elastance Curve

⁶The curve above represents a diastolic elastance curve for the left ventricle.
- The curve relates left ventricular pressure to left ventricular volume.
- Pressure is on the y-axis and volume (left ventricular) on the x-axis.
- The curve has a slope in any given point as illustrated by the tangent line and this slope corresponds to ventricular stiffness or elastance.
- Similarly, ventricular compliance or "distensibility" would be the mathematical inverse of the slope at that point.
- Notice that the relationship between left ventricular pressure and volume is not a straight line but a curve, indicating that elastance increases with left ventricular volume. At the point on the curve corresponding to end of diastole, both the volume at this point [end-diastolic volume] and pressure [end-diastolic pressure] may be used to reflect left ventricular preload. The elastance increases at large end-diastolic volume emphasizes the nonlinearity in the relationship.
  - The author⁶ notes that this curve should be referred to as an elastance curve given that the pressure change is in response to volume change. During systole, the pressure change, secondary to ventricular contraction, causes the volume change therefore, in that case, compliance would be the correct term.
- Concerning curve shape, note that the curve is relatively flat throughout most of the physiological range before beginning to curve upward. This observation means that left ventricular volume can increase without significant increases in left ventricular pressure -- meaning that the ventricle is relatively easy to fill.
  - However, at volumes. > 140 ml (above the typical value), the curve begins to rise rather steeply. One conclusion is that the heart is rather difficult to "overfill" since the increase in pressure tends to act in opposition to the increase in left ventricular end-diastolic volume. Another way of making this point is that the "stiffer heart" would be harder to fill. Furthermore, sarcomere length does not increase above the optimal length of 2.2m such that the force of ventricular contraction is not adversely affected much.

⁶P-V Ventricular Loop

The curve above illustrates a pressure-volume loop for the left ventricle and also illustrates the point corresponding to mitral and aortic valve opening and closing.

⁶PV Loops: Shifts due to Change in Preload

⁶The above curve adds a case (2) in which preload has been increased relative to case 1. This is clear from the higher LVEDV for loop 2. Afterload may be compared in the two cases by evaluating the slopes of the line defined by these 2 points: end-systolic point to LVEDV point. Note that the lines for cases 1 and 2 are parallel, indicative of the same afterload in the 2 cases. Also, contractility is the same for the two cases since both end-systolic points are on the same line [the line is defined here by 3 points, the LV volume point on the x-axis (point 1), the end-systolic point for curve 1 (point label D in the first figure above), and the end-systolic point for curve 2. Since the curve 2 end-systolic point lies on the same line at that defined by points 1 and 2, one may conclude that contractility has not changed. Preload is best represented by the end-diastolic volume (LVEDV). End diastolic pressure is a less reliable index of preload since it does not take into account variation in ventricular compliance (distensibility; stiffness)

⁶Altered Afterload and PV Loop Analysis

⁶The curve above reflects the case in which afterload has been increased. This conclusion is reached by comparing 2 slopes [line 1 defined by the LVEDV point on the x-axis with the end-systolic pressure volume point for case 1; line 2 defined by the LVEDV point on the x-axis with the end-systolic pressure volume point for case 2] These slopes are clearly different, indicative of different afterloads. The increased afterload in case 2 is also noted in the greater angle between the x-axis and the afterload line (LVEDV point to endsystolic pressure volume point) compared to case 1. In this case we know that preload has not be altered since both curves exhibit the same LVEDV and we know that the contractility has not changed since loop 1 and loop 2 end-systolic points (D) lie on same line. Another way of looking at the contractility is that the angle defined by the x-axis line and the contractility line remains constant in the 2 cases. With increased contractility the pressure-volume line (say for case 2 would have been rotated counterclockwise, showing increased slope.

⁶Contractility Changes and the Effect of this Change on the LV P-V Loop

As suggested earlier, an increase in contractility (curve 2) is noted by a leftward and upward shift in end-systolic point position. We also note the increased slope exhibited by curve 2. A single afterload line describes this case, so afterload was constant in this condition as was preload since both curves exhibit the same LVEDV. Finally, note the larger area described by loop 2. This area increase represents an increase in external work performed by the ventricle and is defined by pressure multiplied by volume. More work is required for ejection of the increased stroke volume.

¹Methods to estimate ESPVR have included contrast ventriculography, scintigraphy, echocardiography, etc.

Echocardiography has a limitation due to limited dimensional assessment.
- More current technology including three-dimensional reconstructions of echocardiographic data may facilitate more accurate volume determinations.
- Even with conventional echocardiography, reasonable methods have been developed to assess ESPVR in patients.
  - Femoral artery pressure is used to as an estimate ventricular pressure and left ventricular cross-sectional area is used instead of left ventricular volume estimates.
  - With these approximations, rapid estimates of left ventricular contractility may be made.

A limitation in this process is related to the two-dimensional data rather than a full 3-D reconstruction of the ventricle which can be done using echocardiography.

Without the complete surface representation of the ventricle, anomalies due to myocardial ischemia such as akinetic regions or poorly contracting regions may lead to incorrect volume estimates.
- ESPVR as a measure of contractility itself has been challenged from the point of view that the relationship could be affected by altered preload and afterload.
If filling pressures are used as representing preload, then Frank-Starling relationships are curvilinear; however, Frank-Starling relationships turn out to be rectilinear if end diastolic volumes are used to represent preload (see below).
- The slope of this relationship ("preload recruitable stroke work or PRSW") can indicate changes in myocardial contractile state.
- The authors of this relationship indicated later than the area under the line was a more sensitive indicator of myocardial contractility and was, at least within physiological ranges, probably insensitive to preload and afterload changes.

^1,5Linear PRSW between stroke work and end-diastolic volume [This is to be compared to the more common curvilinear representation of the Frank-Starling relationship]

¹Using the indices of contractility described above, myocardial effects on anesthetics may be evaluated.

For example, using papillary muscle preparations, inhalational anesthetic-induced dose-dependent decreases in maximal fiber shortening velocity, mean maximal developed force, and dP/dt have been described.
Considering dP/dt, the percentage decrease appeared comparable in considering isoflurane, enflurane and halothane.
- High doses of isoflurane were not associated with increased left ventricular filling pressures, by contrast to that observed with enflurane or halothane.
- As a result, isoflurane may be somewhat less of a myocardial depressant than enflurane or halothane in this assay system.

Another approach utilized the slope of the ESPVR in assessing contractility.

This method was applied to both intact, chronically instrumented, unpremedicated dogs and patients following cardiopulmonary bypass.
Halothane and enflurane depressed, to comparable extent, myocardial contractility (at equianesthetic levels).

0.7 MAC for both agents was needed to reduce end systolic elastance (slope of end-systolic pressure-diameter relationship) by 20%.

^1,⁵Halothane vs. Enflurane Effects on Myocardial Depression

"Comparison of effects of halothane versus enflurane on myocardial depression, measured as the anesthetic concentration that inhibits inotropic state by 20 percent of the control value (ID₂₀). ID₂₀ for both anesthetics is 0.7 MAC. E_ES= slope of the end-systolic pressure-diameter relation"^1,⁵

¹Park, KW, Haering, JM, Reiz, S, Lowenstein, E Effects of Inhalation Anesthetics on Systemic Hemodynamics and the Coronary Circulation in Cardiac Anesthsia, Fourth Edition (Kaplan, JA, ed; Reich, Dl and Konstadt, SN, Assoc eds) W.B. Saunders Co. A Divsion of Harcourt Bract and Company, Philadelphia, 1999. This chapter is the primary reference for all above material, except as noted.
- ²Suga, H, Sagawa, K, Shoukas, AA: Load independence of instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res 32: 314, 1973. -second sourced from reference 1.
- ⁵Van Trigt, P, Christian, CC, Fagraeus, L, et al: "Myocardial depression by anesthetic agents [halothane, enflurane, and nitrous oxide]: Quantitation based on end-systolic pressure-dimension relations" Am J Cardiol 53: 243, 1984---second sourced from reference 1.
³Tam, J, CV notes, Cardiac Performance I, University of Manitoba, Dept. of Medicine, Cardiology
⁴Gore, RW, The Heart as a Pump: Lecture 10, Cardiovascular Physiology 485, University of Arizona
- ⁵Glower, DD, Spratt, JA, Snow, ND, et al: Linearity of the Frank-Starling relationship in the intact heart: The concept of preload recruitable stroke work. Circulation 71: 994, 1985.--second sourced from reference 1.
⁶Brandis, K., Anesthesia Self-Education Modules, Chapter 3, Queensland Anaesthesia,