Influence of Volatile Anesthetics on Left Ventricular Afterload In Vivo: Differences between Desflurane and Sevoflurane

All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care Committee of the Medical College of Wisconsin. All procedures conformed to the Guiding Principles in the Care and Use of Animals of the American Physiological Society and were performed in accordance with the Guide for the Care and Use of Laboratory Animals.*

Surgical implantation of instruments has been described previously in detail. [18]Briefly, under general anesthesia and aseptic surgical conditions, dogs (n = 8) underwent a left thoracotomy, and a high-fidelity micromanometer was inserted into the left ventricle for measurement of continuous LV pressure and the maximum rate of increase in LV pressure (dP/dt^max). Heparin-filled catheters were placed in the proximal descending thoracic aorta, the right atrium, and the left atrium for measurement of aortic pressure, fluid administration, and calibration of the LV micromanometer, respectively. An ultrasonic transit-time flow probe was positioned around the ascending thoracic aorta for measurement of continuous aortic blood flow. A pair of miniature ultrasonic segment length transducers were implanted in the LV subendocardium for measurement of changes in regional contractile function. All instrumentation was secured, tunneled between the scapulae, and exteriorized via several small incisions. The pericardium was left wide open, the chest wall closed in layers, and the pneumothorax evacuated by a chest tube.

All dogs received systemic analgesics (fentanyl) as needed after surgery. Dogs were allowed to recover a minimum of 7 days before experimentation during which time all were treated with intramuscular antibiotics (40 mg/kg cephalothin and 4.5 mg/kg gentamicin) and were trained to stand quietly in an animal sling during recording of hemodynamics. An ultrasonic amplifier was used to monitor segment length signals. End-systolic and end-diastolic segment lengths were measured at 30 ms before maximum negative LV dP/dt and just prior to the onset of LV isovolumic contraction, respectively. Percent segment shortening was calculated using the equation: percent segment shortening = (end-diastolic segment length -- end-systolic segment length) *symbol* 100 *symbol* end-diastolic segment length sup -1. Hemodynamic data were continuously recorded on a polygraph and digitized by a computer interfaced with an analog to digital converter. [18].

Aortic input impedance spectra were obtained from digitized, steady-state aortic blood pressure and aortic blood flow waveforms. [20,21]Briefly, data files consisting of 4,096 points were sampled at 100 Hz and divided into five 2,048-point bins with 1,536 point overlap. [18]A Hamming window was applied to each bin to reduce side lobe leakage. The autopower spectrum of the aortic blood pressure [P^pp(omega)], aortic blood flow [P^ff(omega)] and cross power spectrum between aortic pressure and blood flow wave forms [P^pf(omega)] were determined using a Welch periodogram technique. [22,23]Each Zⁱⁿ(omega) spectrum was calculated as a function of frequency (omega) using the formula: Zⁱⁿ(omega) = P^pp(omega) *symbol* [P^pf(omega)] sup -1 and corrected for the phase response and position of the aortic flow probe and aortic pressure transducer as described previously. [18]Typical Zⁱⁿ(omega) magnitude and phase spectra in the conscious state and during desflurane and sevoflurane anesthesia are depicted in Figure 1and Figure 2, respectively. Correlation of aortic pressure and flow waveforms at each frequency of Zⁱⁿ(omega) was determined using the magnitude squared coherence (MSC), where magnitude squared coherence (omega) = [P^pf(omega)²*symbol* [P^pp(omega) *symbol* P^ff(omega)] sup -1. All Zⁱⁿ(omega) data with magnitude squared coherence values < 0.8 were discarded.

Windkessel model parameters were derived from the calculated Z sub in (omega) spectra. [18]Characteristic aortic impedance (Z^c) was determined as the mean of the magnitude of Zⁱⁿ(omega) (Zⁱⁿ(omega)) between 2 and 15 Hz. [21,24,25]Total arterial resistance (R) was calculated as the difference between the value of Zⁱⁿ(omega) at zero frequency and Z^c.

The magnitude of Zⁱⁿ(omega) at zero frequency was equal to systemic vascular resistance determined as the ratio of mean arterial pressure and mean aortic blood flow. [17]Total arterial compliance (C) was calculated using the formula: C = (A^d*symbol* MAQ) *symbol* [MAP *symbol* (P^es- P^ed)] sup -1, where A^d= the area under the diastolic portion of the arterial pressure curve, MAQ = mean aortic blood flow, MAP = mean arterial pressure, and P^esand P^ed= end-systolic and end-diastolic aortic pressure, respectively. [26]The diastolic period used for the calculation of C was defined as the time between the dichrotic notch and minimal aortic pressure. The value of C was determined from the average of five consecutive beats for each intervention.

Dogs were assigned to receive desflurane or sevoflurane in a random manner on separate experimental days. Fluid deficits were replaced with 0.9% saline (500 ml), and maintenance fluids (0.9% saline) were continued (3 ml *symbol* kg sup -1 *symbol* h sup -1) for the duration of each experiment. After instruments were calibrated, baseline systemic hemodynamics were recorded under steady-state conditions in the conscious state. Continuous aortic blood pressure and aortic blood flow waveforms were recorded for later generation and analysis of Zⁱⁿ(omega). After inhalational induction and tracheal intubation, anesthesia was maintained during positive pressure ventilation at 1.1, 1.3, 1.5, or 1.7 minimum alveolar concentration (MAC; end-tidal) desflurane or sevoflurane in an air and oxygen (25%) mixture. The order of MAC was assigned randomly. The canine MAC values for desflurane and sevoflurane used in this investigation were 7.20 and 2.36%, respectively. End-tidal concentrations of desflurane and sevoflurane were measured at the tip of the endotracheal tube by an infrared gas analyzer (Datex Capnomac, Helsinki, Finland) that was calibrated with known standards before and during experimentation. Hemodynamics and aortic pressure and blood flow waveforms were recorded after 30 min of equilibration at each anesthetic concentration. Arterial blood gas tensions were maintained at conscious levels by adjustment of air and oxygen concentrations and respiratory rate throughout the experiment. Emergence was allowed to occur at the completion of each experiment. Dogs were allowed to recover at least 2 days before subsequent experimentation. Thus, a total of 16 experiments were performed in 2 groups (desflurane and sevoflurane) using the same 8 dogs.

Statistical analysis of data within and between groups in the conscious state and during anesthetic interventions were performed by multiple analysis of variance with repeated measures followed by application of Student's t test with Duncan's correction for multiplicity. The slope of the total arterial compliance-MAP relationship was determined by linear regression for each anesthetic. Parallelism of the linear slopes of the compliance-pressure data also was determined using the method of Tallarida and Murray. [27]Changes within and between groups were considered significant when P < 0.05. The data were expressed as mean +/-SEM.

Desflurane caused a significant (P < 0.05) increase in heart rate (86 +/-2 during control to 143+/-6 beats/min at 1.7 MAC) and dose-related decreases in systolic, diastolic, and MAP (100+/-4 during control to 68+/-5 mmHg at 1.7 MAC), LV systolic pressure, and stroke volume (Table 1). No change in LV end-diastolic pressure was observed. Dose-related decreases in dP/dt^max(2457+/-124 during control to 1297+/-102 mmHg/s at 1.7 MAC) and percent segment shortening were observed in desflurane-anesthetized dogs, consistent with a negative inotropic effect. Desflurane also caused significant reductions in cardiac output and systemic vascular resistance at 1.7 MAC. A dose-related decrease in R (3,170+/-188 during control to 2441+/-220 dynes *symbol* second *symbol* centimeter sup -5 at 1.7 MAC; Figure 3) occurred. However, no changes in total arterial compliance (C) and characteristic aortic impedance (Z^c) were observed during anesthesia with desflurane (Figure 3).

Sevoflurane produced hemodynamic actions that were somewhat different than those produced by desflurane (Table 2). Sevoflurane also caused an increase in heart rate (88+/-4 during control to 129 +/-4 beats/min at 1.7 MAC). Dose-related decreases in systolic, diastolic, and MAP (99+/-5 during control to 61+/-4 mmHg at 1.7 MAC), LV systolic pressure, and stroke volume were observed in dogs anesthetized with sevoflurane. These sevoflurane-induced decreases in systolic, diastolic, and MAPs and LV systolic pressure were greater than those produced by desflurane. No changes in LV end-diastolic pressure occurred. Sevoflurane decreased myocardial contractility as indicated by dose-related declines in dP/dt^max(2,343+/-161 during control to 1,051+/-80 mmHg/s at 1.7 MAC) and percent segment shortening. These sevoflurane-induced negative inotropic effects were similar to those observed with desflurane. In contrast to the findings with desflurane, sevoflurane produced dose-related decreases in cardiac output (2.4+/-0.2 during control to 1.5+/-0.2 l/min at 1.7 MAC). Systemic vascular resistance and R were also unchanged in sevoflurane-anesthetized dogs. Sevoflurane caused dose-related increases in Z^c(139+/-10 during control to 194+/-14 dynes *symbol* second *symbol* centimeter sup -5 at 1.7 MAC) and C (0.57 +/-0.05 during control to 0.79+/-0.05 ml/mmHg at 1.7 MAC; Figure 3), suggesting that alterations in the mechanical properties of the aorta were primarily responsible for changes in LV afterload during administration of this volatile anesthetic. No difference in the slope of the compliance-pressure relationship was observed between sevoflurane (-1.87 *symbol* 10 sup -3 ml *symbol* mmHg sup -2) and desflurane (-1.67 *symbol* 10 sup -3 ml *symbol* mmHg sup -2, t = -0.18, P > 0.05) groups.

Calculated systemic vascular resistance (the ratio of MAP to mean arterial blood flow) is used commonly to estimate LV afterload in vivo. Although this index provides a qualitative description of arterial resistance to LV ejection, systemic vascular resistance cannot be used to strictly quantify alterations in afterload because this index ignores the mechanical properties of the arterial wall, fails to account for the potential effects of arterial wave reflection, and does not consider the dynamic, pulsatile nature of arterial blood pressure and blood flow. [28]In contrast, Zⁱⁿ(omega) has been shown to be a quantitative measure of LV afterload that incorporates arterial viscoelasticity, frequency-dependence, and wave reflection. [17]Vasoactive drugs, including volatile and intravenous anesthetics, have been shown to alter Zⁱⁿ(omega) by affecting the mechanical properties of the arterial vascular tree. [18,19,24,29]However, changes in Zⁱⁿ(omega) produced by pharmacologic agents are difficult to quantify in a physiologically relevant way because analysis of Zⁱⁿ(omega) is conducted in the frequency domain. As a result, Zⁱⁿ(omega) often is interpreted using a simplified electrical model of the arterial system known as the three-element Windkessel. [21]The Windkessel model displays most of the frequency-dependent features of Zⁱⁿ(omega). [30]Windkessel-derived variables can be used to estimate Zⁱⁿ(omega) as a function of frequency: Zⁱⁿ(omega) = Z^c+ R *symbol* (1 + j *symbol* omega *symbol* C *symbol* R) sup -1, where Z^c= characteristic aortic impedance, R = total arterial resistance, C = total arterial compliance, and j = (-1)¹/2. [31]Z^cis determined by the Poiseullian resistance of the aorta and the compliance of this vessel. Characteristic aortic impedance is represented as a resistor in the model for simplicity and because its value does not vary significantly with frequency. [29,32]R represents the combined Poiseullian resistances of the entire arterial vascular tree. The sum of R and Z^cis mathematically equivalent to systemic vascular resistance calculated as the ratio of MAP to mean aortic blood flow. The magnitude of Z^cis small in relation to R owing to the relative contributions to systemic vascular resistance of the aorta and the remaining arterial circulation, respectively. Total arterial compliance is the energy storage component of the Windkessel. These elements of the arterial system interact with the mechanical properties of the left ventricle to determine overall cardiovascular performance.

In the current investigation, Windkessel variables were used to quantify Zⁱⁿ(omega) spectra in the conscious state and during desflurane and sevoflurane anesthesia. The results indicate that desflurane caused a dose-related reduction in R concomitant with decreases in calculated systemic vascular resistance. These findings confirm and extend the results of previous studies demonstrating that desflurane-induced decreases in systemic vascular resistance contribute to declines in MAP. [2-5]Decreases in total arterial and systemic vascular resistance caused by desflurane were similar to those observed with isoflurane and propofol (Table 3) in previous investigations from our laboratory. [18,19]In contrast to the findings with isoflurane and propofol, however, desflurane did not alter C and Z^c. These results indicate that desflurane reduces LV afterload by affecting resistance arterioles and not the mechanical properties of the aorta. Total arterial compliance is primarily determined by the compliance of the aorta itself [33,34]and is inversely related to intraluminal pressure and radius. [35,36]Changes in characteristic aortic impedance also are determined by the inherent viscoelastic properties of the aorta and are inversely related to the fourth power of its radius. [29]A pressure-induced decrease in aortic diameter may result in increases in both C and Z^c. When compared to the results of our previous study, [18]desflurane maintained mean aortic pressure to a relatively greater degree than isoflurane at approximate end-tidal concentrations of 1.3, 1.5, and 1.7 MAC. Thus, the failure of desflurane to increase C or Z^cat higher anesthetic concentrations in the current study is probably related to the less pronounced reductions in mean aortic pressure and, presumably aortic diameter, produced by this agent when compared to its structural analog.

In contrast to the findings with desflurane, no changes in R and systemic vascular resistance occurred during administration of sevoflurane. These findings are similar to those observed previously with halothane [18]and indicate that sevoflurane does not affect LV afterload by altering peripheral arteriolar tone in dogs. Unlike desflurane, sevoflurane also increased C and Z^c, suggesting that this inhalational agent affects aortic compliance and impedance. However, sevoflurane caused relatively greater declines in mean aortic pressure than desflurane in dogs. These findings suggest that sevoflurane-induced increases in C and Z^cwere determined primarily by pressure-dependent reductions in aortic diameter and not by alterations in the fundamental mechanical properties of this great vessel. The slopes of the compliance-pressure relationship for sevoflurane and desflurane observed in the current investigation were not different than those of isoflurane (-1.41 *symbol* 10 sup -3 ml *symbol* mmHg sup -2; t = 1.02 vs. desflurane, P > 0.05; t = 1.13 vs. sevoflurane, P > 0.05) and halothane (-1.43 *symbol* 10 sup -3 ml *symbol* mmHg sup -2; t = 0.68 vs. desflurane, P > 0.05; t = 0.79 vs. sevoflurane, P > 0.05) as found in our previous study. [18]These results indicate that volatile anesthetics produce similar compliance-pressure relationships that remain relatively flat between MAPs of 50 and 100 mmHg. In contrast, propofol and sodium nitroprusside cause significant increases in the slope of the compliance-pressure relation over this range of MAPs, [18,19]indicating that these arterial vasodilators probably exert direct actions on the mechanical properties of the aorta.

Total arterial compliance represents an important component of afterload that has recently been shown to directly influence LV wall stress and myocardial oxygen consumption independent of alterations in systemic vascular resistance. [37]Thus, although desflurane, isoflurane, [18]and propofol [19]cause dose-related reductions in R, propofol may have the most beneficial effects on LV afterload because of simultaneous and more profound increases in C (Table 3). Such an increase in C may improve the rectifying characteristics of the aorta, a feature that could theoretically reduce LV energy expenditure during ejection, maintain diastolic arterial pressure, and enhance coronary perfusion under these conditions. The sevoflurane-induced increases in Z sub c that occurred at 1.5 and 1.7 MAC may indicate a greater resistance to LV ejection at these concentrations. These increases in Z^cresult in wasted LV energy transfer and less efficient coupling between the left ventricle and arterial circulation. [29]These effects of changes in Z sub c should be observed relative to the changes in the magnitude of R and C. The impact of changes in Z^cis small in comparison to changes in R and C.

The current results must be interpreted within the constraints of several possible limitations. The calculation of Zⁱⁿ(omega) was performed with arterial pressure waveforms measured using a chronically implanted, fluid-filled catheter. Despite the use of appropriate corrections for the magnitude and phase of Zⁱⁿ(omega), [17]an improved frequency response may have been obtained with a high-fidelity micromanometer placed at the aortic root. Zⁱⁿ(omega) magnitude spectra obtained in anesthetized dogs were somewhat less continuous than those obtained in the conscious state because more frequencies between the fundamental and corresponding harmonics were excluded on the basis of mean squared coherence criteria. Generation of multiple heart rates by random cardiac pacing during anesthesia would have provided a greater number of fundamental and harmonic frequencies, resulting in more continuous Zⁱⁿ(omega) magnitude spectra in the presence of desflurane or sevoflurane. However, the observed spectral discontinuity resembles spectra generated with standard Fourier series analysis, an established method for evaluating aortic input impedance under a variety of physiologic conditions. [17,29].

In summary, desflurane and sevoflurane produce differential effects on LV afterload determined with Zⁱⁿ(omega) and interpreted using a three-element Windkessel model. Desflurane, but not sevoflurane, caused dose-related reductions in R and systemic vascular resistance, indicating that this new volatile anesthetic decreases LV afterload by affecting peripheral arteriolar tone. In contrast, sevoflurane, but not desflurane, increased C and Z^cat higher anesthetic concentrations concomitant with greater reductions in MAP. The results indicate that desflurane and sevoflurane cause changes in Zⁱⁿ(omega) that are similar to those described previously with isoflurane and halothane, respectively, in chronically instrumented dogs. [18].

The authors thank Dave Schwabe and John Tessmer, for technical assistance, and Angela Barnes, for preparation of the manuscript.

*Guide for the Care and Use of Laboratory Animals, Department of Health and Human Services publication NIH 85-23. Washington, DC, Department of Health, Education, and Welfare, 1985.