In coronary surgery patients, analysis of changes in variables of contraction and relaxation during an increase in cardiac load permits dynamic assessment of left ventricular (LV) functional reserve. A postural change induced by leg elevation identifies a subgroup of patients with load-dependent impairment of LV function. These patients respond to leg elevation with a decrease in stroke volume and dP/dtmax , a delayed myocardial relaxation with enhanced load dependence of LV pressure decrease, and a marked increase in LV end-diastolic pressure (EDP) (1 2
β-Adrenergic stimulation improves LV contraction (inotropic effect) and accelerates LV relaxation (lusitropic effect) (3–5
Methods
The study was performed in 25 patients scheduled for elective coronary bypass surgery. The study was approved by our Institutional Ethical Committee, and written informed consent was obtained. Patients with an ejection fraction of more than 40% and with a LV EDP of less than 15 mm Hg during preoperative hemodynamic evaluation were considered. Patients undergoing repeat coronary surgery, unstable angina, concurrent valve repair, or aneurysm resection were excluded.
Anesthesia and Surgery
Preoperative cardiac medication, including β-blocking drugs, calcium channel blocking drugs, and nitrates were continued until the morning of surgery. Premedication consisted of intramuscular glycopyrolate 2 μg/kg, droperidol 30 μg/kg, and fentanyl 1 μg/kg. In the operating room, patients received routine monitoring including 5-lead electrocardiogram (ECG) radial and pulmonary artery catheters, pulse oximetry, capnography, and blood and urine bladder temperature monitoring. Anesthesia was induced with fentanyl 20 μg/kg, diazepam 0.1 mg/kg, and pancuronium bromide 0.1 mg/kg. An additional dose of 30 μg/kg fentanyl was administered before sternotomy. Patients’ lungs were ventilated with a FiO2 of 0.5; when necessary, isoflurane 0.2%–0.4% was added to the air–oxygen mixture. Standard median sternotomy and pericardiotomy were performed. After sternotomy, isoflurane was discontinued in all patients. The aorta was cannulated, and epicardial pacemaker wires were attached to the right atrium and right ventricle.
Venous drainage during cardiopulmonary bypass (CPB) was accomplished with a two-stage venous cannula inserted in the right atrium. A ventricular sump was inserted in the left ventricle through the right superior pulmonary vein. Perfusion flow on CPB was 2.4 L · m−2 · min−1 in nonpulsatile mode. In all patients, the left internal thoracic artery was used in addition to one or more saphenous vein grafts. In all patients included in this study, complete revascularization could be performed.
Separation from CPB was performed using the standard protocol, described previously (1
Experimental Protocol
Twenty-five patients were included in the study. In 15 patients, only LV pressures were measured, whereas in 10 patients combined pressure and volume measurements were performed. In the 15 patients, a sterilized, prezeroed electronic micromanometer (MTC®P3Fc catheter, Dräger Medical Electronics, Best, The Netherlands; frequency response = 100 KHz) was positioned in the LV cavity through the apical dimple. The catheter was connected to a Hewlett Packard monitor (HP78342A, Hewlett Packard, Brussels, Belgium). The output signals of the pressure transducer system were digitally recorded together with the ECG signals at 1-ms intervals (Codas, DataQ, Akron, OH). Zero and gain setting of the tipmanometer were also checked against a high-fidelity pressure gauge (Druck Ltd., Leicester, UK) after removal.
In 10 patients, a combined micromanometer transducer conductance catheter (F6, Millar) was inserted via the femoral artery into the left ventricle for measurement of LV pressures and volumes. The correct position of the conductance catheter was verified by the inspection of the LV pressure waveform and the segmental conductance signals. The conductance catheter was connected to a Leycom Sigma-5DF signal conditioner processor (CardioDynamics, Zoetermeer, The Netherlands) to measure LV volumes. The method is based on the measurement of the time-varying electrical conductances of five segments of blood in the left ventricle (6 Vc ) creates an offset, which can be estimated by injecting 5-mL hypertonic (8%) saline into the pulmonary artery. Estimation of Vc was performed with the dedicated package CONDUCT-PC using an algorithm that indicates the best Vc values. Conductance catheter stroke volume was calibrated by thermodilution stroke volume, determined by thermodilution cardiac output measurement (Vigilance Monitor, Model VGS2, Baxter). The CONDUCT-PC (Cardiodynamics) software package was used for acquisition and analysis of conductance catheter data. Blood resistance, Vc , and baseline cardiac output were measured before the start of the protocol.
The effects of leg elevation were evaluated before and during administration of dobutamine. First, leg elevation was performed in baseline conditions. After a period of 10 min to allow for a return of hemodynamic variables to baseline, dobutamine was started at a dose of 5 μg · kg−1 · min−1 during 5 min, and leg elevation was then repeated.
Measurements before CPB were recorded before venous canulation. After separation from CPB, a stabilization period of 10 min was permitted to prevent time-dependent changes in ventricular function with alteration of preload (7
Measurements were obtained with mechanical ventilation suspended at end-expiration. During the protocol, heart rate was maintained constant by means of atrioventricular sequential pacing at a fixed heart rate of 90 bpm with an atrioventricular interval of 150 ms. Paced heart rate was identical before and after CPB. In none of the patients did intrinsic heart rate exceed paced heart rate. Measurements consisted of recordings of consecutive ECG and LV pressure tracings during an increase of systolic and diastolic LV pressures obtained by raising the caudal part of the surgical table by 45°, resulting in raising of the legs. Leg raising resulted in a rapid beat-to-beat increase in LV pressures and dimensions. Care was taken to have at least 10 consecutive beats for analysis. After recording the data, ventilation was resumed and the surgical table was returned to horizontal.
Data Analysis
EDP was timed at the peak of the R-wave on ECG. The effects on LV load and function were evaluated by the EDP, peak LV pressure, LV pressure at dP/dtmin (=end-systolic pressure [ESP]), and dP/dtmax . Effects of leg elevation on rate of LV pressure fall were evaluated by dP/dtmin , and the time constant τ of isovolumic relaxation. τ was calculated based on the monoexponential model with nonzero asymptote using LV pressure values from dP/dtmin to a cutoff value of 10 mm Hg above EDP (8 P (t ) =P 0 · e −t /τ +P ∞ (8 P ∞ is a nonzero asymptote, P 0 is an amplitude constant, t is time, and τ is the time constant. Time constant τ was linearly fit to the corresponding ESP, and the slope R (ms/mm Hg) of this relation was calculated. R quantified changes in τ, induced by the change in ESP, and quantified afterload dependence of the rate of LV pressure fall (9 R . Sample correlation coefficients of the ESP − τ relationships yielded values of r > 0.93 in all patients. In the 10 patients who were instrumented with the conductance catheter, end-diastolic volume (EDV), end-systolic volume (ESV), slopes (Ees), and axis intercepts (V 0) of the ESP–ESV relationships were analyzed additionally.
Data before and after leg raising were compared using two-way analysis of variance for repeated measurements. Interaction analysis revealed whether effects of leg raising were different at baseline and after dobutamine. Posttest analysis was performed using the Bonferroni-Dunn test. Relations in hemodynamic variables were analyzed using linear regression analysis computing Pearson’s correlation coefficient. Slopes and intercepts of the different relationships were compared using t -test analysis (10 P < 0.05.
Results
Demographic and intraoperative data of the patients included are presented in Table 1 . Table 2 summarizes the hemodynamic data of leg elevation before (control) and after dobutamine before the start of CPB. Dobutamine increased peak LV pressure, and dP/dtmax , whereas EDP remained unchanged. EDV was unaltered and ESV decreased, hence stroke volume increased. Ees and stroke work both increased. Corresponding changes in dP/dtmax and time constant of isovolumic relaxation, and τ induced by dobutamine are displayed in Fig. 1A . Effects of dobutamine on dP/dtmax and τ were coupled: patients who developed the most pronounced increase in dP/dtmax also had the most pronounced decrease of τ (y = 1.6 − 0.05 ×x ;r = 0.83;P < 0.001). After CPB, effects of dobutamine were similar as before CPB (Table 3 ). A similar coupling between changes in dP/dtmax and changes in τ was observed as before CPB (Fig. 1B ) (y = 0.9 − 0.05 ×x ;r = 0.76;P < 0.001; no significant difference in Ees and V0).
Table 1: Preoperative and Intraoperative Data
Table 2: Pre-CPB: Effects of Leg Elevation in Control Conditions and with Dobutamine
Figure 1: Effects of dobutamine (open circles) on dP/dtmax and τ. Corresponding changes in dP/dtmax and τ with regard to baseline values are displayed before cardiopulmonary bypass (pre-CPB) and after cardiopulmonary bypass (post-CPB). Dobutamine altered dP/dtmax and τ to a varying degree. The response of dP/dtmax and τ to dobutamine was coupled: the larger the increase in dP/dtmax , the more pronounced the decrease in τ. A similar observation was present after separation from CPB.
Table 3: Post-CPB: Effects of Leg Elevation in Control Conditions and with Dobutamine
The effects of leg elevation during dobutamine were compared with the effects of leg elevation in control conditions. Under dobutamine, the increase in peak LV pressure and dP/dtmax was higher than at control. The increase in EDV was higher, whereas the increase in EDP was less pronounced. The increase in ESV with leg elevation was less under dobutamine than at control and, accordingly, Ees was steeper. A representative example of the effects of leg elevation at control and during dobutamine is displayed in Fig. 2 .
Figure 2: Representative example of the effects of leg elevation in control conditions (top panel) and during dobutamine (bottom panel) in one patient. Pressure-volume loops of consecutive heart beats are displayed in each panel. With dobutamine, the increase in peak left ventricular (LV) pressure with leg elevation was larger than at control. The increase in end-diastolic volume was also larger, whereas the increase in end-diastolic pressure was less pronounced. The increase in end-systolic volume with leg elevation was less after dobutamine than at control and, accordingly, slope was steeper.
The effects of leg elevation on myocardial relaxation were evaluated by analysis of R . The inset of Fig. 3 illustrates R . R represents the load dependence of LV pressure decrease and is the slope of the relation between τ and ESP measured in consecutive beats during the pressure increase with leg elevation. A wide variability in R was observed with individual values ranging from −0.33 to 1.70 ms/mm Hg. This means that LV pressure decrease accelerated in some patients, but remained unchanged or even slowed in other patients. After dobutamine, individual values ranged from −0.40 to 0.72 ms/mm Hg.
Figure 3: Plots relating individual values of R to corresponding changes in dP/dtmax (A) and changes in end-diastolic pressure (EDP) (B) before cardiopulmonary bypass (pre-CPB) and after separation from cardiopulmonary bypass (post-CPB; C and D). The inset illustrates the meaning of R . Time constant τ was linearly fit to the corresponding end-systolic pressure (ESP), and the slope R (ms/mm Hg) of this relation was calculated. R quantified changes in τ, induced by the change of end-systolic pressure and quantified afterload dependence of the rate of left ventricular relaxation. Afterload dependence was lower after dobutamine (open circles) than at control (filled squares). A close relationship was observed between individual R values and corresponding changes in dP/dtmax and changes in end-diastolic pressure, both pre-cardiopulmonary bypass and post-cardiopulmonary bypass. Values shifted along the same relationship with a more pronounced increase in dP/dtmax , a reduced load dependence of left ventricular pressure decrease, and a smaller increase in end-diastolic pressure after dobutamine.
Variables of contraction and relaxation were coupled. A close relationship was found between changes in dP/dtmax and individual values of R (Fig. 3A ). Patients who developed with leg elevation a decrease in dP/dtmax also manifested a marked slowing of LV pressure decrease, indicating more pronounced load dependence of LV pressure decrease. With dobutamine, the relationship shifted to the right and downward. There was no difference in Ees and V0 of the relationships between dP/dtmax and R at control or with dobutamine (relationship at control:y = 0.99 − 0.007 ×x , r = 0.84, P < 0.001; relationship with dobutamine:y = 0.74 − 0.004 ×x , r = 0.75;P < 0.001).
Load dependence of LV pressure decrease was coupled with the magnitude of changes in EDP with leg elevation. A close relationship was observed between the individual values of R and changes in EDP with leg elevation EDP (Fig. 3B ). Patients with marked load dependence of LV pressure decrease were also the patients who developed a marked increase in EDP. Conversely, patients with low load dependence of LV pressure decrease had only a minor increase in EDP. With dobutamine, the relationship shifted downward and to the left. There was no difference in Ees and V0 of the relationships between EDP and R at control or with dobutamine (relationship at control:y = −0.27 + 0.17 ×x , r = 0.84, P < 0.001; relationship with dobutamine:y = −0.37 + 0.16 ×x , r = 0.73;P < 0.001).
Post-CPB, effects of leg elevation were similar to pre-CPB, both at control and after dobutamine (see Table 3 ). A similar coupling was observed between changes in dP/dtmax with leg elevation and R [control:y = 0.81 − 0.008 ×x (r = 0.85;P < 0.001); with dobutamine:y = 0.71 − 0.006 ×x (r = 0.76, P < 0.001); no significant difference in Ees and V0 between control and dobutamine before and after CPB;Fig. 3C ] and between changes in EDP with leg elevation and R [control:y = −0.26 ± 0.14 ×x (r = 0.85;P < 0.001); with dobutamine:y = −0.42 ± 0.18 ×x (r = 0.74;P < 0.001); no significant difference in Ees and V0 between control and dobutamine before and after CPB;Fig. 3D ].
Discussion
In the perioperative period, an increase in cardiac load by a postural change permitted identification of a subgroup of patients who developed a load-dependent impairment of LV function. When cardiac load was increased by leg elevation, these patients developed a decrease in stroke volume and dP/dtmax , a delayed myocardial relaxation with enhanced load dependence of LV pressure decrease and a marked increase in LV EDP (1 11,12 13,14 2
We indicated that, in coronary surgery patients, β-adrenergic stimulation with dobutamine improved the length-dependent regulation of myocardial function. In addition, it appeared that dobutamine not only improved LV contraction and relaxation, but also that the coupling between variables of contraction and relaxation was preserved with dobutamine.
The effects of β-adrenergic modulation on myocardial contraction and relaxation have been well established. β-adrenergic drugs improve myocardial contractility and accelerate relaxation (3–5 15–17 3,17 18,19 20 20
The effects of dobutamine on variables of contraction and relaxation paralleled each other: the larger the change in dP/dtmax , the more important the change in τ (Fig. 1 ). Previous investigators who examined the effects of β-agonists on contraction and relaxation, have reported variable coupling relations. Parker et al. (5 21
Several methodological issues deserve attention. Different effects of leg elevation at baseline and during dobutamine were not caused by a time-dependent effect. From preliminary experiments, it had appeared that effects of leg elevation were similar when repeated twice at a 10-min interval.
Heart rates during the protocols were regulated with cardiac pacing, which was identical before and after CPB. The use of pacing eliminated variations in heart rate between patients and within the same patient as a confounding factor. However, it should be acknowledged that pacing altered normal LV conduction patterns, and this might have somewhat enhanced load dependence of LV pressure decrease, as experimentally demonstrated in the canine heart (22 23
With respect to the reported results on Ees, it should be noted that the effects of leg elevation should be interpreted as data projecting on the higher curvilinear part of the systolic pressure–volume relationship (24,25
In conclusion, our study demonstrated in coronary surgery patients with a preoperative ejection fraction >40% that β-adrenergic stimulation with dobutamine improved length-dependent regulation of myocardial function during leg elevation.
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