Pharmacodynamic Analysis of the Influence of Propofol on Left Ventricular Long-Axis Systolic Performance in Cardiac Surgical Patients

Abstract

Background: Propofol induced a decline in the left ventricular (LV) systolic performance in non-cardiac surgery. We tested the hypothesis that propofol decreased the LV contractile function by dose dependent manner in cardiac surgery patients.

Methods: Anesthesia was maintained with target-controlled infusions of propofol and remifentanil in cardiac surgery patients. With a fixed effect-site concentration (Ce) of remifentanil (20 ng/mL) after sternotomy, the Ce of propofol was adjusted to maintain a Bispectral index of 40-60 (Ce1). Mitral annular Doppler tissue image tracings and other echocardiographic variables, including end-diastolic and end-systolic volumes, stroke volume, and mitral inflow pulse wave Doppler profile at Ce1, were recorded using transesophageal echocardiography. Echocardiographic recordings were repeated after the Ce-values of propofol were doubled and tripled at 10-minute intervals (defined as Ce2 and Ce3, respectively). Serial changes in echocardiographic variables for each Ce of propofol were assessed using generalized linear mixed effect modeling. The pharmacodynamic relationship between the Ce of propofol and peak systolic mitral annular velocity (Sm) was analyzed by logistic regression using non-linear mixed effect modeling (NONMEM).

Results: Means of Ce1, Ce2, and Ce3 were 0.8, 1.6, and 2.4 μg/mL, respectively, and their means of Sm (95% confidence interval) were 9.7 (9.3-10.2), 8.7 (8.2-9.1), and 7.5 cm/sec (7.0-8.0), respectively (P < 0.01). Ce values of propofol and Sm showed a significant inter-correlation and predictability (intercept, 10.8; slope-1.0 in generalized mixed linear modeling; P < 0.01). Ce values producing 10% and 20% decline of Sm with 50%-probability were 1.4 and 2.1 μ/mL, respectively.

Conclusion: Propofol reduces LV systolic long-axis performance in a dose-dependent manner.

Trial registration: ClinicalTrials.gov Identifier: NCT01826149.

Keywords: Doppler Tissue Imaging; Pharmacodynamics; Propofol; Systolic Long-Axis Performance.

Conflict of interest statement

The authors have no potential conflicts of interest to disclose.

© 2019 The Korean Academy of Medical Sciences.

Figures

Fig. 1. Serial changes in (A) Sm and (B) EF with increments in Ce of propofol from Ce1 to Ce3. (A) As propofol concentration increases from Ce1 (0.8 ± 0.1) to Ce2 (1.6 ± 0.2) and Ce3 (2.4 ± 0.3), Sm was decreased. (B) As propofol concentration increases from Ce1 (0.8 ± 0.1) to Ce2 (1.6 ± 0.2) and Ce3 (2.4 ± 0.3), EF was decreased. The error bars indicate the standard error at each concentration.

Sm = peak systolic velocity of the mitral annulus descending toward the apex, EF = ejection fraction, Ce = effect-site concentration. *P < 0.05.

Fig. 2. Serial changes in (A) EDV, (B) ESV, (C) Ea, (D) SVRI with increments in Ce of propofol from Ce1 to Ce3. While (A) EDV and (D) SVRI was decreased as effect site of concentration of propofol increases, (B) ESV was significantly increased. (C) Ea was maintained during the entire range of propofol's effect site concentrations. The changes in EDV, EA, and SVRI according to concentration were not significant. The error bars indicates the standard error.

EDV = end diastolic volume, ESV = end systolic volume, Ea = total arterial elastance, SVRI = systemic vascular resistance index, Ce = effect-site concentration. *P < 0.05.

Fig. 3. The relationship between the probability of a 10% (A) and 20% (B) decrease in the Sm from baseline and the Ce of propofol. (A) The estimate of the Ce50 (Ce50−10%, the effect-site concentration of propofol associated with a 50% probability of a decrease in the Sm) with RSE and interindividual variability presented as % coefficient variation was 1.4 μg/mL (13.3, 39.9%). The mean Ce95 (Ce95−10%, the effect-site concentration of propofol associated with a 95% probability of a decrease in the Sm) was 3.86 μg/mL for a 10% decrease in the Sm. The estimate of γ (the steepness of the concentration-vs.-response relation) with RSE and interindividual variability presented as % coefficient variation was 2.9 (43.1, 40.1%) for a 10% decrease in the Sm. Interindividual random variability was modeled using a log-normal model. (B) The estimate of the Ce50 (Ce50−20%, the effect-site concentration of propofol associated with a 50% probability of a decrease in the Sm) with RSE and interindividual variability presented as % coefficient variation was 2.14 μg/mL (12.5, 42.7%). The mean Ce95 (Ce95−20%, the effect-site concentration of propofol associated with a 95% probability of a decrease in the Sm) was 4.23 μg/mL for a 20% decrease in the Sm. The estimate of γ with RSE and interindividual variability presented as % coefficient variation was 4.3 (36.8, 12.5%) for a 20% decrease. Interindividual random variability was modeled using a log-normal model.

RSE = relative standard error.