The effect of cardiac output on the pharmacokinetics and pharmacodynamics of propofol during closed-loop induction of anesthesia.

BACKGROUND AND OBJECTIVE: Intraoperative hemodynamic stability is essential to safety and post-operative well-being of patients and should be optimized in closed-loop control of anesthesia. Cardiovascular changes inducing variations in pharmacokinetics may require dose modification. Rigorous investigational tools can strengthen current knowledge of the anesthesiologists and support clinical practice. We quantify the cardiovascular response of high-risk patients to closed-loop anesthesia and propose a new application of physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) simulations to examine the effect of hemodynamic changes on the depth of hypnosis (DoH). METHODS: We evaluate clinical hemodynamic changes in response to anesthesia induction in high-risk patients from a study on closed-loop anesthesia. We develop and validate a PBPK-PD model to simulate the effect of changes in cardiac output (CO) on plasma levels and DoH. The wavelet-based anesthetic value for central nervous system monitoring index (WAVCNS) is used as clinical end-point of propofol hypnotic effect. RESULTS: The median (interquartile range, IQR) changes in CO and arterial pressure (AP), 3 min after induction of anesthesia, are 22.43 (14.82-36.0) % and 26.60 (22.39-35.33) % respectively. The decrease in heart rate (HR) is less marked, i.e. 8.82 (4.94-12.68) %. The cardiovascular response is comparable or less enhanced than in manual propofol induction studies. PBPK simulations show that the marked decrease in CO coincides with high predicted plasma levels and deep levels of hypnosis, i.e. WAVCNS < 40. PD model identification is improved using the PBPK model rather than a standard three-compartment PK model. PD simulations reveal that a 30% drop in CO can cause a 30% change in WAVCNS. CONCLUSIONS: Significant CO drops produce increased predicted plasma concentrations corresponding to deeper anesthesia, which is potentially dangerous for elderly patients. PBPK-PD model simulations allow studying and quantifying these effects to improve clinical practice.

Mathematical modeling of gravitational effects on the circulation: importance of the time course of venous pooling and blood volume changes in the lungs.

A dip in blood pressure (BP) in response to head-up tilt (HUT) or active standing might be due to rapid pooling in the veins below the heart (preload) or muscle activation-induced drop in systemic vascular resistance (afterload). We hypothesized that, in the cardiovascular response to passive HUT, where, in contrast to active standing, little BP dip is observed, features affecting the preload play a key role. We developed a baroreflex model combined with a lumped-parameter model of the circulation, including viscoelastic stress-relaxation of the systemic veins. Cardiac contraction is modeled using the varying-elastance concept. Gravity affects not only the systemic, but also the pulmonary, circulation. In accordance with the experimental results, model simulations do not show a BP dip on HUT; the tilt-back response is also realistic. If it is assumed that venous capacities are steady-state values, the introduction of stress-relaxation initially reduces venous pooling. The resulting time course of venous pooling is comparable to measured impedance changes. When venous pressure-volume dynamics are neglected, rapid (completed within 30 s) venous pooling leads to a drop in BP. The direct effect of gravity on the pulmonary circulation influences the BP response in the first approximately 5 s after HUT and tilt back. In conclusion, the initial BP response to HUT is mainly determined by the response of the venous system. The time course of lower body pooling is essential in understanding the response to passive HUT.

Human cerebral venous outflow pathway depends on posture and central venous pressure.

Internal jugular veins are the major cerebral venous outflow pathway in supine humans. In upright humans the positioning of these veins above heart level causes them to collapse. An alternative cerebral outflow pathway is the vertebral venous plexus. We set out to determine the effect of posture and central venous pressure (CVP) on the distribution of cerebral outflow over the internal jugular veins and the vertebral plexus, using a mathematical model. Input to the model was a data set of beat-to-beat cerebral blood flow velocity and CVP measurements in 10 healthy subjects, during baseline rest and a Valsalva manoeuvre in the supine and standing position. The model, consisting of 2 jugular veins, each a chain of 10 units containing nonlinear resistances and capacitors, and a vertebral plexus containing a resistance, showed blood flow mainly through the internal jugular veins in the supine position, but mainly through the vertebral plexus in the upright position. A Valsalva manoeuvre while standing completely re-opened the jugular veins. Results of ultrasound imaging of the right internal jugular vein cross-sectional area at the level of the laryngeal prominence in six healthy subjects, before and during a Valsalva manoeuvre in both body positions, correlate highly with model simulation of the jugular cross-sectional area (R(2) = 0.97). The results suggest that the cerebral venous flow distribution depends on posture and CVP: in supine humans the internal jugular veins are the primary pathway. The internal jugular veins are collapsed in the standing position and blood is shunted to an alternative venous pathway, but a marked increase in CVP while standing completely re-opens the jugular veins.