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. 2022 Jun;36(3):849-860.
doi: 10.1007/s10877-021-00717-w. Epub 2021 May 10.

Development of an automated closed-loop β-blocker delivery system to stably reduce myocardial oxygen consumption without inducing circulatory collapse in a canine heart failure model: a proof of concept study

Takuya Nishikawa  1 , Kazunori Uemura  2 , Yohsuke Hayama  2 , Toru Kawada  2 , Keita Saku  2 , Masaru Sugimachi  2
Affiliations

Development of an automated closed-loop β-blocker delivery system to stably reduce myocardial oxygen consumption without inducing circulatory collapse in a canine heart failure model: a proof of concept study

Takuya Nishikawa et al. J Clin Monit Comput. 2022 Jun.

Abstract

Beta-blockers are well known to reduce myocardial oxygen consumption (MVO2) and improve the prognosis of heart failure (HF) patients. However, its negative chronotropic and inotropic effects limit their use in the acute phase of HF due to the risk of circulatory collapse. In this study, as a first step for a safe β-blocker administration strategy, we aimed to develop and evaluate the feasibility of an automated β-blocker administration system. We developed a system to monitor arterial pressure (AP), left atrial pressure (PLA), right atrial pressure, and cardiac output. Using negative feedback of hemodynamics, the system controls AP and PLA by administering landiolol (an ultra-short-acting β-blocker), dextran, and furosemide. We applied the system for 60 min to 6 mongrel dogs with rapid pacing-induced HF. In all dogs, the system automatically adjusted the doses of the drugs. Mean AP and mean PLA were controlled within the acceptable ranges (AP within 5 mmHg below target; PLA within 2 mmHg above target) more than 95% of the time. Median absolute performance error was small for AP [median (interquartile range), 3.1% (2.2-3.8)] and PLA [3.6% (2.2-5.7)]. The system decreased MVO2 and PLA significantly. We demonstrated the feasibility of an automated β-blocker administration system in a canine model of acute HF. The system controlled AP and PLA to avoid circulatory collapse, and reduced MVO2 significantly. As the system can help the management of patients with HF, further validations in larger samples and development for clinical applications are warranted.

Keywords: Automated drug delivery; Beta-blocker; Closed-loop control; Hemodynamics.

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Conflict of interest statement

KS received research funding from Omron Healthcare Co., Ltd., Abiomed Japan K.K., and Zeon Medical Inc., and honoraria from Abiomed Japan K.K. KU received research funding from A&D Co., Ltd.

Figures

Fig. 1
Fig. 1
a Schematic representation of the automated drug delivery system to control arterial pressure (AP) and left atrial pressure (PLA). From measured AP, PLA, right atrial pressure (PRA) and cardiac output (CO), the system calculates hemodynamic parameters comprising SL (slope of Frank-Starling curve for left ventricle), SR (slope of Frank-Starling curve for right ventricle), stressed blood volume (V) and systemic vascular resistance (R). From SR, R, target AP (AP*) and target PLA (PLA*), the system determines target SL (SL*) and V (V*). The infusion rate of landiolol is controlled by a proportional-integral (PI) controller to minimise the difference between SL* and SL (ΔSL). The infusion rate of dextran and injection of furosemide are controlled by a nonlinear (N-L) controller to minimise the difference between V* and V (ΔV). By controlling SL and V, AP and PLA reach preset target values. b Equations used in parameter calculation and determination of target parameters. PRA* indicates target PRA, and SR* indicates target SR. c Details of the controllers of drugs. Kp, proportional gain; Ki, integral gain. s is a Laplace operator, and 1/s indicates integration
Fig. 2
Fig. 2
Echocardiographic variables of cardiac function measured before (Normal) and after three weeks of rapid cardiac pacing to induce heart failure (HF). LVDD, left ventricular end-diastolic dimension; LVDS, left ventricular end-systolic dimension; EF, ejection fraction. *p < 0.05 vs. normal
Fig. 3
Fig. 3
Representative time series data of one dog during hemodynamic control by the automated drug delivery system. a Infusion rates of landiolol and dextran, and cumulative doses of dextran and furosemide; b slope of Frank-Starling curve for left ventricle (SL) and stressed blood volume (V); c mean arterial pressure (AP) and mean left atrial pressure (PLA); d heart rate (HR) and coronary flow (CF); e absolute performance error (|PE|) for AP and PLA. Navy blue and red lines indicate measured and target values, respectively
Fig. 4
Fig. 4
Summarised time series data of six dogs during hemodynamic control by the automated drug delivery system. Data are expressed as median (solid line) and interquartile range (blue area). a Infusion rates of landiolol and dextran, and cumulative doses of dextran and furosemide; b difference between measured and target values of slope of Frank-Starling curve for left ventricle (SL) and stressed blood volume (V); c difference between measured and target values of mean arterial pressure (AP) and mean left atrial pressure (PLA); d absolute performance error (|PE|) for AP and PLA
Fig. 5
Fig. 5
Summarised hemodynamic and energetics data of six dogs obtained at 0 min, 30 min, and 60 min after the system was activated. Boxes represent median and interquartile range. Whiskers represent minimum and maximum values. Outliers are represented as circles. AP, arterial pressure; PLA, left atrial pressure; PRA, right atrial pressure; HR, heart rate; CO, cardiac output; CF, coronary flow; SL, slope of Frank-Starling curve for left ventricle; R, systemic vascular resistance; V, stressed blood volume; MVO2, cardiac oxygen consumption; *p < 0.05 vs. 0 min, **p < 0.05 vs. 30 min
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