Mikhail Y. Maslov

Drug infusion system manifold dead-volume impacts the delivery response time to changes in infused medication doses in vitro and also in vivo in anesthetized swine.

BACKGROUND: IV infusion systems can be configured with manifolds connecting multiple drug infusion lines to transcutaneous catheters. Prior in vitro studies suggest that there may be significant lag times for drug delivery to reflect changes in infusion rates set at the pump, especially with low drug and carrier flows and larger infusion system dead-volumes. Drug manifolds allow multiple infusions to connect to a single catheter port but add dead-volume. We hypothesized that the time course of physiological responses to drug infusion in vivo reflects the impact of dead-volume on drug delivery. METHODS: The kinetic response to starting and stopping epinephrine infusion ([3 mL/h] with constant carrier flow [10 mL/h]) was compared for high- and low-dead-volume manifolds in vitro and in vivo. A manifold consisting of 4 sequential stopcocks with drug entering at the most upstream port was contrasted with a novel design comprising a tube with separate coaxial channels meeting at the downstream connector to the catheter, which virtually eliminates the manifold contribution to the dead-volume. The time to 50% (T50) and 90% (T90) increase or decrease in drug delivery in vitro or contractile response in a swine model in vivo were calculated for initiation and cessation of drug infusion. RESULTS: The time to steady state after initiation and cessation of drug infusion both in vitro and in vivo was much less with the coaxial low-dead-volume manifold than with the high-volume design. Drug delivery after initiation in vitro reached 50% and 90% of steady state in 1.4 ± 0.12 and 2.2 ± 0.42 minutes with the low-dead-volume manifold and in 7.1 ± 0.58 and 9.8 ± 1.6 minutes with the high-dead-volume manifold, respectively. The contractility in vivo reached 50% and 90% of the full response after drug initiation in 4.3 ± 1.3 and 9.9 ± 3.9 minutes with the low-dead-volume manifold and 11 ± 1.2 and 17 ± 2.6 minutes with the high-dead-volume manifold, respectively. Drug delivery in vitro decreased by 50% and 90% after drug cessation in 1.9 ± 0.17 and 3.5 ± 0.61 minutes with the low-dead-volume manifold and 10.0 ± 1.0 and 17.0 ± 2.8 minutes with the high-dead-volume manifold, respectively. The contractility in vivo decreased by 50% and 90% with drug cessation in 4.1 ± 1.1 and 14 ± 5.2 with the low-dead-volume manifold and 12 ± 2.7 and 23 ± 5.6 minutes with the high-dead-volume manifold, respectively. CONCLUSIONS: The architecture of the manifold impacts the in vivo biologic response, and the drug delivery rate, to changes in drug infusion rate set at the pump.

High concentrations of drug in target tissues following local controlled release are utilized for both drug distribution and biologic effect: An example with epicardial inotropic drug delivery

Local drug delivery preferentially loads target tissues with a concentration gradient from the surface or point of release that tapers down to more distant sites. Drug that diffuses down this gradient must be in unbound form, but such drug can only elicit a biologic effect through receptor interactions. Drug excess loads tissues, increasing gradients and driving penetration, but with limited added biological response. We examined the hypothesis that local application reduces dramatically systemic circulating drug levels but leads to significantly higher tissue drug concentration than might be needed with systemic infusion in a rat model of local epicardial inotropic therapy. Epinephrine was infused systemically or released locally to the anterior wall of the heart using a novel polymeric platform that provides steady, sustained release over a range of precise doses. Epinephrine tissue concentration, upregulation of cAMP, and global left ventricular response were measured at equivalent doses and at doses equally effective in raising indices of contractility. The contractile stimulation by epinephrine was linked to drug tissue levels and commensurate cAMP upregulation for IV systemic infusion, but not with local epicardial delivery. Though cAMP was a powerful predictor of contractility with local application, tissue epinephrine levels were high and variable--only a small fraction of the deposited epinephrine was utilized in second messenger signaling and biologic effect. The remainder of deposited drug was likely used in diffusive transport and distribution. Systemic side effects were far more profound with IV infusion which, though it increased contractility, also induced tachycardia and loss of systemic vascular resistance, which were not seen with local application. Local epicardial inotropic delivery illustrates then a paradigm of how target tissues differentially handle and utilize drug compared to systemic infusion.

Infusion System Carrier Flow Perturbations and Dead-volume: Large Effects on Drug Delivery In Vitro and Hemodynamic Responses in a Swine Model

BACKGROUND:We have previously shown that, at constant carrier flow, drug infusion systems with large dead-volumes (V) slow the time to steady-state drug delivery in vitro and pharmacodynamic effect in vivo compared to those with smaller V. In this study, we tested whether clinically relevant alterations in carrier flow generate perturbations in drug delivery and pharmacodynamic effect, and how these might be magnified when V is large. METHODS:Drug delivery in vitro or mean arterial blood pressure (MAP) and ventricular contractility (max dP/dt) in a swine model were quantified during an infusion of norepinephrine (fixed rate 3 mL/h) with a crystalloid carrier (10 mL/h). The carrier flow was transiently halted for either 10 minutes or 20 minutes and then restarted. In separate experiments, a second drug infusion (50 mL over 10 minutes) was introduced into the same catheter lumen used by a steady-state norepinephrine infusion. The resulting perturbations in drug delivery and biologic effect were compared between drug infusion systems with large and small V. RESULTS:Halting carrier flow immediately decreased drug delivery in vitro, and MAP and max dP/dt. These returned to steady state before restarting carrier flow with the small, but not the large, V. Resuming carrier flow after 10 minutes resulted in a transient increase in drug delivery in vitro and max dP/dt in vivo, which were of longer duration and greater area under the curve (AUC) for larger V. MAP also increased for longer duration for larger V. Resuming the carrier flow after 20 minutes resulted in greater AUCs for drug delivery, MAP, and max dP/dt for the larger V. Adding a second infusion to a steady-state norepinephrine plus carrier flow initially resulted in a drug bolus in vitro and augmented contractility response in vivo, both greater with a larger V. Steady-state drug delivery resumed before the secondary infusion finished. After the end of the secondary infusion drug delivery, MAP and max dP/dt decreased over minutes. Drug delivery and max dP/dt returned to steady state more quickly with the small V. CONCLUSIONS:Stopping and resuming a carrier flow, or introducing a second medication infusion, impacts drug delivery in vitro and biologic response in vivo. Infusion systems with small dead-volumes minimize these perturbations and dampen the resulting hemodynamic instability. Alterations in carrier flow impact drug delivery, resulting in substantial effects on physiologic responses. Therefore, infusion systems for vasoactive drugs should be configured with small V when possible.

Generation of purified nitric oxide from liquid N2O4 for the treatment of pulmonary hypertension in hypoxemic swine.

Inhaled nitric oxide (NO) selectively dilates pulmonary blood vessels, reduces pulmonary vascular resistance (PVR), and enhances ventilation-perfusion matching. However, existing modes of delivery for the treatment of chronic pulmonary hypertension are limited due to the bulk and heft of large tanks of compressed gas. We present a novel system for the generation of inhaled NO that is based on the initial heat-induced evaporation of liquid N2O4 into gas phase NO2 followed by the room temperature reduction to NO by an antioxidant, ascorbic acid cartridge just prior to inhalation. The biologic effects of NO generated from liquid N2O4 were compared with the effects of NO gas, on increased mean pulmonary artery pressure (mPAP) and PVR in a hypoxemic (FiO2 15%) swine model of pulmonary hypertension. We showed that NO concentration varied directly with the fixed cross sectional flow of the outflow aperture when studied at temperatures of 45, 47.5 and 50°C and was independent of the rate of heating. Liquid N2O4-sourced NO at 1, 5, and 20 ppm significantly reduced the elevated mPAP and PVR induced by experimental hypoxemia and was biologically indistinguishable from gas source NO in this model. These experiments show that it is feasible to generate highly purified NO gas from small volumes of liquid N2O4 at concentrations sufficient to lower mPAP and PVR in hypoxemic swine, and suggest that a miniaturized ambulatory system designed to generate biologically active NO from liquid N2O4 is achievable.

Computer control of drug delivery by continuous intravenous infusion: bridging the gap between intended and actual drug delivery.

Background:Intravenous drug infusion driven by syringe pumps may lead to substantial temporal lags in achieving steady-state delivery at target levels when using very low flow rates (“microinfusion”). This study evaluated computer algorithms for reducing temporal lags via coordinated control of drug and carrier flows. Methods:Novel computer control algorithms were developed based on mathematical models of fluid flow. Algorithm 1 controlled initiation of drug infusion and algorithm 2 controlled changes to ongoing steady-state infusions. These algorithms were tested in vitro and in vivo using typical high and low dead volume infusion system architectures. One syringe pump infused a carrier fluid and a second infused drug. Drug and carrier flowed together via a manifold through standard central venous catheters. Samples were collected in vitro for quantitative delivery analysis. Parameters including left ventricular max dP/dt were recorded in vivo. Results:Regulation by algorithm 1 reduced delivery delay in vitro during infusion initiation by 69% (low dead volume) and 78% (high dead volume). Algorithmic control in vivo measuring % change in max dP/dt showed similar results (55% for low dead volume and 64% for high dead volume). Algorithm 2 yielded greater precision in matching the magnitude and timing of intended changes in vivo and in vitro. Conclusions:Compared with conventional methods, algorithm-based computer control of carrier and drug flows can improve drug delivery by pump-driven intravenous infusion to better match intent. For norepinephrine infusions, the amount of drug reaching the bloodstream per time appears to be a dominant factor in the hemodynamic response to infusion.

Local Epicardial Inotropic Drug Delivery Allows Targeted Pharmacologic Intervention with Preservation of Myocardial Loading Conditions

Local myocardial application of inotropes may allow the study of pharmacologically augmented central myocardial contraction in the absence of confounding peripheral vasodilating effects and alterations in heart loading conditions. Novel alginate epicardial (EC) drug releasing platforms were used to deliver dobutamine to the left ventricle of rats. Pressure-volume analyses indicated that although both local and systemic intravenous (i.v.) use of inotropic drugs increase stroke volume and contractility, systemic infusion does so through heart unloading. Conversely, EC application preserves heart load and systemic blood pressure. EC dobutamine increased indices of contractility with minimal rise in heart rate and lower reduction in systemic vascular resistance than i.v. infusion. Drug sampling showed that dobutamine concentration was 650-fold higher in the anterior wall than in the inferior wall. The plasma dobutamine concentration with local delivery was about half as much as with systemic infusion. These data suggest that inotropic EC delivery has a localized effect and augments myocardial contraction by different mechanisms than systemic infusion, with far fewer side effects. These studies demonstrate a pharmacologic paradigm that may improve heart function without interference from effects on the vasculature, alterations in heart loading, and may ultimately improve the health of heart failure patients.

Inhaled Nitric Oxide Augments Left Ventricular Assist Device Capacity by Ameliorating Secondary Right Ventricular Failure.

Clinical right ventricular (RV) impairment can occur with left ventricular assist device (LVAD) use, thereby compromising the therapeutic effectiveness. The underlying mechanism of this RV failure may be related to induced abnormalities of septal wall motion, RV distension and ischemia, decreased LV filling, and aberrations of LVAD flow. Inhaled nitric oxide (NO), a potent pulmonary vasodilator, may reduce RV afterload, and thereby increase LV filling, LVAD flow, and cardiac output (CO). To investigate the mechanisms associated with LVAD-induced RV dysfunction and its treatment, we created a swine model of hypoxia-induced pulmonary hypertension and acute LVAD-induced RV failure and assessed the physiological effects of NO. Increased LVAD speed resulted in linear increases in LVAD flow until pulse pressure narrowed. Higher speeds induced flow instability, LV collapse, a precipitous fall of both LVAD flow and CO. Nitric oxide (20 ppm) treatment significantly increased the maximal achievable LVAD speed, LVAD flow, CO, and LV diameter. Nitric oxide resulted in decreased pulmonary vascular resistance and RV distension, increased RV ejection, promoted LV filling and improved LVAD performance. Inhaled NO may thus have broad utility for the management of biventricular disease managed by LVAD implantation through the effects of NO on LV and RV wall dynamics.

Delivery of drugs, growth factors, genes and stem cells via intrapericardial, epicardial and intramyocardial routes for sustained local targeted therapy of myocardial disease

ABSTRACT Introduction: Local myocardial delivery (LMD) of therapeutic agents is a promising strategy that aims to treat various myocardial pathologies. It is designed to deliver agents directly to the myocardium and minimize their extracardiac concentrations and side effects. LMD aims to enhance outcomes of existing therapies by broadening their therapeutic window and to utilize new agents that could not be otherwise be implemented systemically. Areas covered: This article provides a historical overview of six decades LMD evolution in terms of the approaches, including intrapericardial, epicardial, and intramyocardial delivery, and the wide array of classes of agents used to treat myocardial pathologies. We examines delivery of pharmaceutical compounds, targeted gene transfection and cell implantation techniques to produce therapeutic effects locally. We outline therapeutic indications, successes and failures as well as technical approaches for LMD. Expert opinion: While LMD is more complicated than conventional oral or intravenous administration, given recent advances in interventional cardiology, it is safe and may provide better therapeutic outcomes. LMD is complex as many factors impact pharmacokinetics and biologic result. The choice between routes of LMD is largely driven not only by the myocardial pathology but also by the nature and physicochemical properties of the therapeutic agents.

Infusion System Architecture Impacts the Ability of Intensive Care Nurses to Maintain Hemodynamic Stability in a Living Swine Simulator.

Background:The authors have previously shown that drug infusion systems with large common volumes exhibit long delays in reaching steady-state drug delivery and pharmacodynamic effects compared with smaller common-volume systems. The authors hypothesized that such delays can impede the pharmacologic restoration of hemodynamic stability. Methods:The authors created a living swine simulator of hemodynamic instability in which occlusion balloons in the aorta and inferior vena cava (IVC) were used to manipulate blood pressure. Experienced intensive care unit nurses blinded to the use of small or large common-volume infusion systems were instructed to maintain mean arterial blood pressure between 70 and 90 mmHg using only sodium nitroprusside and norepinephrine infusions. Four conditions (IVC or aortic occlusions and small or large common volume) were tested 12 times in eight animals. Results:After aortic occlusion, the time to restore mean arterial pressure to range (t1: 2.4 ± 1.4 vs. 5.0 ± 2.3 min, P = 0.003, average ± SD), time-out-of-range (tOR: 6.2 ± 3.5 vs. 9.5 ± 3.4 min, P = 0.028), and area-out-of-range (pressure–time integral: 84 ± 47 vs. 170 ± 100 mmHg·min, P = 0.018) were all lower with smaller common volumes. After IVC occlusion, t1 (3.7 ± 2.2 vs. 7.1 ± 2.6 min, P = 0.002), tOR (6.3 ± 3.5 vs. 11 ± 3.0 min, P = 0.007), and area-out-of-range (110 ± 93 vs. 270 ± 140 mmHg·min, P = 0.003) were all lower with smaller common volumes. Common-volume size did not impact the total amount infused of either drug. Conclusions:Nurses did not respond as effectively to hemodynamic instability when drugs flowed through large common-volume infusion systems. These findings suggest that drug infusion system common volume may have clinical impact, should be minimized to the greatest extent possible, and warrants clinical investigations.

Hemorheological parameters and their correlations in OXYS rats: A new model of hyperviscosity syndrome

Rheohaemapheresis aims to normalize major rheological parameters and is used to treat patients with dry age-related macular degeneration (AMD). While effective, this approach is invasive and requires specially trained personnel. Therefore, the search for novel effective compounds with hemorheological properties that can be taken orally to treat AMD is justified. The use of a robust rodent model of AMD with high blood viscosity is crucial to test the efficacy of potential hemorheological drugs to treat this disease. The objective of this study was to investigate whether OXYS rats, generally used as an animal model of AMD, have hyperviscosity syndrome. The results of this study show that blood viscosity in OXYS rats at low (3-10 s -1) and high (45-300 s -1) shear rates were 14-20% and 7-10% higher than in Wistar rats, while hematocrit and plasma viscosity were not different. Red blood cells (RBCs) in OXYS rats were more prone to aggregation as shown by 39% shorter half-time than in Wistar rats. RBCs were also more rigid in OXYS than in Wistar rats as shown by 21-33% lower index of elongation at the shear stress of 1-7 Pa. These data indicate that OXYS rats have hyperviscosity syndrome as the result of abnormal RBC deformability and aggregation. We propose to use OXYS rats as an animal model for preclinical studies to test compounds with hemorheological properties aimed to treat AMD.