Pump-driven clinical infusions: laboratory comparison of pump types, fluid composition and flow rates on model drug delivery applying a new quantitative tool, the pharmacokinetic coefficient of short-term variation (PK-CV).

Critically ill or anesthetized patients commonly receive pump-driven intravenous infusions of potent, fast-acting, short half-life medications for managing hemodynamics. Stepwise dosing, e.g. over 3-5 min, adjusts physiologic responses. Flow rates range from < 0.1 to > 30 ml/h, depending on pump type (large volume, syringe) and drug concentration. Most drugs are formulated in aqueous solutions. Hydrophobic drugs are formulated as lipid emulsions. Do the physical and chemical properties of emulsions impact delivery compared to aqueous solutions? Does stepwise dose titration by the pump correlate with predicted plasma concentrations? Precise, gravimetric, flow rate measurement compared delivery of a 20% lipid emulsion (LE) and 0.9% saline (NS) using different pump types and flow rates. We measured stepwise delivery and then computed predicted plasma concentrations following stepwise dose titration. We measured the pharmacokinetic coefficient of short-term variation, (PK-CV), to assess pump performance. LE and NS had similar mean flow rates in stepwise rate increments and decrements between 0.5 and 32 ml/h and continuous flows 0.5 and 5 ml/h. Pharmacokinetic computation predictions suggest delayed achievement of intended plasma levels following dose titrations. Syringe pumps exhibited smaller variations in PK-CV than large volume pumps. Pump-driven deliveries of lipid emulsion and aqueous solution behave similarly. At low flow rates we observed large flow rate variability differences between pump types showing they may not be interchangeable. PK-CV analysis provides a quantitative tool to assess infusion pump performance. Drug plasma concentrations may lag behind intent of pump dose titration.

Performance of a Continuous Subcutaneous Insulin Infusion (CSII) Pump With Acoustic Volume and Flow Sensing in Simulated High-Consequence Situations.

Goal: An insulin pump's failure to deliver insulin in the right amount at the right time is a preventable cause of hospitalization. We evaluated key performance metrics of a novel insulin pump that prevents "silent insulin non-delivery" caused by blockage, delivery of air and site leakage. This is accomplished via an acoustic sensor that measures the volume of insulin delivered with each pulse in real-time. Methods: We tested long and short-term flow accuracy, occlusion-detection time and pressure, and air management of the new device (ND) versus 3 U.S. commercial insulin pumps (CIPs) using standardized methods. Results: The ND outperformed CIPs on long-term basal flow rate error. Occlusion detection was 5 to 22.5 times faster depending on the basal rate and resulted in significantly lower (2 to 5x) pressures at time of occlusion. With air included in the drug reservoir, the tested CIPs can infuse air without detection, while the ND prevented air delivery without interruption. Conclusions: Bench tests of the ND versus 3 commercially available pumps showed improved occlusion detection and air management without flow performance tradeoffs. Additionally, the lower delivery pressure measured at time of occlusion suggests a substantially lower potential for site leakage at both basal and bolus rates. These enhancements combine to decrease the likelihood of silent insulin non-delivery.

Lag times to steady state drug delivery by continuous intravenous infusion: direct comparison of peristaltic and syringe pump performance identifies contributions from infusion system dead volume and pump startup characteristics.

Time lags between the initiation of a continuous drug infusion and achievement of a steady state delivery rate present an important safety concern. At least 3 factors contribute to these time lags: (1) dead volume size, (2) the ratio between total system flow and dead volume, and (3) startup delay. While clinicians employ both peristaltic pumps and syringe pumps to propel infusions, there has been no head-to-head comparison of drug delivery between commercially available infusion pumps with these distinct propulsion mechanisms. We quantified the delivery of a model drug by peristaltic and syringe pumps at clinically relevant flow rates using spectrophotometric absorbance. Delivery curves were modeled and compared, and the time required to reach 5% (T5), 50% (T50), and 95% (T95) of the intended delivery rate was reported. The ability to overcome the combined effects of startup delay and dead volume differed between syringe and peristaltic pumps. T5, T50, and T95 were shorter for the peristaltic pump at higher flow rates. T50 and T95 were shorter for the syringe pump at lower flow rates. The ability to overcome the effects of dead volume was overall similar between the syringe and peristaltic pumps, as was the response to consecutive changes in drug infusion rates. Startup delay and dead volume in carrier-based infusion systems cause substantial time lags to reaching intended delivery rates. Peristaltic and syringe pumps are similarly susceptible to dead volume effects. Startup performance differed between peristaltic and syringe pumps; their relative performance may be dependent on flow rate.

Evaluation of Clinical Infusion Pump Performance Through Downstream Microdrop Monitoring: A Preliminary Study.

As low-flow infusion is becoming more prevalent for clinical care, there is an increasing need for better evaluation of clinical infusion pump performance at low flow rates and in ways that are accessible to the clinical community. However, the current method in international standard require specialized facilities, costly equipment, long durations of testing, and the data produced is hard to interpret. We propose downstream microdrop monitoring (DMM) as a low-cost, easy-to-perform, and easy-to-interpret alternative. In particular, we show that the count and timing of microdrops are useful for evaluating flow accuracy and flow uniformity at low flow rates.

Can mHealth Technology Help Mitigate the Effects of the COVID-19 Pandemic?

Goal: The aim of the study herein reported was to review mobile health (mHealth) technologies and explore their use to monitor and mitigate the effects of the COVID-19 pandemic. Methods: A Task Force was assembled by recruiting individuals with expertise in electronic Patient-Reported Outcomes (ePRO), wearable sensors, and digital contact tracing technologies. Its members collected and discussed available information and summarized it in a series of reports. Results: The Task Force identified technologies that could be deployed in response to the COVID-19 pandemic and would likely be suitable for future pandemics. Criteria for their evaluation were agreed upon and applied to these systems. Conclusions: mHealth technologies are viable options to monitor COVID-19 patients and be used to predict symptom escalation for earlier intervention. These technologies could also be utilized to monitor individuals who are presumed non-infected and enable prediction of exposure to SARS-CoV-2, thus facilitating the prioritization of diagnostic testing.

Design, implementation, and evaluation of a physiological closed-loop control device for medically-induced coma.

Concerns regarding reliability and safety, as well as uncertainties about what constitutes adequate performance evaluation, have impeded the clinical translation of PCLC devices. We describe an attempt to address these challenges through design, implementation, and evaluation of a PCLC device for delivering medically-induced coma, with the intention to eventually conduct a clinical trial. This device works by automatically adjusting the infusion rate of propofol - a general anesthetic - in response to an electroencephalogram (EEG) pattern called burst suppression. We also designed and implemented a computational patient model which interfaces with hardware and produces realistic EEG signals in response to propofol infusion. The computational patient model is used in hardware-in-the-loop studies to evaluate the behavior of our PCLC device under realistic perturbations. Finally, we have tested the performance of our PCLC device in rodents. Results from these studies suggest that closed-loop control of medically-induced coma in humans is feasible and robust. Consequently, our work produced a PCLC device and relevant pre-clinical evidence in support of a pilot clinical trial.

An in vitro analysis of central venous drug delivery by continuous infusion: the effect of manifold design and port selection.

BACKGROUND: Central venous catheters are used extensively in anesthesia and critical care. Multiport manifolds allow for simultaneous administration of multiple medication infusions into a common central venous catheter lumen. The structures of such manifolds vary considerably. In this study, we quantitatively compared, in a laboratory model of continuous drug infusion, the drug delivery dynamics of a traditional stopcock manifold and a microinfusion manifold constructed to minimize dead volume. METHODS: A syringe pump infused a saline carrier solution at a low flow rate frequently used in an intensive care unit (10 mL/h) through a multiport manifold connected to the 16-gauge lumen of a standard 16-cm triple-lumen catheter. The model drug methylene blue (3 mL/h) joined the carrier flow at the first, second, or fourth stopcock of a traditional manifold or 1 of 2 positions in a microinfusion manifold, a new device designed to minimize dead volume. Effluent samples were collected every minute for quantitative spectrophotometric analysis of delivery onset and offset. RESULTS: Onset and offset times differed significantly among individual ports of the traditional 4-stopcock manifold. There was also a significant difference between the 2 ports of the microinfusion manifold, but this was less pronounced. Both ports of the microinfusion manifold yielded delivery dynamics that were similar to the most downstream port of the 4-stopcock manifold. There was good correlation between dynamic data and dead volume for each of the manifolds. CONCLUSIONS: Using a traditional stopcock manifold, port selection significantly affects drug delivery dynamics for continuous infusions. The findings provide quantitative support for the concept that the most critical infusion should join the system at the manifold port closest to the patient. Port selection was less important for the microinfusion manifold and dynamics were faster compared with the second and fourth ports of the stopcock manifold. The smaller dead volumes of the microinfusion manifold minimize unwanted delays in drug delivery onset and offset allowing more precise control over drug delivery by continuous infusion.

Central venous catheter infusions: a laboratory model shows large differences in drug delivery dynamics related to catheter dead volume.

OBJECTIVE: Central venous catheters (CVCs) are conduits for drug infusions. Dead volumes of different CVC lumens vary considerably. This study quantitatively evaluated drug delivery dynamics of CVCs in a laboratory model of continuous drug infusion. DESIGN: CVCs studied included a triple-lumen catheter (16-gauge and 18-gauge lumens), the proximal infusion port of a pulmonary artery catheter, and a 9-Fr introducer sheath, with and without a pulmonary artery catheter in the lumen. One syringe pump infused a carrier. A second pump infused the model drug methylene blue (3 mL/hr), joining the carrier immediately upstream of the CVC. Samples were collected every minute for quantitative analysis. SETTING: Laboratory model. SUBJECTS: None. INTERVENTIONS: At low fixed flow rates, experiments characterized drug delivery kinetics of different CVCs. Data collection then assessed effects of increased carrier flow. MEASUREMENT AND MAIN RESULTS: The time to steady-state delivery after initiation of methylene blue infusion differed between CVCs. At a carrier flow of 10 mL/hr, the fastest achievement of steady-state delivery was with the 18-gauge lumen of a triple-lumen catheter. The 9-Fr introducer had the slowest time to achieve steady-state delivery. Other CVCs had intermediate kinetics. Reducing drug delivery from steady state to zero after cessation of methylene blue infusion was fastest with the 18-gauge lumen and slowest with the 9-Fr introducer. Increasing carrier flow rates from 10 to 60 mL/hr hastened the time to target for initiation and cessation of methylene blue delivery. CONCLUSIONS: Experiments demonstrate large differences between CVCs in the dynamics for delivery of model drug methylene blue. Achieving targeted steady-state delivery, and termination of a planned continuous drug infusion, may be far slower than typically appreciated. Delivery kinetics depend on the dead volume and the rate of carrier flow. Safe and effective management of continuous drug infusions depends on understanding the dynamics of the delivery system.