title: Ramped-rate vs continuous-rate infusions: An in vitro comparison of convection enhanced delivery protocols.
abstract: BACKGROUND
  Convection enhanced delivery (CED) is a technique using infusion convection currents to deliver therapeutic agents into targeted regions of the brain. Recently, CED is gaining significant acceptance for use in gene therapy of Parkinson's disease (PD) employing direct infusion into the brain. CED offers advantages in that it targets local areas of the brain, bypasses the blood-brain barrier (BBB), minimizes systemic toxicity of the therapeutics, and allows for delivery of larger molecules that diffusion driven methods cannot achieve. Investigating infusion characteristics such as backflow and morphology is important in developing standard and effective protocols in order to successfully deliver treatments into the brain. Optimizing clinical infusion protocols may reduce backflow, improve final infusion cloud morphology, and maximize infusate penetrance into targeted tissue.
  
  
  OBJECTIVE
  The purpose of the current study was to compare metrics during ramped-rate and continuous-rate infusions using two different catheters in order to optimize current infusion protocols. Occasionally, the infusate refluxes proximally up the catheter tip, known as backflow, and minimizing this can potentially reduce undesirable effects in the clinical setting. Traditionally, infusions are performed at a constant rate throughout the entire duration, and backflow is minimized only by slow infusion rates, which increases the time required to deliver the desired amount of infusate. In this study, we investigate the effects of ramping and various infusion rates on backflow and infusion cloud morphology. The independent parameters in the study are: ramping, maximum infusion rate, time between rate changes, and increments of rate changes.
  
  
  METHODS
  Backflow was measured using two methods: i) at the point of pressure stabilization within the catheter, and ii) maximum backflow as shown by video data. Infusion cloud morphology was evaluated based on the height-to-width ratio of each infusion cloud at the end of each experiment. Results were tabulated and statistically analyzed to identify any significant differences between protocols.
  
  
  RESULTS
  The experimental results show that CED rampedrate infusion protocols result in smaller backflow distances and more spherical cloud morphologies compared to continuous-rate infusion protocols ending at the same maximum infusion rate. Our results also suggest internal-line pressure measurements can approximate the time-point at which backflow ceases.
  
  
  CONCLUSIONS
  Our findings indicate that ramping CED infusion protocols can potentially minimize backflow and produce more spherical infusion clouds. However, further research is required to determine the strength of this correlation, especially in relation to maximum infusion rates.
authors.affiliation: Equal authors ; Department of Neurological Surgery, University of Wisconsin, Madison, WI, 53792;
authors.forename: Dominic
authors.initials: D
authors.lastname: Schomberg
authors.affiliation: Equal authors ; Department of Neurological Surgery, University of Wisconsin, Madison, WI, 53792; ; Department of Biomedical Engineering, University of Wisconsin, Madison, WI, 53706;
authors.forename: Anyi
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin, Madison, WI, 53706;
authors.forename: Hope
authors.initials: H
authors.lastname: Marshall
authors.affiliation: Department of Neurological Surgery, University of Wisconsin, Madison, WI, 53792;
authors.forename: Gurwattan
authors.initials: G
authors.lastname: Miranpuri
authors.affiliation: Department of Neurological Surgery, University of Wisconsin, Madison, WI, 53792; ; Department of Biomedical Engineering, University of Wisconsin, Madison, WI, 53706; ; Restorative Neurosciences Foundation, Madison, Wisconsin, 53705, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Sillay
keywords: Backflow; Continuous-rate Infusion Protocol; Convection-enhanced delivery; Direct Brain Infusion; Parkinson’s Disease; Ramped-rate Infusion Protocol