Convection Enhanced Delivery to the Brain: Preparing for Gene Therapy and Protein Delivery to the Brain for Functional and Restorative Neurosurgery by Understanding Low-Flow Neurocatheter Infusions Using the Alaris® System Infusion Pump

Abstract

BackgroundConvection enhanced delivery (CED) is an emerging form of direct brain infusion therapy employed in human functional and restorative neurosurgery clinical trials delivering protein, viral vectors for gene therapy, and siRNA.PurposePressure monitoring has become a vital tool in ensuring infusion safety and success. We report details of this benchmark first trial of the use of a leading syringe infusion pump system capable of low-flow infusions.MethodsLow-flow infusion performance of the FDA approved Alaris® System syringe pump, commonly used at our institution, was assessed during in vitro and ex vivo CED infusions. In vitro infusion cloud morphology and line pressure were analyzed utilizing a neuroinfusion catheter and delivering volumes and flow rates proposed for a human gene therapy protocol for Parkinson’s disease.ResultsPressure monitoring results correlated with previously published in-line pressure monitoring results however the time to peak with catheter occlusion was extended due to the method of pressure monitoring with this device.ConclusionMRI compatible infusion pumps used for brain delivery injectables, pressure monitoring is set to be a guiding instrument for the health care professional employing this emerging form of infusion-to-brain delivery. Further development of infusion pump technology is warranted to allow for infuse/withdraw mode, infusion pressure graphical and numerical display, and pressure monitoring without the need for an inflatable reservoir pressure device. MRI safe infusion systems will need to be available and nursing staff educated to prepare infusions within the high-field environment.

Advances in Molecular Imaging of Locally Delivered Targeted Therapeutics for Central Nervous System Tumors

“…New approaches are now being investigated to allow for multiple deliveries to achieve higher or more prolonged regional concentrations of therapeutics. These rely on either multiple surgical interventions or on implantable devices (such as pumps connected to a pre-implanted catheter) that allow for longer infusion times [ 64 , 65 ].…”

Current status of intratumoral therapy for glioblastoma

“…Backflow-free catheter designs are being developed that has increased the flow rates to higher values that include: channel-inducing catheters and dual-action backflow-free catheters [15]. Pumps that provide a longer continuous lower flow rate are being utilized to prevent backflow such as the AlarisÒ pumps and Medtronic Synchromed-II pumps [16,17]. These pump systems are implantable and provide continuous flow at flow rates at 5lL/min.…”

Image-guided Convection-enhanced Delivery into Agarose Gel Models of the Brain

“…Convection-enhanced delivery (CED) has been proposed as a treatment option for a broad spectrum of neurological disorders including malignant brain tumors, epilepsy, metabolic disorders, neurodegenerative diseases (such as Parkinson disease) 1 , stroke, and trauma 2 . CED employs positive pressure bulk flow for the distribution of a drug or other infusate.…”

“…Advances in catheter design 10 , infusion technique 11 , line pressure monitoring 2 , and real time MRI monitoring to correct for brain shift 12,13 , optimize multiple collinear infusions 14 , and monitor for infusate loss 15 have increased the safety and efficacy of the treatment 10 . Additional importance has been placed on the catheter design and infusion strategy including flow rate.…”