Mansoor M. Aman M.D., Ammar Mahmoud M.D., Ali Valimahomed M.D., Krishnan Chakravarthy M.D. Ph.D, Dawood Sayed M.D., Timothy Deer M.D.
Abstract:
Intrathecal drug delivery has an established role in the management of chronic pain and spasticity disorders. The purpose of this educational review is to highlight the important similarities and differences between the two current platforms including Medtronic SynchroMed™ II and Flowonix Prometra II.
Introduction:
Targeted drug delivery platforms are recognized as a safe, therapeutic and cost effective in managing spasticity, multifactorial refractory chronic non-cancer and malignant cancer-associated pain (1-7). An intrathecal spinal catheter is connected to a pump reservoir delivering medications that agonize or antagonize various receptors including opioid, sodium channel, calcium channel, alpha-adrenergic and gamma–aminobutyric acid (GABA-B) (8-10). The two current generation intrathecal pump systems that are commonly utilized are the Medtronic SynchroMed™ II and Flowonix Prometra II. The decision for which device to utilize may be based upon physician preference and familiarity, differences in technology, MRI compatibility, and available support in locale. Both company’s medical devices are FDA approved and undergo routine reviews as manufacturers change production methods or revise components of the pump in order to improve safety and accuracy. The purpose of this review is to highlight key similarities and differences in both available intrathecal pump systems.
Device selection should be individualized and guided by patient specific factors, while accounting for manufacturer differences. Both the Medtronic SynchroMed II and Flowonix Prometra II are indicated for the treatment of pain and spasticity, however the Flowonix Prometra II system was only recently approved for baclofen in February 2020.
Implant and Refill Procedure:
The surgical technique for implanting both pumps is relatively similar and beyond the scope of this review. Both catheters can be visualized on fluoroscopic examination. The Medtronic Ascenda catheter has a radiopaque tip (Figure 1A), while the Prometra II catheter has a larger radiopaque catheter tip improving visualization (Figure 1B). Both catheters offer a suture-less connection between the intraspinal catheter and pump. It is worth noting that the catheter stem for Prometra II is flexible and the SynchroMed™ II stem is rigid. This may impact the technique of implant, but no prospective comparative data exists in this two catheter materials. In regards to anchoring the pump to a fascial plane, the SynchroMed™ II has four prearranged metal rings (Figure 2A) while the Prometra II pump has a 360-degree silicon suture ring (Figure 2B). Ultrasound examination of both pumps demonstrates differences in the shape of the refill port, where the SynchroMed™ II port is flush and the Prometra II port is elevated (Figure 3A and 3B).
Differences in Core Technology and MRI Compatibility:
Movement of cerebral spinal fluid (CSF) is not laminar or circulatory, instead it is oscillatory and turbulent. It is influenced by both cardiac, and respiratory cycles, and the surrounding microenvironments created by various neural structures (12, 13). Although these properties of CSF flow can lead to limited intrathecal drug distribution, various intrathecal pump infusion settings can optimize drug delivery. Injection kinetics and volume are two of the main variables that influence the spread of intrathecal medications in the cerebral spinal fluid (CSF). Agent specific biochemical properties such as lipophilicity and hydrophilicity will also influence spread (13).
The Medtronic SynchroMed™ II utilizes a peristaltic pump roller system to drive the medication intrathecally. Average clinical accuracy is rated at 101% while manufacturer bench accuracy allows for ±14.5 % deviation for precision of flow rate between 85.5%-114.5%. Measurement error is ± 10% and based upon expected volume infused, and not actual reservoir residual. Wesemann et al. assessed the clinical accuracy and measured drug residual volumes at time of refill found an average of 2.5% over infusion than what was programmed when analysis was done on a per-refill basis (14). A recent retrospective review of 149 patients with 755 individual encounters over 2.5 years demonstrated a tendency to under infuse as both the 20 mL and 40 mL pumps aged, while remaining within the aforementioned error rates. (15). No over infusions were seen in this cohort. The SynchroMed™ II is labeled MRI conditional at 3.0 and 1.5 Tesla under specific conditions. Before MRI, the therapy should be discontinued, and restarted after the scan. In the event that therapy is not discontinued, a “motor stall event” will occur with automatic restart within 30 minutes of the scan. It is recommended to interrogate the system within 24 hours after MRI to ensure the pump has restarted appropriately.
The Flowonix Prometra II system uses a non-motorized gas pressurized valve gated dose regulation system and has an accuracy of 97.4%, with a 90% confidence interval of 96.8%-98.0% as evaluated in the prospective, multi-center PUMP study (16). Bench accuracy labeling specifications allow for a range of 85%-115%. Accuracy reported in a long-term follow up at an average of 2.5 years was 97.9% (17). Unlike the Medtronic device which has post market studies, the PUMP study was the only major trial conducted of this device published in peer review. A long-term open label prospective study evaluating the safety of Prometra in 401 implanted patients between 2013-2016 reported promising interim results in 2017 at a national meeting (18). Primary endpoint was long term granuloma formation at five years with secondary measures of pump failure rate, battery end of life and device related adverse events. There was a 0.25% incidence of granuloma formation and 1.5% serious adverse events such as cellulitis at the implant site, pump pocket infection, bacterial meningitis, post dural puncture headache. The Polyanalgesic Consensus Conference (PACC) recommendations should be followed to improve long-term safety (19) and optimize therapy (13). Bolusing of intrathecal medications can be advantageous in order to increase injection velocity, overcome baseline pulsatile CSF flow, dose a larger portion of the spinal cord faster, increase medication density over a larger portion of the spinal cord, obtain more rostral spread of medication, and prevent higher local concentrations of medication at the catheter site – thus reducing incidence of granuloma (20). The Prometra II pump is labelled MRI conditional at 1.5 Tesla however it requires pre-MRI discontinuation of therapy, emptying the medication from the pump reservoir, followed by a post-MRI interrogation and re-initiation of therapy (21). In contrast to older generation Prometra pump; the Prometra II has a flow-activated valve, which serves as a safety measure to avoid over infusion of drug by shutting off drug flow when the pump is exposed to strong magnetic fields (emergent MRI). However, manufacturer guidance should be followed.
Programming capabilities:
Both systems offer a variety of programming capabilities through Bluetooth enabled, secure and intuitive physician programmers. Medtronic offers a touch screen tablet with a wireless communicator for programming, and a patient controlled demand bolus function through their Personal therapy Management (PTM) device. The Flowonix programmer is a touch screen phone (Figure 4A and 4B) and similarly allows for patient controlled demand blouses through their Personal therapy Controller (PTC) device. Both patient control devices need to be placed over the patients pump in order to deliver a bolus. Special consideration regarding the site of pump reservoir implantation is crucial especially in those where implantation is being considered at the back, to ensure the patient can reach the pump site to allow successful activation and accurate delivery of patient activated demand boluses. Both systems allow the clinician to program the number of boluses delivered each day, duration of time over which the bolus is administered, and designate lockout periods to tailor to patient specific needs.
Since the Flowonix’s Prometra II intrathecal pump is a non-motorized gas pressurized valve-gated bolusing pump, the volume of medication which is delivered per bolus from the pump remains constant (reported 97% accuracy). It is dependent on the volume of the pump accumulator, which is approximately 2 mcL (varies between 2-3 mcL). The pump is capable of delivering a medication bolus once every six seconds, or ten times per minute, and can achieve a maximum of up to 28.8 ml of medication per day (22). This system does not require a basal flow rate and can be set to 0 ml/day. This may be particularly important when microdosing with potent chemical neuromodulation such as Ziconitide.
The Flowonix pump offers a “Constant Flow” regimen in which the provider sets the desired daily medication dose. Based on the medication concentration, the computer then calculates the number of boluses (2 mcL) that are needed in a 24-hour time period to achieve the correct daily dose. It will then equally disperse the medication delivery over the course of the day to maintain a relative steady state. The “Multiple Rates” regimen delivers up to four different rates which repeat daily. The dose and start / stop times for each period are programmed by the clinician for each rate. The minimum time period for each rate is 1 minute.
The “Periodic Flow” regimen delivers medication in a sequence of periodic infusions with a basal dose. It is worth noting that the basal rate on the pump can be set to zero; thus, in actuality no basal rate is required between boluses. The maximum number of bolus is 1 per hour or 24 periods in the course of a day.
The Medtronic SynchroMed™ II has multiple programming capabilities that are available including the “Simple Continuous” setting, which allows for the total daily dose to be divided by twenty-four hours and constantly infused. A “Flex Dosing” regimen enables the physician to schedule fixed doses that are bloused at specified intervals throughout the day, in addition to a basal infusion. By decreasing the time over which the Flex Dosing is delivered, medication delivery velocity can be increased in order accomplish more cephalad spread of medication. A demand bolus at 1 ml/min will have sixty times the velocity of an infusion at 1 ml/hr.
Conclusion:
In summary, both Medtronic SynchroMed™ II and Flowonix Prometra II have clinical accuracy in their technology, established record of safety, and a multitude of programming capabilities [Table 1]. The important similarities and differences were discussed in this educational review as familiarity with both systems is advantageous when implanting and/or managing patients with targeted drug delivery devices.
Appendix:
| Specification | Flowonix: Prometra II | Medtronic: Synchromed II |
|---|
| Delivery Mechanism | Valve-gated (gas pressurized) bolusing pump | Peristaltic (motorized) continuous pump |
| Dose Dispenser | Dosing Chamber surrounded by electronic valves | 3 Rotors, motor and ball bearings |
| Dose Volume | 2 mcL | Variable |
| Pump Stem | Flexible silicone | Rigid titanium |
| Cather Tip | Radiopaque (Tungsten) | Radiopaque (Titanium) |
| Catheter Length | 110 cm | 89 - 104.1 cm |
| Catheter Openings | 8 side ports (located in distal 1 cm) | 4 |
| Resevoir Volume | 20 cc or 40 cc | 20 cc or 40 cc |
| Pump Diameter | 69 mm | 72 mm |
| Pump Height | 20 mm | 19.5 mm (20 cc), *** (40 cc) |
| Weight (Unfilled) | 150 grams | 165 grames (20 cc), *** (40 cc) |
| Anchoring | 360 plastic suture ring | 4 metal suture loop holes |
| Flow Rate | 0.0 – 28.8 ml/day | 0.048 – 24 ml/day |
| Minimal Flow Rate | 0 ml/day | 0.048 ml/day |
| Maximal Flow Rate | 28.8 ml/day | 24.0 ml/day |
| Clinical Flow Accurancy | 98% | 101% |
| Bench Flow Accuracy | Range of 85%-115% | Range of 85.5%-114.5% |
| Refill Septum | Elevated, 8 mm diameter | Flush, 6.8 mm diameter |
| Fill Port Pressure | 22.5 PSI | 3-5 PSI |
| Battery Life | 10 years | 7 years |
| MRI Compatibility | MRI Conditional: Empty prior to MRI; Refill following | Full body 1.5T & 3T MRI Conditional : Interrogate following MRI |
| On Label Medications | Morphine, Baclofen, Ziconitide | Morphine, Baclofen, Ziconitide |
| Flow modes | Continuous Flow, Multiple Flow, Periodic Flow, Demand Bolus | Simple Continuous, Flex Dosing, Demand Bolus |
| Patient controller | Touch screen, dedicated dosing button, must be placed over the pump, auditory tone when medication delivered | Touch screen phone device, dedicated dosing button, needs to be placed over device for demand bolusing |
| Interogator | Wireless touch screen phones | Wireless touch screen phones |
| Company Years on the Market | 8 | 71 |
| Disadvantages | Constant velocity, may be more difficult to target medication to small area, need to empty pump prior to MRI | Decreased accuracy, increased granuloma formation, potential for motor stalls, shorter battery life, basal rate required, need to interrogate after MRI |
| Advantages | Longer battery life, pressurized access port provides confidence that needle is inside pump possibly decreasing incidence of pocket fills, high velocity boluses allows more raustral medication spread, less affected by environmental factors such as altitude and temperature, Periodic Flow, larger radioopaque catheter tip | Hassle free MRI workflow, intuitive tablet for physician programming and patient demand bolus smartphone, multiple peer reviewed publications documenting safety and accuracy within bench metrics , radioopaque catheter tip |
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