Intrathecal baclofen (ITB), administered by an implanted pump, has emerged as an efficacious therapy for the treatment of hypertonicity in pediatrics. Although ITB has been used for more than 20 years clinically, much is still unknown about the most optimal dosing regimens and intrathecal catheter tip placement. Clinician experience, animal research, and advanced imaging is guiding the use of ITB. The rationale for high cervical catheter tip placement and pulsating flex dosing is described.
Key points
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High cervical catheter tip placement in intrathecal baclofen (ITB) therapy may be more efficacious.
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Pulsating, bolus, or flex dosing of ITB may be more efficacious than simple continuous infusion.
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There is a large concentration gradient within the cerebral spinal fluid (CSF).
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CSF flow oscillates along a craniocaudal axis and is not a continuous mixing flow as once portrayed.
Introduction
Nature of the Problem
Intrathecal baclofen (ITB) administered by an implanted pump was approved by the US Food and Drug Administration for the treatment of spasticity of cerebral origin in 1996. Intrathecal baclofen results in fewer systemic side effects than enteral baclofen with higher efficacy. Regarding cerebral palsy, efficacy evidence for managing spasticity was first published in 2000. There has been increasing evidence that ITB is an efficacious treatment for spasticity in children. Most of the studies assessing efficacy are based on a simple continuous infusion of ITB and little is mentioned regarding daily dosing or catheter tip placement.
Overall, patient satisfaction with intrathecal baclofen is high. Krach and colleagues showed that intrathecal baclofen therapy does not adversely affect the mortality of patients receiving this therapeutic modality compared with a matched cohort. One retrospective review found that after 1 year of ITB treatment, the mean ITB dose when treating spasticity was approximately 300 μg per day. Despite more than 20 years of clinical use of ITB, there are several unanswered questions, including the ideal catheter tip placement and dosing regimens.
Pulsatile Dosing
Progressive dose increases are thought to be caused by tolerance, defined as requiring a higher dose to achieve the same degree of desired effect. Most practitioners experience this soon after a new ITB pump is implanted. Many patients are well controlled on relatively low doses soon after implantation, but the magnitude of effect quickly dissipates, requiring dose escalation. Pulsatile bolus doses have been proposed as an effective and safe treatment strategy to reverse the need for increasing ITB dosages in patients with the probable tolerance to ITB. There is a paucity of reports regarding ITB dosing regimens as alternative to simple continuous infusion. The published reports have been retrospective case series. Interestingly, most clinicians reserve flex or bolus dosing for more severe cases or cases of primarily dystonia that were relatively unresponsive to simple continuous ITB therapy. This supports the notion that pulsatile bolus dosing of ITB may be more efficacious. No studies have compared the efficacy of simple continuous infusion to pulsatile bolus dosing.
Catheter Tip Location
There is one report reviewing the association of catheter tip location and daily dosing. The catheter tip location was variable because no intraoperative imaging was used to determine the catheter tip location. There was a trend for the higher catheter tip placement, resulting in lower daily doses ( Table 1 ); however, “linear regression showed that a higher-level intrathecal catheter needs a lower dose, but this was not significant.”
| Level | Number | Mean Dose (μg/d) | SE |
|---|---|---|---|
| Cervical | 9 | 197.8 | ±78.1 |
| Thoracic | 81 | 266.2 | ±23.4 |
| Lumbar | 15 | 228.6 | ±49.5 |
| Sacral | 3 | 466.7 | ±280.4 |
Theory Behind Catheter Tip Location and Pulsatile Dosing
We know there is a significant concentration gradient that develops in the cerebral spinal fluid (CSF) for almost all naturally occurring proteins, neurotransmitters, and metabolites. The exact mechanism of this is unknown. There is also a concentration gradient for ITB. Bernards demonstrated that the concentration of baclofen is only 0.5% at a distance of 5 cm in comparison with the catheter tip at a steady state with a continuous low dose infusion. This was dramatically increased to almost 50% with a high-dose continuous infusion. However, this was increased even further when a single large bolus was administered. The large bolus raised the concentration at 5 cm to within 75% of the catheter tip and was still 23% at 10 cm. At either continuous infusion rate, the concentration at 10 cm was virtually undetectable. It is hypothesized by the author that the source of energy to facilitate the greater drug distribution within the CSF is the kinetic energy imparted to the drug by the act of the injection. The drug infusion in a simple continuous infusion is almost imperceptible. The faster infusion and especially the bolus imparts a slight, but observable, forward motion to the injectate, and differences among the drug distributions may be in part the result of differences in kinetic energy associated with the different infusion rates.
In addition to concentration gradients within the CSF, it has been demonstrated that the CSF flow oscillates along a craniocaudal axis. There is not a continuous mixing flow caudad along the posterior surface of the spinal cord and returning cephalad along the anterior surface as if it were a river, which was once portrayed. Enzmann and Pelc showed that the flow velocity is greatest in the cervical spine and is essentially absent in the distal lumbar sac. The higher flow velocities in the cervical spine in comparison with the lumbar spine may help disperse the ITB over a larger area. The higher CSF flow should result in a lower concentration gradient over a longer spinal segment in the cervical spine in comparison with the lumbar region. The lack of CSF flow in the lumbosacral spine also may explain why the patients with sacral catheter tip placements required more than double the dose in comparison with the patients with a cervical catheter tip.
Many practitioners note a decrease in efficacy when changing to a higher concentration of ITB despite no change in the actual daily dose. The higher concentration results in a lower volume infusion, which is accompanied by less kinetic energy. The previously described mechanism of kinetic energy may account for this difference in therapeutic effect.
Case Report Demonstration of Theory
A 15-year-old boy with Gross Motor Function Classification System IV spastic quadriparetic cerebral palsy underwent implantation of an ITB pump. In the early postoperative period, his dose was titrated to 350 μg per day using a simple continuous infusion. His delivery method was changed from simple continuous infusion to a flex dosing regimen with bolus administration every 4 hours. Because the pump being used (Synchromed II; Medtronic, Minneapolis, MN) has a minimum basal rate of 0.002 mL per hour or 4 μg per hour when using a 2000 μg/mL concentration, the 4-hour bolus dose was programmed to be 40 μg, which made the total daily dosage 335 μg, a 4.3% reduction in total daily dosing. Within 12 hours, he had clear symptoms of overdose with nausea, vomiting, lethargy, and confusion but unchanged heart rate, blood pressure, respiratory rate, and pulse oximetry measurements. The bolus dose was decreased by an additional 25% to 30 μg every 4 hours with a resulting total daily dosage of 275 μg. Over the next 12 hours, there was complete resolution of the overdose symptoms and the resulting tone management was comparable to the original 350-μg simple continuous infusion despite a more than 20% reduction in the total daily dosage.
Postimplantation Titration
An additional advantage of pulsatile bolus dosing in comparison with simple continuous infusions is that it allows for a more rapid initial titration of the dose. Because sudden large dose changes are typically not well tolerated, the dose escalation with a simple continuous infusion is a relatively slow process with increases of 10% to 20% per adjustment. With a bolus administration schedule, each bolus can be progressively larger, resulting in a relatively high daily dose increase that is generally well tolerated because it is a small dose increase every 3 to 4 hours in comparison with the total daily dosage. The pump must be reprogrammed within 24 hours or the bolus dose will drop back down to initial dose and benefit of the dose escalation will be lost. A typical postimplantation titration is included in Box 1 starting with postoperative day 1. The functional total daily dosage can be increased by 102% within 48 hours. This large of an increase in a simple continuous infusion would place the patient at a high risk for overdose.
| Postoperative Day 1 | ||
|---|---|---|
| Start Time (h:min) | Dose (μg) | Duration (h:min) |
| Monday–Sunday | ||
| Basal Rate 4.00 μg/h | ||
| 00:00 | 4.00 | 00:05 |
| 04:00 | 5.00 | 00:05 |
| 08:00 | 6.00 | 00:05 |
| 12:00 | 1.00 | 00:05 |
| 16:00 | 2.00 | 00:05 |
| 20:00 | 3.00 | 00:05 |
| Total 114.86 μg/d | ||
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