- Email: [email protected]
Complex Dosing Schedules for Continuous Intrathecal Baclofen Infusion
Complex Dosing Schedules for Continuous Intrathecal Baclofen Infusion Linda E. Krach, MD*, Robert L. Kriel, MD†‡, and Andrea C. Nugent, MPH† The objective of the present study was to understand the clinical reasons for changes from simple continuous to complex (flex) dosing for tone reduction in individuals receiving intrathecal baclofen. Methodology was a retrospective chart review study of 164 individuals (95 male, 69 female) at a multi-specialty children’s hospital who were followed for at least 1 year for intrathecal baclofen management. Eighty-two persons were in the simple continuous only group and 82 also were on complex schedules at least once during the follow-up period. Mean age at most recent follow-up was 18 years and 0 months (median, 15 years and 8 months; standard deviation, 8 years and 0 months; range, 6-45). The top three clinical reasons for switching dosing method were to (1) optimize intrathecal baclofen effect, (2) treat predictable daily tone variation, and (3) manage signs and symptoms of intrathecal baclofen withdrawal or underdelivery. In both groups, 90% of individuals had cerebral palsy, and mean baseline leg Ashworth scores were the same in both groups (mean, 3.7; standard deviation, 0.7). Mean total daily dose at chart review was higher in complex dosing (429.3 vs 211.9 g/day), as was mean follow-up time (4.8 vs 3.9 years). Case examples are presented. © 2007 by Elsevier Inc. All rights reserved. Krach LE, Kriel RL, Nugent AC. Complex dosing schedules for continuous intrathecal baclofen infusion. Pediatr Neurol 2007;37:354-359.
pump system that is widely used allows the option of programming the pump to deliver medication at a constant or variable rate. Although this feature allowing for variable rate of delivery has been available for several years and has been discussed at meetings, there have been few journal publications describing clinical experience using it. In a retrospective review of 50 patients receiving intrathecal baclofen, Rawlins [12] reported that this variable rate of delivery mode was used in 54% of patients and was the most common infusion mode in individuals with cerebral palsy. However, clinical rationale for its use was noted only for treatment of nighttime spasms in individuals with multiple sclerosis [12]. A summary of a consensus conference discussed the use of complex programming options for variations in muscle tone during the patient’s typical 24 hour day [13]. A recent publication reported prolonged spasticity reduction with a single bolus of intrathecal baclofen [14]. The question arises whether this prolonged effect could be used clinically with those chronically receiving intrathecal baclofen. The objective of the present study was to understand the clinical reasons for changes from simple continuous to complex (flex) dosing for spasticity reduction in individuals receiving continuous infusions of intrathecal baclofen by programmable pump. Factors such as patient demographics, clinical diagnosis, degree of spasticity, and provider were considered. Also, we provide illustrative case examples. Methods
Introduction Increased muscle tone is found in most persons with cerebral palsy [1]. Continuous intrathecal baclofen infusion is effective in reducing muscle tone of cerebral origin such as occurs in persons with cerebral palsy [2-11]. The
From *Pediatric Rehabilitation Medicine at †Gillette Children’s Specialty Healthcare and ‡Pediatrics and Neurology at Hennepin County Medical Center, St. Paul, Minnesota.
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This retrospective descriptive study was conducted at Gillette Children’s Specialty Healthcare, a regional, multispecialty pediatric center in the Midwestern United States. Subjects in the present study represent a non-randomized, consecutive case series of children and adults who underwent pump implantation after January 1, 1999, and had at least 1 year of continuous treatment with intrathecal baclofen and follow-up at
Communications should be addressed to: Dr. Krach; Pediatric Rehabilitation Medicine; Gillette Children’s Specialty Healthcare; 200 East University Avenue; St. Paul, MN 55101. E-mail: [email protected] Received March 8, 2007; accepted June 27, 2007.
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2007.06.020 ● 0887-8994/07/$—see front matter
this institution. Approval to conduct the study was obtained from the Institutional Review Board at the University of Minnesota. Electronic databases were queried to identify subjects and medical records were reviewed. Data were collected for each participant at the time of intrathecal baclofen pump implantation and at each subsequent follow-up visit in which a change in dose delivery method was made. Information obtained included items such as gender, primary diagnosis, and managing clinician. Other variables obtained were: intrathecal baclofen dose and mode of delivery (simple continuous or complex), duration of time with pump, number of changes back and forth from simple continuous to complex dosing methods, clinical reasons for infusion delivery mode change, length of follow-up, and Ashworth Scale scores at baseline and any change in delivery mode. A single bolus to refill the catheter after concentration change, catheter aspiration, or as a method to evaluate symptoms of underdelivery were not considered complex infusion methods. For individuals previously tried on complex dosing who were on simple continuous dosing at the most recent follow-up (N ⫽ 29) the average Ashworth Scale scores at the first switch back from complex dosing to simple continuous were considered “most recent.” Individuals missing Ashworth scores at one or more visits were excluded from the analysis. The Ashworth Scale was used to grade tone and is defined as follows: 1 ⫽ normal, 2 ⫽ catch with rapid movement of a joint, 3 ⫽ resistance throughout the range of movement which, however, is readily attained, 4 ⫽ considerable increase in tone with difficult passive movement, 5 ⫽ rigidity [15,16]. Bilateral scores were included for hip abduction, hip adduction, knee extension, knee flexion, ankle dorsiflexion, and plantar flexion. In addition to Ashworth scores, the clinical reasons why providers chose to switch the dose infusion method were determined. The reasons for change in dose infusion method from simple continuous to complex dosing were then grouped into one of the following categories: (1) variation of the participant’s tone at predictable times of the day; (2) bolus infusions on a daily schedule to optimize intrathecal baclofen effect; and (3) manage signs of underdelivery. Changes made due to programming limitations (catheter/pump replacement surgery, pump study, catheter aspiration, indium scan/dye study, or dose concentration change) were excluded from the present study. For the majority of the implanted pumps, the software allowed only for simple continuous dosing at the time of surgery or concentration change, because of the need to allow time for the fluid in the catheter and pump internal tubing to be replaced by the new concentration. Newer pumps and software no longer have this limitation. Reasons for change in intrathecal baclofen delivery dosing method from complex back to simple continuous dosing fell into the following categories: (1) complex dosing did not produce the desired effect; (2) the individual was experiencing excessive tone fluctuation. Information about complications and intrathecal baclofen pump explantations were obtained for individuals in the complex dosing group who were tried on complex dosing schedules three or more times during the follow-up period. This was done in order to ascertain the frequency of known dose-related complications in this subgroup with more experience on complex dosing schedules. After data analysis, providers 1 to 3 were asked under what circumstances they typically consider changing to complex dosing, for what circumstances they deliver different doses in 24 hours, and under what circumstances they program to deliver boluses with low doses in between. Providers were also invited to share general comments.
Participants Participants were at least 3 years of age, had sufficient body mass to accommodate an intrathecal baclofen pump, had pump placement after January 1, 1999, and had been followed for continuous intrathecal baclofen infusion management at Gillette Children’s Specialty Healthcare for at least 1 year after implantation.
To be considered for intrathecal baclofen pump implantation at Gillette, individuals must have clinically significant tone with a mean Ashworth Scale score of at least 3 in the legs and goals for tone reduction. This tonal abnormality could be spasticity, dystonia, or a mixture of the two. Individuals were excluded from participation if they were not managed by Gillette clinicians, were not followed for at least 1 year, or had a degenerative disorder or spinal cord injury as an etiology for increased tone. Those included in the study had static encephalopathy from any of the causes of cerebral palsy or after later events such as traumatic brain injury or anoxic encephalopathy. Three of the individuals who met inclusion criteria and were in the complex dosing group were selected by the first author as illustrative case examples.
Providers A total of six physicians and two nurse practitioners provided intrathecal baclofen pump management for the subjects in this series who received complex dosing. Only two physicians and one nurse practitioner managed the pumps for 93% of these individuals. Therefore, when evaluating differences related to provider only the top three providers were included in the analysis. For all other analyses, the entire cohort was included.
Statistical Analysis SPSS software version 13.0 was used for all statistical analyses (SPSS, Chicago, IL). In addition to descriptive statistics, analyses of variance (denoted with an F statistic), t tests, Pearson’s correlations, and chisquare tests were run. The primary focus of the analyses is the 82 individuals who were on complex dosing schedules. A series of 2 ⫻ 3 chi-square analyses (each possible reason for change ⫽ yes/no by three providers) were run in order to determine whether or not certain reasons for change were more common by provider. Each “reason for change” variable (e.g., predictable daily tone variation) was considered binomial (yes/no).
Results Sample Characteristics In all, 164 children and adults met the inclusion criteria; 95 were male (60%) and 69 were female (40%). Ninety percent had cerebral palsy; the remainder had static encephalopathy due to postnatal insults. The mean baseline Ashworth score was 3.7 (standard deviation, 0.7). All were started on simple continuous dosing at time of pump implantation. Ages at time of most recent follow-up visit ranged from 6 to 45 years with mean age of 18 years and 0 months (median, 15 years and 8 months; standard deviation, 8 years and 0 months). Individuals had been receiving intrathecal baclofen from 1 to 7 years with mean of 4.3 years (median, 4.5; standard deviation, 1.6) (Table 1). Eighty-two (50%) of the individuals were tried on complex dosing at some point during the follow-up period. Individuals in the complex dosing group had been tried on complex dosing anywhere from one to six times (M, 2.1; standard deviation, 1.2). The reasons for this high number of changes included the programming limitations noted previously. When individuals on complex dosing required medication concentration changes, catheter replacement, catheter aspiration, or other activities that required refilling the catheter with a concentration of medication differ-
Krach et al: Complex Dosing for Intrathecal Baclofen 355
Table 1.
Participant characteristics by dosing delivery method
Age at time of current dose, years, mean (SD) Cerebral palsy, no. (%) Baseline leg Ashworth score, mean (SD) ITB dose at chart review, g/day, mean/median (SD)* Duration of follow-up, years, mean (SD)†
Simple (N ⴝ 82)
Complex (N ⴝ 82)
All Subjects (N ⴝ 164)
17.5 (8.7) 74 (90.2) 3.7 (0.7) 211.9/185.0 (122.7) 3.9 (1.6)
18.2 (7.5) 74 (90.2) 3.7 (0.6) 429.3/310.1 (393.2) 4.8 (1.4)
18.0 (8.0) 148 (90.2) 3.7 (0.7) 320.1/223.1 (310.3) 4.3 (1.6)
* Mean intrathecal baclofen dose was significantly higher in the complex dosing group (t ⫽ ⫺4.8, P ⬍ 001). Mean number of years of follow-up was significantly higher in the complex dosing group (t ⫽ ⫺3.6, P ⬍ 0.001).
†
Abbreviations: ITB ⫽ Intrathecal baclofen SD ⫽ Standard deviation
ent than what was present in the catheter, simple continuous dosing was required. Daily dose differed significantly between the simple continuous dosing group (mean, 211.9; standard deviation, 122.9) and the complex dosing group (mean, 429.3; standard deviation, 393.2) (t ⫽ ⫺4.8, P ⬍ 0.001). Duration of intrathecal baclofen therapy was significantly longer in the complex dosing group (mean, 4.8; standard deviation, 1.4) than the simple continuous dosing group (mean, 3.9; standard deviation, 1.6) (t ⫽ ⫺3.6, P ⬍ 0.001). Reasons for Change in Dose Infusion Method The most frequent clinical reason for initial change to complex dosing was to treat predictable daily muscle tone variation (N ⫽ 35, 42.7%), the second was to optimize intrathecal baclofen effect (N ⫽ 28, 34.1%). Of the 82 individuals on complex dosing, 23 (28%) were returned to simple continuous dosing for programming limitation reasons. The most common clinical reason for the second change to complex dosing was to manage predictable tone fluctuations (13/29, 45%). Ashworth Scores Average bilateral Ashworth scores were reported at pump implantation and most recent follow-up for 137 individuals. There was a significant improvement in mean average scores from 3.7 to 2.2 (t ⫽ 20.3, P ⬍ 0.001). However, there was no significant difference in the rate of average score improvement between simple continuous dosing vs complex dosing groups. Ashworth scores for the complex dosing group were collected at visits when a dose infusion method change was made. For the complex dosing group, for 67 (82%) individuals the average Ashworth scores were documented at (1) intrathecal baclofen pump implantation, (2) the first attempt on complex dosing, and (3) the most recent followup. A single-group repeated-measures analysis of variance was conducted and there was not a significant Ashworth score difference from the time of first attempt on complex
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dosing to the most recent follow-up (mean, 2.3 to 2.2). There were, however, significant improvements in scores from the time of intrathecal baclofen pump implantation to both the first attempt on complex dosing and the most recent follow-up visit (F ⫽ 136.7, P ⬍ 0.001). Provider Differences Three providers (Providers 1, 2, and 3) made the majority of dose delivery method decisions (Table 2). Providers 1 and 2 were physicians and provider 3 was a nurse practitioner. Each had several years of experience with intrathecal baclofen pump management. There were differences among the three providers with regard to decisions to change from simple continuous to complex dosing. Provider 1, who had been following individuals for a significantly longer period of time than had provider 3 (F ⫽ 5.0, P ⬍ 0.01), also started patients on complex dosing schedules significantly sooner than provider 3 (F ⫽ 5.5, P ⬍ 0.01). Mean baseline Ashworth scores were the same for participants treated by these three providers. In order to examine whether or not reasons for changing individuals from simple continuous dosing to complex dosing (or vice versa) differed by provider, the initial three visits in which a dose infusion method change was made were examined. The clinic visits of focus were (1) the first change from simple continuous to complex dosing, (2) the first change from complex back to simple continuous dosing, and (3) the second change from simple continuous to complex dosing. For providers 1, 2, and 3 there were 76 changes from simple continuous dosing to complex dosing, of which 18 cases changed back to simple continuous dosing (Table 2). Providers 1, 2, and 3 changed more back to complex dosing, because of assuming care from some of the other providers. The most common reasons why providers changed delivery method are shown in Table 2. At change 1, provider 1 more frequently decided to change intrathecal baclofen dosing delivery method to optimize the effect of intrathecal baclofen than did the other two providers (2 ⫽ 8.6, P ⫽ 0.01). While the most common reason overall for
Table 2.
Reasons for change in dose delivery method by provider
Change 1. Simple to complex Predictable daily tone variation Optimize ITB effect with boluses* Manage signs of underdelivery Other Total Change 2. Complex to simple Complex dosing ineffective Excessive tone fluctuation Other Total Change 3. Simple to complex Predictable daily tone variation Optimize ITB effect with boluses Manage signs of underdelivery Other Total
Provider 1
Cases, no. (%) Provider 2
Provider 3
10 (35.7) 15 (53.6) 1 (3.6) 2 (7.1) 28 (100.0)
12 (42.9) 6 (21.4) 1 (3.6) 9 (32.1) 28 (100.0)
12 (60.0) 4 (20.0) 0 (0.0) 4 (20.0) 20 (100.0)
1 (50) 0 (0.0) 1 (50) 2 (100.0)
3 (27.3) 1 (9.1) 7 (63.6) 11 (100.0)
1 (20) 1 (20) 3 (60) 5 (100.0)
6 (46.1) 5 (38.5) 0 (0.0) 2 (15.4) 13 (100.0)
2 (22.2) 4 (44.5) 1 (11.1) 2 (22.2) 9 (100.0)
3 (60.0) 1 (20.0) 0 (0.0) 1 (20.0) 5 (100)
* Significant at P ⬍ 0.05 level. A 2 ⫻ 3 chi-square analysis (providers 1-3 by “Reason for change” [yes/no]) was run for the first three visits in which dose delivery mode was changed. “Other providers” were excluded from analyses. Abbreviation: ITB ⫽ Intrathecal baclofen
dosing changes made at change 1 was due to predictable daily tone fluctuation, there was not a significant difference across the three providers. Lastly, at change 3 the main clinical reasons for switching patients back to complex dosing was to prevent predictable daily tone fluctuations. The proportion changed for this reason was similar for all providers. Overall, management of predictable tone fluctuations was the most frequent reason for changes from simple to complex intrathecal baclofen dose delivery method. The providers described several potential reasons for changing to complex dosing from simple continuous dosing. Providers 1 and 2 (the two physicians) noted that they consider changing to complex dosing when the total daily dose has continued to climb in an effort to achieve control of tone but the side effects of sedation or impaired trunk control have become a limiting factor. All providers consider changing to complex dosing when an individual has experienced a suspected problem with the delivery of intrathecal baclofen (pump or catheter related) and have had a positive response to a programmed bolus of intrathecal baclofen. Also, all would consider change from simple continuous dosing to complex dosing if there were predictable variations in tone during the course of the day. All providers program the changes in this case 1-2 hours before the anticipated need, to allow time for the delay noted in clinical response. To minimize the total daily dose in individuals with relatively low trunk tone and high extremity tone, all providers report that they use boluses with low doses in between the boluses. For these patients, the boluses were delivered at set intervals throughout the course of the day, usually starting with 3-4 evenly spaced
boluses in 24 hours. The nurse practitioner also reports using complex dosing for individuals who tend to assume extensor postures. Twenty-two individuals had complications related to complex dose therapy; five had 3 events and four had 2 events. There were 14 episodes of excessive tone reduction, 6 with sedation, 5 with nausea, 4 with constipation or decreased bowel motility, 3 with urinary retention, and 1 each with dizziness, depression, and stress incontinence. None were serious and all resolved with a dose adjustment. Illustrative Case Examples Case 1 is a 27-year-old woman with mixed tone quadriparetic cerebral palsy. She can communicate verbally, provide history, and use a power wheelchair for her mobility. She presented at the clinic with signs and symptoms of intrathecal baclofen withdrawal, including rapidly increasing tone, spasms, tingling and itching. She was on 635 g/24 hours. In the clinic, her pump was programmed to deliver a bolus of 100 g over 15 minutes, and within 30-60 minutes of completion of the bolus, her tone began to improve and she felt more comfortable. To keep her total daily dose nearly the same but deliver boluses periodically, her pump was reprogrammed to provide a 68-g bolus over 15 minutes followed by 13 g/hour for 4 hours and 33 minutes and to repeat these two steps for a total of five boluses in 24 hours, delivering a total of 635.75 g/24 hours. Her signs and symptoms of intrathecal baclofen underdelivery resolved on the same total daily dose of intrathecal baclofen that she had been
Krach et al: Complex Dosing for Intrathecal Baclofen 357
on at the time of her presentation with intrathecal baclofen withdrawal. Case 2 is a boy, 10 years 11 months old, with quadriparetic cerebral palsy with mixed muscle tone and an average Ashworth score of 3 and impaired trunk control. His daily intrathecal baclofen dose was 150 g/day. His pump was reprogrammed to provide 20-g boluses every 12 hours, with a rate of 4 g/hour in between, resulting in a total daily dose of 132 g. Subsequently, trunk control improved and his average Ashworth score was 2. Ashworth scores were decreased with a smaller total daily dose of intrathecal baclofen. Case 3 is a boy, 5 years 3 months old, with combined spasticity and dystonia. Because of a desire to minimize the total daily dose of intrathecal baclofen, his programming was changed so that he would receive 50-g boluses with a low rate in between while awake and a continuous rate at night. After the change, parents noted increased ease of applying and improved tolerance of orthoses and improved sleep. While on simple continuous dosing, he received 543.2 g/day and had an Ashworth score of 3.7. On his complex dosing, he received 582.9 g/day and had an Ashworth score of 2.7. If he had been maintained on simple continuous dosing, his dose would have been increased by at least 10% and therefore would have been higher than he actually received on complex dosing. Discussion Half of those in the present study were on complex (flex) dosing mode at some point during the follow-up period. This is very similar to the findings of Rawlins [12] in her retrospective review of 50 patients receiving intrathecal baclofen at her center. At Gillette Children’s Specialty Healthcare (the study institution), all individuals are started on simple continuous dosing. The mean daily baclofen dose was higher in the complex dosing group. This is consistent with the report of providers 1 and 2, that they tend to change to complex dosing when they are not seeing the desired clinical effect with simple continuous dosing. Lower Ashworth scores were sometimes noted when delivering intrathecal baclofen as periodic boluses with a low hourly rate between the boluses without changing the total daily intrathecal baclofen dose or with small changes (as illustrated by the case examples). This suggests that for some individuals boluses are more effective in lowering hypertonicity. This is consistent with the prolonged effect of an intrathecal baclofen bolus reported by Baguley et al. [14]. Historically, one of the first reasons for trying complex programming with boluses at Gillette was feedback from individuals that, although they had an improvement in their muscle tone after intrathecal baclofen pump implantation, they did not feel as good as when they had received their trial bolus dose. This corresponds to our category “optimize intrathecal baclofen effect.” We hypothesize that a bolus causes flooding of receptors and improved
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tone reduction. Concern has been expressed that chronic intrathecal baclofen exposure could result in downregulation of receptors and tachyphylaxis [14-17]. Bolus dose programming might decrease that occurrence. Flexibility of dosing schedules for intrathecal baclofen infusion is useful both for long- and short-term situations, as demonstrated by the three illustrative cases presented here. Half of those in the present series received complex dosing at some point. The clinical response to a programmed bolus for an individual with intrathecal baclofen withdrawal can provide helpful information and may reduce symptoms of withdrawal. Some individuals have predictable daily changes in their motor tone, and higher baclofen doses at times of increased tone would seem logical. Others had a somewhat opposite pattern and benefited from periodic dose decreases. Although excluded from the present study, changes in dosing mode were needed postoperatively, or during suspected catheter malfunction. This was due to programming limitations that would not allow for programming a bolus to refill the catheter and pump tubing and then resume the complex dosing mode. Newer pumps and software now allow for this to be accomplished, eliminating this common reason for programming change. Complications attributed to complex dosing schedules were minimal and primarily occurred during or immediately after increased rate of intrathecal baclofen delivery. The overall frequency of this type of dose-related complication was within the range of what has been previously reported in the literature [2,3,5,11,18,19]. It was surprising to find that the use of complex dosing schedules appears to depend more on the decisions and opinions of the provider than on identifiable patient characteristics such as baseline tone or diagnosis. This retrospective study could not establish whether the different providers responded in a consistent way to reported signs and symptoms. The observation that the provider with the longest experience in managing intrathecal baclofen pump patients had the highest percentage of patients receiving complex dosing suggests that increasing clinical experience was influential in the decision to use complex dosing. The present study has a number of limitations. This is a retrospective study, and because subjects were not assigned to a treatment schedule and stratified by baseline tone scores it is impossible to comment on the clinical efficacy of complex dosing in achieving the goals of patient and clinician. We are contemplating a design for a study to address the use of these methods of dosing on a prospective basis. Overall, complex dosing was generally well tolerated, and many subjects continue to be on such schedules. There appear to be benefits to the use of this type of programming for some individuals. Support for manuscript preparation was provided by Medtronic, Inc.
References [1] Matthews DJ, Wilson P. Cerebral palsy. In: Molnar GE, Alexander MA, editors. Pediatric rehabilitation, 3rd ed. Philadelphia: Hanley & Belfus, 1999:193-217. [2] Albright AL, Barron WB, Fasick PP, Polinko P, Janosky J. Continuous intrathecal baclofen infusion for spasticity of cerebral origin. JAMA 1993;270:2475-7. [3] Albright AL, Gilmartin R, Swift D, Krach LE, Ivanhoe CB, McLaughlin JF. Long-term intrathecal baclofen therapy for severe spasticity of cerebral origin. J Neurosurg 2003;98:291-5. [4] Albright AL, Awaad Y, Muhonen M, et al. Performance and complications associated with the synchromed 10-mL infusion pump for intrathecal baclofen administration in children. J Neurosurg 2004;101(1 Suppl):64-8. [5] Armstrong RW, Steinbok P, Cochrane DD, Kube SD, Fife SE, Farrell K. Intrathecally administered baclofen for treatment of children with spasticity of cerebral origin. J Neurosurg 1997;87:409-14. [6] Butler C, Campbell S. Evidence of the effects of intrathecal baclofen for spastic and dystonic cerebral palsy. Dev Med Child Neurol 2000;42:634-45. [7] Campbell SK, Almeida GL, Penn RD, Corcos DM. The effects of intrathecally administered baclofen on function in patients with spasticity. Phys Ther 1995;75:352-62. [8] Gilmartin R, Bruce D, Storrs B, et al. Intrathecal baclofen for management of spastic cerebral palsy: multicenter trial. J Child Neurol 2000;15:71-7. [9] Krach LE. Pharmacotherapy of spasticity: oral medications and intrathecal baclofen. J Child Neurol 2001;16:31-6.
[10] Krach LE, Kriel RL, Gilmartin RC, et al. Hip status in cerebral palsy after on year of continuous intrathecal baclofen infusion. Pediatr Neurol 2004;30:163-8. [11] Stempien L, Tsai T. Intrathecal baclofen pump use for spasticity: a clinical survey. Am J Phys Med Rehabil 2000;79:536-41. [12] Rawlins PK. Intrathecal baclofen therapy over 10 years. J Neurosci Nurs 2004;36:322-7. [13] Ridley B, Rawlins PK. Intrathecal baclofen therapy: ten steps toward best practice. J Neurosci Nurs 2006;38:72-82. [14] Baguley IJ, Bailey KM, Slewa-Younan S. Prolonged antispasticity effects of bolus intrathecal baclofen. Brain Inj 2005;19: 545-8. [15] Ashworth B. Preliminary trial of carisoprodol in multiple sclerosis. Practitioner 1964;192:540-2. [16] Lee K-C, Carson L, Kinnin E, Patterson V. The Ashworth Scale: a reliable and reproducible method of measuring spasticity. J Neurol Rehabil 1989;3:205-9. [17] Meythaler JM, Guin-Renfroe S, Grabb P, Hadley MN. Longterm continuously infused intrathecal baclofen for spastic-dystonic hypertonia in traumatic brain injury: 1-year experience. Arch Phys Med Rehabil 1999;80:13-9. [18] Plassat R, Berbe BP, Menei P, Menegalli D, Mathe JF, Richard I. Treatment of spasticity with intrathecal baclofen administration: long-term follow-up, review of 40 patients. Spinal Cord 2004;42:686-93. [19] Krach LE, Kriel RL, Gilmartin R, et al. GMFM 1 year after continuous intrathecal baclofen infusion. Pediatr Rehabil 2005;8: 207-13.
Krach et al: Complex Dosing for Intrathecal Baclofen 359
pump system that is widely used allows the option of programming the pump to deliver medication at a constant or variable rate. Although this feature allowing for variable rate of delivery has been available for several years and has been discussed at meetings, there have been few journal publications describing clinical experience using it. In a retrospective review of 50 patients receiving intrathecal baclofen, Rawlins [12] reported that this variable rate of delivery mode was used in 54% of patients and was the most common infusion mode in individuals with cerebral palsy. However, clinical rationale for its use was noted only for treatment of nighttime spasms in individuals with multiple sclerosis [12]. A summary of a consensus conference discussed the use of complex programming options for variations in muscle tone during the patient’s typical 24 hour day [13]. A recent publication reported prolonged spasticity reduction with a single bolus of intrathecal baclofen [14]. The question arises whether this prolonged effect could be used clinically with those chronically receiving intrathecal baclofen. The objective of the present study was to understand the clinical reasons for changes from simple continuous to complex (flex) dosing for spasticity reduction in individuals receiving continuous infusions of intrathecal baclofen by programmable pump. Factors such as patient demographics, clinical diagnosis, degree of spasticity, and provider were considered. Also, we provide illustrative case examples. Methods
Introduction Increased muscle tone is found in most persons with cerebral palsy [1]. Continuous intrathecal baclofen infusion is effective in reducing muscle tone of cerebral origin such as occurs in persons with cerebral palsy [2-11]. The
From *Pediatric Rehabilitation Medicine at †Gillette Children’s Specialty Healthcare and ‡Pediatrics and Neurology at Hennepin County Medical Center, St. Paul, Minnesota.
354
PEDIATRIC NEUROLOGY
Vol. 37 No. 5
This retrospective descriptive study was conducted at Gillette Children’s Specialty Healthcare, a regional, multispecialty pediatric center in the Midwestern United States. Subjects in the present study represent a non-randomized, consecutive case series of children and adults who underwent pump implantation after January 1, 1999, and had at least 1 year of continuous treatment with intrathecal baclofen and follow-up at
Communications should be addressed to: Dr. Krach; Pediatric Rehabilitation Medicine; Gillette Children’s Specialty Healthcare; 200 East University Avenue; St. Paul, MN 55101. E-mail: [email protected] Received March 8, 2007; accepted June 27, 2007.
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2007.06.020 ● 0887-8994/07/$—see front matter
this institution. Approval to conduct the study was obtained from the Institutional Review Board at the University of Minnesota. Electronic databases were queried to identify subjects and medical records were reviewed. Data were collected for each participant at the time of intrathecal baclofen pump implantation and at each subsequent follow-up visit in which a change in dose delivery method was made. Information obtained included items such as gender, primary diagnosis, and managing clinician. Other variables obtained were: intrathecal baclofen dose and mode of delivery (simple continuous or complex), duration of time with pump, number of changes back and forth from simple continuous to complex dosing methods, clinical reasons for infusion delivery mode change, length of follow-up, and Ashworth Scale scores at baseline and any change in delivery mode. A single bolus to refill the catheter after concentration change, catheter aspiration, or as a method to evaluate symptoms of underdelivery were not considered complex infusion methods. For individuals previously tried on complex dosing who were on simple continuous dosing at the most recent follow-up (N ⫽ 29) the average Ashworth Scale scores at the first switch back from complex dosing to simple continuous were considered “most recent.” Individuals missing Ashworth scores at one or more visits were excluded from the analysis. The Ashworth Scale was used to grade tone and is defined as follows: 1 ⫽ normal, 2 ⫽ catch with rapid movement of a joint, 3 ⫽ resistance throughout the range of movement which, however, is readily attained, 4 ⫽ considerable increase in tone with difficult passive movement, 5 ⫽ rigidity [15,16]. Bilateral scores were included for hip abduction, hip adduction, knee extension, knee flexion, ankle dorsiflexion, and plantar flexion. In addition to Ashworth scores, the clinical reasons why providers chose to switch the dose infusion method were determined. The reasons for change in dose infusion method from simple continuous to complex dosing were then grouped into one of the following categories: (1) variation of the participant’s tone at predictable times of the day; (2) bolus infusions on a daily schedule to optimize intrathecal baclofen effect; and (3) manage signs of underdelivery. Changes made due to programming limitations (catheter/pump replacement surgery, pump study, catheter aspiration, indium scan/dye study, or dose concentration change) were excluded from the present study. For the majority of the implanted pumps, the software allowed only for simple continuous dosing at the time of surgery or concentration change, because of the need to allow time for the fluid in the catheter and pump internal tubing to be replaced by the new concentration. Newer pumps and software no longer have this limitation. Reasons for change in intrathecal baclofen delivery dosing method from complex back to simple continuous dosing fell into the following categories: (1) complex dosing did not produce the desired effect; (2) the individual was experiencing excessive tone fluctuation. Information about complications and intrathecal baclofen pump explantations were obtained for individuals in the complex dosing group who were tried on complex dosing schedules three or more times during the follow-up period. This was done in order to ascertain the frequency of known dose-related complications in this subgroup with more experience on complex dosing schedules. After data analysis, providers 1 to 3 were asked under what circumstances they typically consider changing to complex dosing, for what circumstances they deliver different doses in 24 hours, and under what circumstances they program to deliver boluses with low doses in between. Providers were also invited to share general comments.
Participants Participants were at least 3 years of age, had sufficient body mass to accommodate an intrathecal baclofen pump, had pump placement after January 1, 1999, and had been followed for continuous intrathecal baclofen infusion management at Gillette Children’s Specialty Healthcare for at least 1 year after implantation.
To be considered for intrathecal baclofen pump implantation at Gillette, individuals must have clinically significant tone with a mean Ashworth Scale score of at least 3 in the legs and goals for tone reduction. This tonal abnormality could be spasticity, dystonia, or a mixture of the two. Individuals were excluded from participation if they were not managed by Gillette clinicians, were not followed for at least 1 year, or had a degenerative disorder or spinal cord injury as an etiology for increased tone. Those included in the study had static encephalopathy from any of the causes of cerebral palsy or after later events such as traumatic brain injury or anoxic encephalopathy. Three of the individuals who met inclusion criteria and were in the complex dosing group were selected by the first author as illustrative case examples.
Providers A total of six physicians and two nurse practitioners provided intrathecal baclofen pump management for the subjects in this series who received complex dosing. Only two physicians and one nurse practitioner managed the pumps for 93% of these individuals. Therefore, when evaluating differences related to provider only the top three providers were included in the analysis. For all other analyses, the entire cohort was included.
Statistical Analysis SPSS software version 13.0 was used for all statistical analyses (SPSS, Chicago, IL). In addition to descriptive statistics, analyses of variance (denoted with an F statistic), t tests, Pearson’s correlations, and chisquare tests were run. The primary focus of the analyses is the 82 individuals who were on complex dosing schedules. A series of 2 ⫻ 3 chi-square analyses (each possible reason for change ⫽ yes/no by three providers) were run in order to determine whether or not certain reasons for change were more common by provider. Each “reason for change” variable (e.g., predictable daily tone variation) was considered binomial (yes/no).
Results Sample Characteristics In all, 164 children and adults met the inclusion criteria; 95 were male (60%) and 69 were female (40%). Ninety percent had cerebral palsy; the remainder had static encephalopathy due to postnatal insults. The mean baseline Ashworth score was 3.7 (standard deviation, 0.7). All were started on simple continuous dosing at time of pump implantation. Ages at time of most recent follow-up visit ranged from 6 to 45 years with mean age of 18 years and 0 months (median, 15 years and 8 months; standard deviation, 8 years and 0 months). Individuals had been receiving intrathecal baclofen from 1 to 7 years with mean of 4.3 years (median, 4.5; standard deviation, 1.6) (Table 1). Eighty-two (50%) of the individuals were tried on complex dosing at some point during the follow-up period. Individuals in the complex dosing group had been tried on complex dosing anywhere from one to six times (M, 2.1; standard deviation, 1.2). The reasons for this high number of changes included the programming limitations noted previously. When individuals on complex dosing required medication concentration changes, catheter replacement, catheter aspiration, or other activities that required refilling the catheter with a concentration of medication differ-
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Table 1.
Participant characteristics by dosing delivery method
Age at time of current dose, years, mean (SD) Cerebral palsy, no. (%) Baseline leg Ashworth score, mean (SD) ITB dose at chart review, g/day, mean/median (SD)* Duration of follow-up, years, mean (SD)†
Simple (N ⴝ 82)
Complex (N ⴝ 82)
All Subjects (N ⴝ 164)
17.5 (8.7) 74 (90.2) 3.7 (0.7) 211.9/185.0 (122.7) 3.9 (1.6)
18.2 (7.5) 74 (90.2) 3.7 (0.6) 429.3/310.1 (393.2) 4.8 (1.4)
18.0 (8.0) 148 (90.2) 3.7 (0.7) 320.1/223.1 (310.3) 4.3 (1.6)
* Mean intrathecal baclofen dose was significantly higher in the complex dosing group (t ⫽ ⫺4.8, P ⬍ 001). Mean number of years of follow-up was significantly higher in the complex dosing group (t ⫽ ⫺3.6, P ⬍ 0.001).
†
Abbreviations: ITB ⫽ Intrathecal baclofen SD ⫽ Standard deviation
ent than what was present in the catheter, simple continuous dosing was required. Daily dose differed significantly between the simple continuous dosing group (mean, 211.9; standard deviation, 122.9) and the complex dosing group (mean, 429.3; standard deviation, 393.2) (t ⫽ ⫺4.8, P ⬍ 0.001). Duration of intrathecal baclofen therapy was significantly longer in the complex dosing group (mean, 4.8; standard deviation, 1.4) than the simple continuous dosing group (mean, 3.9; standard deviation, 1.6) (t ⫽ ⫺3.6, P ⬍ 0.001). Reasons for Change in Dose Infusion Method The most frequent clinical reason for initial change to complex dosing was to treat predictable daily muscle tone variation (N ⫽ 35, 42.7%), the second was to optimize intrathecal baclofen effect (N ⫽ 28, 34.1%). Of the 82 individuals on complex dosing, 23 (28%) were returned to simple continuous dosing for programming limitation reasons. The most common clinical reason for the second change to complex dosing was to manage predictable tone fluctuations (13/29, 45%). Ashworth Scores Average bilateral Ashworth scores were reported at pump implantation and most recent follow-up for 137 individuals. There was a significant improvement in mean average scores from 3.7 to 2.2 (t ⫽ 20.3, P ⬍ 0.001). However, there was no significant difference in the rate of average score improvement between simple continuous dosing vs complex dosing groups. Ashworth scores for the complex dosing group were collected at visits when a dose infusion method change was made. For the complex dosing group, for 67 (82%) individuals the average Ashworth scores were documented at (1) intrathecal baclofen pump implantation, (2) the first attempt on complex dosing, and (3) the most recent followup. A single-group repeated-measures analysis of variance was conducted and there was not a significant Ashworth score difference from the time of first attempt on complex
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dosing to the most recent follow-up (mean, 2.3 to 2.2). There were, however, significant improvements in scores from the time of intrathecal baclofen pump implantation to both the first attempt on complex dosing and the most recent follow-up visit (F ⫽ 136.7, P ⬍ 0.001). Provider Differences Three providers (Providers 1, 2, and 3) made the majority of dose delivery method decisions (Table 2). Providers 1 and 2 were physicians and provider 3 was a nurse practitioner. Each had several years of experience with intrathecal baclofen pump management. There were differences among the three providers with regard to decisions to change from simple continuous to complex dosing. Provider 1, who had been following individuals for a significantly longer period of time than had provider 3 (F ⫽ 5.0, P ⬍ 0.01), also started patients on complex dosing schedules significantly sooner than provider 3 (F ⫽ 5.5, P ⬍ 0.01). Mean baseline Ashworth scores were the same for participants treated by these three providers. In order to examine whether or not reasons for changing individuals from simple continuous dosing to complex dosing (or vice versa) differed by provider, the initial three visits in which a dose infusion method change was made were examined. The clinic visits of focus were (1) the first change from simple continuous to complex dosing, (2) the first change from complex back to simple continuous dosing, and (3) the second change from simple continuous to complex dosing. For providers 1, 2, and 3 there were 76 changes from simple continuous dosing to complex dosing, of which 18 cases changed back to simple continuous dosing (Table 2). Providers 1, 2, and 3 changed more back to complex dosing, because of assuming care from some of the other providers. The most common reasons why providers changed delivery method are shown in Table 2. At change 1, provider 1 more frequently decided to change intrathecal baclofen dosing delivery method to optimize the effect of intrathecal baclofen than did the other two providers (2 ⫽ 8.6, P ⫽ 0.01). While the most common reason overall for
Table 2.
Reasons for change in dose delivery method by provider
Change 1. Simple to complex Predictable daily tone variation Optimize ITB effect with boluses* Manage signs of underdelivery Other Total Change 2. Complex to simple Complex dosing ineffective Excessive tone fluctuation Other Total Change 3. Simple to complex Predictable daily tone variation Optimize ITB effect with boluses Manage signs of underdelivery Other Total
Provider 1
Cases, no. (%) Provider 2
Provider 3
10 (35.7) 15 (53.6) 1 (3.6) 2 (7.1) 28 (100.0)
12 (42.9) 6 (21.4) 1 (3.6) 9 (32.1) 28 (100.0)
12 (60.0) 4 (20.0) 0 (0.0) 4 (20.0) 20 (100.0)
1 (50) 0 (0.0) 1 (50) 2 (100.0)
3 (27.3) 1 (9.1) 7 (63.6) 11 (100.0)
1 (20) 1 (20) 3 (60) 5 (100.0)
6 (46.1) 5 (38.5) 0 (0.0) 2 (15.4) 13 (100.0)
2 (22.2) 4 (44.5) 1 (11.1) 2 (22.2) 9 (100.0)
3 (60.0) 1 (20.0) 0 (0.0) 1 (20.0) 5 (100)
* Significant at P ⬍ 0.05 level. A 2 ⫻ 3 chi-square analysis (providers 1-3 by “Reason for change” [yes/no]) was run for the first three visits in which dose delivery mode was changed. “Other providers” were excluded from analyses. Abbreviation: ITB ⫽ Intrathecal baclofen
dosing changes made at change 1 was due to predictable daily tone fluctuation, there was not a significant difference across the three providers. Lastly, at change 3 the main clinical reasons for switching patients back to complex dosing was to prevent predictable daily tone fluctuations. The proportion changed for this reason was similar for all providers. Overall, management of predictable tone fluctuations was the most frequent reason for changes from simple to complex intrathecal baclofen dose delivery method. The providers described several potential reasons for changing to complex dosing from simple continuous dosing. Providers 1 and 2 (the two physicians) noted that they consider changing to complex dosing when the total daily dose has continued to climb in an effort to achieve control of tone but the side effects of sedation or impaired trunk control have become a limiting factor. All providers consider changing to complex dosing when an individual has experienced a suspected problem with the delivery of intrathecal baclofen (pump or catheter related) and have had a positive response to a programmed bolus of intrathecal baclofen. Also, all would consider change from simple continuous dosing to complex dosing if there were predictable variations in tone during the course of the day. All providers program the changes in this case 1-2 hours before the anticipated need, to allow time for the delay noted in clinical response. To minimize the total daily dose in individuals with relatively low trunk tone and high extremity tone, all providers report that they use boluses with low doses in between the boluses. For these patients, the boluses were delivered at set intervals throughout the course of the day, usually starting with 3-4 evenly spaced
boluses in 24 hours. The nurse practitioner also reports using complex dosing for individuals who tend to assume extensor postures. Twenty-two individuals had complications related to complex dose therapy; five had 3 events and four had 2 events. There were 14 episodes of excessive tone reduction, 6 with sedation, 5 with nausea, 4 with constipation or decreased bowel motility, 3 with urinary retention, and 1 each with dizziness, depression, and stress incontinence. None were serious and all resolved with a dose adjustment. Illustrative Case Examples Case 1 is a 27-year-old woman with mixed tone quadriparetic cerebral palsy. She can communicate verbally, provide history, and use a power wheelchair for her mobility. She presented at the clinic with signs and symptoms of intrathecal baclofen withdrawal, including rapidly increasing tone, spasms, tingling and itching. She was on 635 g/24 hours. In the clinic, her pump was programmed to deliver a bolus of 100 g over 15 minutes, and within 30-60 minutes of completion of the bolus, her tone began to improve and she felt more comfortable. To keep her total daily dose nearly the same but deliver boluses periodically, her pump was reprogrammed to provide a 68-g bolus over 15 minutes followed by 13 g/hour for 4 hours and 33 minutes and to repeat these two steps for a total of five boluses in 24 hours, delivering a total of 635.75 g/24 hours. Her signs and symptoms of intrathecal baclofen underdelivery resolved on the same total daily dose of intrathecal baclofen that she had been
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on at the time of her presentation with intrathecal baclofen withdrawal. Case 2 is a boy, 10 years 11 months old, with quadriparetic cerebral palsy with mixed muscle tone and an average Ashworth score of 3 and impaired trunk control. His daily intrathecal baclofen dose was 150 g/day. His pump was reprogrammed to provide 20-g boluses every 12 hours, with a rate of 4 g/hour in between, resulting in a total daily dose of 132 g. Subsequently, trunk control improved and his average Ashworth score was 2. Ashworth scores were decreased with a smaller total daily dose of intrathecal baclofen. Case 3 is a boy, 5 years 3 months old, with combined spasticity and dystonia. Because of a desire to minimize the total daily dose of intrathecal baclofen, his programming was changed so that he would receive 50-g boluses with a low rate in between while awake and a continuous rate at night. After the change, parents noted increased ease of applying and improved tolerance of orthoses and improved sleep. While on simple continuous dosing, he received 543.2 g/day and had an Ashworth score of 3.7. On his complex dosing, he received 582.9 g/day and had an Ashworth score of 2.7. If he had been maintained on simple continuous dosing, his dose would have been increased by at least 10% and therefore would have been higher than he actually received on complex dosing. Discussion Half of those in the present study were on complex (flex) dosing mode at some point during the follow-up period. This is very similar to the findings of Rawlins [12] in her retrospective review of 50 patients receiving intrathecal baclofen at her center. At Gillette Children’s Specialty Healthcare (the study institution), all individuals are started on simple continuous dosing. The mean daily baclofen dose was higher in the complex dosing group. This is consistent with the report of providers 1 and 2, that they tend to change to complex dosing when they are not seeing the desired clinical effect with simple continuous dosing. Lower Ashworth scores were sometimes noted when delivering intrathecal baclofen as periodic boluses with a low hourly rate between the boluses without changing the total daily intrathecal baclofen dose or with small changes (as illustrated by the case examples). This suggests that for some individuals boluses are more effective in lowering hypertonicity. This is consistent with the prolonged effect of an intrathecal baclofen bolus reported by Baguley et al. [14]. Historically, one of the first reasons for trying complex programming with boluses at Gillette was feedback from individuals that, although they had an improvement in their muscle tone after intrathecal baclofen pump implantation, they did not feel as good as when they had received their trial bolus dose. This corresponds to our category “optimize intrathecal baclofen effect.” We hypothesize that a bolus causes flooding of receptors and improved
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tone reduction. Concern has been expressed that chronic intrathecal baclofen exposure could result in downregulation of receptors and tachyphylaxis [14-17]. Bolus dose programming might decrease that occurrence. Flexibility of dosing schedules for intrathecal baclofen infusion is useful both for long- and short-term situations, as demonstrated by the three illustrative cases presented here. Half of those in the present series received complex dosing at some point. The clinical response to a programmed bolus for an individual with intrathecal baclofen withdrawal can provide helpful information and may reduce symptoms of withdrawal. Some individuals have predictable daily changes in their motor tone, and higher baclofen doses at times of increased tone would seem logical. Others had a somewhat opposite pattern and benefited from periodic dose decreases. Although excluded from the present study, changes in dosing mode were needed postoperatively, or during suspected catheter malfunction. This was due to programming limitations that would not allow for programming a bolus to refill the catheter and pump tubing and then resume the complex dosing mode. Newer pumps and software now allow for this to be accomplished, eliminating this common reason for programming change. Complications attributed to complex dosing schedules were minimal and primarily occurred during or immediately after increased rate of intrathecal baclofen delivery. The overall frequency of this type of dose-related complication was within the range of what has been previously reported in the literature [2,3,5,11,18,19]. It was surprising to find that the use of complex dosing schedules appears to depend more on the decisions and opinions of the provider than on identifiable patient characteristics such as baseline tone or diagnosis. This retrospective study could not establish whether the different providers responded in a consistent way to reported signs and symptoms. The observation that the provider with the longest experience in managing intrathecal baclofen pump patients had the highest percentage of patients receiving complex dosing suggests that increasing clinical experience was influential in the decision to use complex dosing. The present study has a number of limitations. This is a retrospective study, and because subjects were not assigned to a treatment schedule and stratified by baseline tone scores it is impossible to comment on the clinical efficacy of complex dosing in achieving the goals of patient and clinician. We are contemplating a design for a study to address the use of these methods of dosing on a prospective basis. Overall, complex dosing was generally well tolerated, and many subjects continue to be on such schedules. There appear to be benefits to the use of this type of programming for some individuals. Support for manuscript preparation was provided by Medtronic, Inc.
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