Introduction
Spasticity is a common complication after an injury or disease that affects the central nervous system (CNS). Examples of such conditions include spinal cord injury (SCI), multiple sclerosis (MS), cerebral palsy (CP), and acquired brain injury (ABI) including stroke (Stevenson, 2010). The pathophysiology of spasticity is complex. It involves several descending tracts that disrupt the pathways that regulate activity in alpha motor neurons, thereby creating an imbalance in the inhibitory and facilitatory regulation between the CNS and the muscles where lack of inhibition dominates. The most important inhibitory neurotransmitter in the CNS is [gamma]-aminobutyric acid (GABA). Baclofen serves as a GABA-B agonist (Ertzgaard et al., 2017; Mukherjee & Chakravarty, 2010; Trompetto et al., 2014).
Intrathecal baclofen (ITB) is used in patients with spasticity that interferes with comfort, active or passive motion, activities of daily living, mobility, positioning, or caregiver assistance (Saulino et al., 2016). The term disabling spasticity is usually used when spasticity is unduly troublesome to patients or caregivers and when it significantly interferes with daily life (Lundstrom et al., 2008; Saulino et al., 2016). Intrathecal baclofen is indicated to relieve the negative consequences of disabling spasticity and increase quality of life. It is considered an effective treatment for spasticity both from a short- and a long-term perspective (Kawano et al., 2018; Lee et al., 2018; Mathur et al., 2014; Natale et al., 2016; Sammaraiee et al., 2019). Intrathecal baclofen treatment is often lifelong and includes regular visits for refills and dose adjustments.
Reported complications of ITB mostly concern catheter-related issues, infection, leakage of cerebrospinal fluid, and rotation of the pump. As a consequence, both patients and healthcare professionals should be educated about the signs of potential adverse effects because of over- and/or under-dosing of ITB treatment (Draulans et al., 2013; Saulino et al., 2016).
Before treatment begins, a test is used to verify an adequate response from ITB, and the result from the test is used as a guideline for the initial dosing. The start dose at pump implantation usually ranges between the initial test dose and double the test dose, depending on the response and its duration during the test. Normally, with a test dose of 50 [mu]g, the start dose is set at 100 [mu]g/day, but with a prolonged test response or negative reactions to the test, such as effects on vital signs or excessive deterioration of function, the start dose is lower (Boster et al., 2016). The goal is to achieve sufficient reduction in spasticity as quickly and safely as possible. This requires multiple dose adjustments based on the patient's condition, symptoms, and response to treatment (Boster et al., 2016). Dosage adjustment occurs with close collaboration with the patient, family, and physician/nurse. The dose is increased until sufficient spasticity relief is achieved. A reason for a potential decrease in dosage could be, for example, impaired posture or impaired ability to transfer. After titration of the initial dose, further dose adjustments are often required for at least 6-18 months (Heetla et al., 2009; McIntyre et al., 2014). The time to achieve a sufficient daily dose differs between patients with a higher dose taking a longer time to achieve. Thus, it is difficult in the early stage of treatment to predict the dose development pattern for each patient.
As rehabilitation professionals, the ability to address expectations is essential for patient satisfaction and to ensure efficiency of patient care (Gunnarsson & Samuelsson, 2015). Provision of accurate information, to include dosing adjustments, to patients and family is essential. To better understand differences in individual dose patterns, patterns can be analyzed over time. The aim of this study was to describe and analyze dosing patterns for patients with ITB treatment over time and to identify possible subgroups demonstrating diversity in patterns.
Methods
This study was part of a multicenter study, including data from six out of the seven main hospitals providing ITB treatment in Sweden. For more information about the larger study, see Gunnarsson et al., (2019). This part of the study focused on ITB dose development. Data were collected retrospectively from the medical records of the six hospitals included in the study.
Participants
The inclusion criteria for this study were patients aged >=18 years old who had been treated with ITB (SynchroMed by Medtronic) for at least 2 years (n = 81). No exclusion criteria were used. For all 81 patients, data on age, gender, diagnosis, date of surgery, complications with ITB treatment, and baclofen doses were collected from medical records.
Procedure
Ethical approval was obtained from the Regional Ethics Committee in Linkoping (Dnr 2014/312-31). The study was conducted according to the Declaration of Helsinki (World Medical Association, 1964). At each ITB department, a study coordinator, often a nurse, was responsible for collecting and storing the data. For each patient, the baclofen dose for every third month during the first 2 years of treatment, was identified retrospectively from the patient's medical record. All data were then pseudonymized and transferred to the main responsible nurse of the study (S. G.). Baclofen doses were collected at the end of 2014 in conjunction with the rest of the data for the multicenter study. Patients in this study began their treatment sometime between October 2010 - September 2012 and data were registered for the patient's first two years with ITB treatment.
Patients were initially grouped based on a visual analysis of ITB doses using Microsoft Excel 2010. Baclofen doses were recorded on the Excel spreadsheet for every third month, resulting in nine measuring points per patient. A one-line graph was developed for each patient, resulting in a figure with 81 line graphs. By carefully observing the graphs, pattern similarities could be discerned, and a structure for possible subgroupings was identified. Based on these observations, the first grouping process was initiated. Patients with similar dose development patterns, that is, similarities between individual line graphs, were placed into four subgroups (see Figure 1 to follow this process). Thus, the initial analyses of the dosing patterns were carried out based on dose development only, without any predetermined criteria or other information regarding the patients.
The next step was to identify the dose criteria for these four subgroups based on variables of importance for dose development, such as dose increase/decrease and dose at 24 months. Through consensus discussions among the authors, five criteria were identified, based on the line graphs (Table 1). Using the Excel spreadsheet, the percentage change in dosage for each patient was calculated for every 3 months and compared with the previous dose. Measuring points were separated into two parts: dose changes up to 6 months and dose changes between 6 and 24 months. The rationale for this was to avoid confusing data of initial dose changes (0-6 months) based on local differences in how to define the initial dose. Graphs with dose fluctuations were examined further based on both percentage and absolute dose change.
Criteria for the different subgroups were further defined, and analyses from each patient's one-line graph were checked and rechecked for inclusion into one of the subgroups, where they best fit (Table 1). A decisive criterion for affiliation with Group 4 was determined, requiring a dose decrease for inclusion. If, at verification of the grouping, the same number of criteria applied for two or more dose groups, the final dose at 24 months was used for group affiliation.
To define the different groups by dosing patterns, the first author (S. G.) performed the preliminary subgrouping based on visual information from the line graphs and the nine measuring points, which was then reviewed. To further increase the trustworthiness of the whole process, the criteria and basis for the grouping of patients were evaluated and discussed by all authors until consensus was reached.
Statistics
Descriptive statistics for the median and interquartile range was used. In addition, the Mann-Whitney U test was used for pairwise comparison of baclofen dosing patterns at 24 months for the four subgroups. Changes in dosing over time were used as an indicator for dose stability. For each individual, these changes in baclofen dose over time were illustrated using the standard deviation for doses registered between 6 and 24 months. In addition, the average standard deviation for each individual dose group was calculated. Fisher's exact test, followed by pairwise comparisons, was used to compare the distribution of dosing groups between the five diagnoses: SCI, MS, CP, ABI and other. The chi-square test was used to compare gender distribution in the dosing groups, and the Mann-Whitney U test was used to compare differences in age.
An initial p value of .05 was adjusted for each type of statistical analysis according to Bonferroni correction. When Bonferroni correction is used to adjust for multiple comparisons, the initial level for accepted p value (p < .05) is divided by the number of comparisons made. This adjusted p value was used to determine accepted level of significance. The statistical analyses were done using IBM SPSS Statistics 25 and/or Microsoft Excel 2010.
Results
The patient group included 44 men and 37 women with an average age at the beginning of ITB treatment being 47 +/- 15.0 years (range: 18-73 years). There was no difference in the doses at 6 or 24 months with regard to gender (p = .097 vs. p = .492), and there was no relevant correlation regarding age (r = -.355 vs. r = -.379).
The analysis of baclofen dosing over time resulted in four different dosing pattern groups: Group 1, stable (n = 35); Group 2, slow increase (n = 17); Group 3, rapid increase (n = 22); and Group 4, fluctuating (n = 7; Figure 2). The stable group (Group 1) had the lowest reported dose at 24 months. In Groups 2 and 3, the dose increased over time; however, in Group 3, the increase was more rapid, and the end dose was higher at 24 months. The dosing pattern in Group 4 was defined as including both increases and decreases in the dose in a more irregular pattern. As described above, the time interval from the start of treatment up to 6 months was analyzed separately. In Group 1, 13 patients needed dose reduction between the start and 6 months, that is, the start dose was too high. In the other groups, this occurred in only one patient in Group 2.
The characteristics of the patients identified in the four dosing pattern groups are shown in Table 2. There was a difference in how the diagnoses were represented in the different dosing groups (p = .001). Significant differences in dose groups were found between patients with MS and SCI (p = .003) and patients with MS and CP (p < 0.001). There were more male patients in Group 3 compared with Group 2 (p = .034), but after adjusting the p value, this was not significant. Patients in Group 3 were younger than the patients in Group 1 (p = .001, adjusted p = .008).
Comparisons of the baclofen dose at 24 months among the subgroups showed a different dose distribution in all subgroups (p < .000). When comparing the subgroups pairwise, a significant (p < .000) difference was found for all pair comparisons, except for the comparison between Groups 3 and 4 (p = .181) and Groups 2 and 4 (p = .166). Changes in dose development over time was used as an indicator for dose stability/instability in registered doses between 6 and 24 months for each individual. The average standard deviation for each dosing group was calculated (Table 3).
Four of the seven patients (57%) in Group 4 reported complications. However, some complications were also documented in the other groups, although the incidence was much lower and involved seven patients in Group 1 (20%), five patients in Group 2 (29%), and four patients in Group 3 (18%). Reported complications were related to the catheter, rotation of the pump, leakage of cerebrospinal fluid, infections, skin irritations, or overdose. Of these complications, the ones associated with dose adjustments were catheter-related complications or overdose.
Discussion
The aim of this study was to describe and analyze dosing patterns for patients with ITB treatment over time and to identify possible subgroups demonstrating diversity in patterns.
Four different dosing pattern subgroups were identified as a result of the process. Patients included in Groups 1-3 had relatively homogeneous dose patterns within their group, whereas patients in Group 4 had a fluctuating pattern with marked variations and were thus more difficult to interpret. Because dose adjustments are based on the patient's condition, symptoms, and response to treatment (Boster et al., 2016), patients in Group 1 (stable) likely responded to the dose very quickly and showed good symptom relief. Patients in Group 2 (slow increase) most likely had quite a fast response as well, but with the need of several, small dose increases to relieve their symptoms. In Group 3 (rapid increase), the treatment probably did not have an early effect, and patients needed higher and more frequent dose increases for symptom relief. The results for patients in Group 4 were fluctuating. A possible explanation for this could be ITB-related complications, leading to dose adjustments in a more irregular pattern.
Complications were verified in several patients. Most of the patients in Group 4 would likely have fit into Groups 1, 2, or 3 if no complications or other adverse events had occurred. Reported complications in Group 4 were mostly catheter related, and one patient had a suspected ITB overdose, all of which affected the dose development. In Groups 1, 2, and 3, reported complications were rotation of the pump, infection, leakage of cerebrospinal fluid, and catheter-related issues. The reason why almost none of the complications in Groups 1-3 affected the dose seemed to be that complications were detected early and remedied quickly. The multiprofessional rehabilitation team include nursing professionals who have a central role and responsibility in evaluating early warning signs of complications and under/overdose to assure appropriate treatment for the patient.
The patients' diagnoses had a role in explaining possible differences in dosing patterns (Table 2). The diagnosis had an impact; however, it might not be the most relevant descriptor for grouping patients on dosing of ITB. No other variables than diagnosis, age, gender or complications were reported in this study. In Nordic countries, it is not a common practice to identify either race or ethnicity in participants without having a specific purpose.
In several studies, researchers have chosen to report daily doses or dose patterns stratified by diagnoses (Clearfield et al., 2016; Maneyapanda et al., 2017; Mathur et al., 2014). The results of this study partially explain some of the inconsistencies in ITB doses in relation to diagnoses between reported studies (Clearfield et al., 2016; Draulans et al., 2013; Saval & Chiodo, 2010). Lower doses for patients with MS and stroke compared with patients with SCI, ABI (traumatic and anoxic), and CP were reported (Clearfield et al., 2016). However, another study reported that during the first 2 years of treatment, there were no differences in doses between patients with MS and those with SCI (Draulans et al., 2013). In addition, no difference between cortical and spinal spasticity has been reported with regard to daily doses, mode of dosing, and dose changes (Saval & Chiodo, 2010).
Another study reported two variations in dosing groups: stable or fluctuating. The criterion for the fluctuating group was an increase of 100 [mu]g over 1 year, and the rest were classified in the stable group with an average daily dose of 230.6 [mu]g/day (50-450 [mu]g/day; Kawano et al., 2018). However, in this study, four subgroups were identified to explain the dose development for the entire sample. Furthermore, frequent increases of more than 10% were identified as an indicator of stability, which was then used to define the third criterion (Table 1).
Because the pathophysiology of spasticity is multifactorial and complex (Mukherjee & Chakravarty, 2010), it is understandable that patients respond differently to ITB treatment. Each lesion is unique; therefore, individual patients present different patterns of spasticity and consequences related to daily living. An assessment of optimal treatment effects needs to be done in collaboration with patients, family, and healthcare professionals and should include the degree of spasticity, as well as the attainment of treatment goals. As clinicians, we need to review existing dosing patterns to further develop clinical guidelines and thereby improve the quality of treatment. This information can better educate and illustrate treatment and dosing regimens for patients and their families. Thus, illustrations of dosing patterns as presented in Figure 2 could be used for explaining dose development over time and for discussions about patient expectations.
Data were gathered from six different hospitals. The departments in these hospitals represent the majority of ITB treatment units in Sweden and thus provided a representative sample of patients undergoing treatment with ITB. Having access to data from all patients at each department, fulfilling the inclusion criteria, increased the representativeness and the generalizability of the results.
Furthermore, baclofen doses were reported retrospectively, which should be viewed as a strength of the study, because participation in the study had no impact on deciding dose adjustments. Apart from ITB doses, no predetermined criteria for grouping existed during the analysis of the dose patterns; accordingly, the analysis was based on dose development exclusively, regardless of other information about the study group.
For the analyses, the measuring points were divided into two parts (start dose to dose up to 6 months and the dose between 6 and 24 months), and then the two periods were studied separately. This was done because the criterion for the start dose was possibly unclear, routines for managing patients after surgery differed between the hospitals, regarding length of hospital stay and the frequency of multiple initial dose changes. Even if a rationale existed for selecting a starting dose, in practice, it might differ between the six hospitals.
This study has some limitations. Additional data on ambulatory status, hemiplegic/paraplegic/quadriplegic, level of independence, degree of spasticity, flexible versus simple continuous programming, other medications, and, in some cases, catheter tip positioning are needed to better analyze and draw conclusions about the most relevant predictors for dosing patterns.
Furthermore, a longer time period would have been preferable for the analyses and description of dose development. Based on clinical experience and previous research (Heetla et al., 2009; McIntyre et al., 2014), a period of 24 months was chosen as an appropriate time for follow-up. The need for continuous dose changes has been reported to last for 18 months in general, followed by a period of dose stability (Heetla et al., 2009). However, it has been reported that patients with ABI require dose increases for a longer time (Maneyapanda et al., 2017). In this study, most patients with ABI (53%) were included in Group 1, the most stable group. Previous studies on patients with SCI have shown that, for some patients, a stable dose was not achieved until 5 years later and was set at a higher dose compared with patients with MS. In comparison, during the first 2 years of treatment, there was no difference between these two groups (Draulans et al., 2013). Our results are in agreement with Draulans et al.'s study, although patients with SCI were included in both Groups 1 and 3 (Table 2).
In conclusion, to the authors' best knowledge, this is the first study to identify and classify subgroups based on baclofen dosing patterns rather than stratifying by diagnosis. This subgrouping may serve as a pilot study with an aim to provide a guide for clinicians. Rehabilitation nurses and colleagues may use the four figures as illustrations of possible dose developments when educating patients, family, and caregivers. The figures illustrate how dose developments differ and how difficult it is to estimate beforehand a patient's optimal dose and how long it will take to attain it. Results from this study could serve as a starting point for future studies aimed at defining phenotype profiles in a longitudinal study. In addition, information on ambulatory status, degree of spasticity, and independence should be included for future studies.
Key Practice Points
* Intrathecal baclofen dose development is difficult to predict.
* Intrathecal baclofen dose development seems to follow different dose patterns.
* Diagnosis is not the only factor associated with dose development.
* For nurses and colleagues working with intrathecal baclofen treatment, study findings regarding differences in dose patterns can be used to inform future patients and family about possible dose development during the first 2 years of treatment.
Conflict of Interest
Stina Gunnarsson reports payment for lectures and speaking services from Medtronic. Per Ertzgaard reports payment for lectures, speaking services, and consultancy from Medtronic, IBSEN, and Allergan. No other conflicts of interest to report.
Funding
Funding for this study was received from the County Council of Ostergotland, the Medical Research Council of Southeast Sweden, and the Swedish Association of Persons With Neurological Disabilities.
Acknowledgments
We would like to thank everyone who contributed to the implementation of the study at each unit: Department of Neurocentre, Norrland University Hospital; Department of Rehabilitation Medicine, Sunderby Hospital; Department of Neurology, Uppsala University Hospital; Department of Neurology, Karolinska University Hospital; and Department of Neuroscience, Skane University Hospital.
References