1 Introduction

Repeated use of Botulinum toxin A (BoNT-A) in children with cerebral palsy (CP) is focally effective and safe in reducing spasticity. Because BoNT-A activity on nerve terminals lasts about 12–16 weeks, repeated applications are considered necessary.^1,2 It has been stated that BoNT-A treatment should be repeated in children with cerebral palsy at six-month intervals, with movement and functional improvement further increasing after each application.^3–5 The intramuscular administration of BoNT-A is painful; therefore, application under sedation or anesthesia increases a child's compliance with and tolerance to repetitive injections.⁶ In addition to palpations, the exclusion of pain provides a more accurate application of BoNT-A to the target muscle. In the application of BoNT-A sans sedation or anesthesia, the child might show resistance to a painful injection, thus making a correct application impossible. This situation can especially prove traumatic in younger children.^1,6

Compared to healthy children, children with cerebral palsy are at a higher risk of anesthesia complications.^7,8 Musculoskeletal system deformities, such as kyphoscoliosis and contractures, encountered in these cases may also cause the development of restrictive lung disease. In fact, swallowing dysfunction, gastroesophageal reflux, and insufficient coughing in these cases may lead to the development of respiratory complications during the postoperative period.^9,10 Muscle atrophy and poor temperature regulation in patients with cerebral palsy tend to lead to hypothermia when these patients are under anesthesia.¹¹ The BoNT-A application procedure is one that could be performed within a short time. Shortening the amount of time spent in the operating room for patients with cerebral palsy can also prevent the development of serious complications, such as hypothermia and hypotension.^6–8

In this study, the aim was to compare the functional outcomes and administered anesthesia types of patients who received repeated BoNT-A. Serial BoNT-A is now a routine form of application for improving function and movement in children with cerebral palsy, which requires repetitive anesthesia applications to be reliable and effective. For this purpose, we tried to determine the most appropriate anesthesia type for multiple applications.

2 Patients and methods

Dr. Behcet Uz Children Hospital is the largest and only tertiary children's hospital in the region and is highly experienced in the diagnosis and treatment of children with cerebral palsy. All cases were composed of those previously evaluated by pediatric neurology, physiotherapy-rehabilitation, and pediatric orthopedics departments and diagnosed with CP. In our institute, once the diagnosis of cases is finalized, serial BoNT-A application is performed at six-month intervals from 24 months of age up to 10 years of age, if necessary. Between January 2008 and January 2018, 75 children with cerebral palsy and a total of 320 procedures undergoing BoNT-A application at least three times consecutively every six months were retrospectively reviewed. The study was approved by the local ethics committee (Approval No: 2018/257) and also this study has been registered and allocated the ACTRN (The Australian and New Zealand Clinical Trial Registry): ACTRN12621001744842. Patient demographic data, number of serial BoNT-A applications, birth time (term-preterm), birth weight, cerebral palsy type, and first BoNT-A application age were recorded.

BoNT-A applications are performed under anesthesia under the supervision of an anesthesiologist in the operating room. The anesthesia protocol includes a pre-anesthetic visit, premedication, monitoring, anesthesia, and recovery time spent in the operating room until a post-procedure Modified Aldrete Recovery Score ≥9 is achieved.¹²

There are three types of anesthesia: midazolam and ketamine with sedation analgesia, anesthetic mask with inhaler anesthetic application, and larengeal mask (LMA) with inhaler anesthetic. The sedation degree of patients during the procedure is desired to be ≥ 4, according to the Ramsay Sedation Scale (deep sedation and general anesthesia).¹³ The functional evaluation of Gross Motor Function Classification System (GMFCS)¹⁴ was taken into consideration and the decrease in classification was grouped and compared as 2-1-0 level.

The application of BoNT-A is performed by the pediatric orthopedic physician if the degree of sedation of patients is ≥ 4, according to the Ramsay Sedation Scale (deep sedation and general anesthesia) and in accordance with the updated European Consensus 2009.¹ BOTOX® (Allergan, USA), as our BoNT-A treatment, was applied to all cases.

After BoNT-A applications were completed, patients' recovery from anesthesia was evaluated with the Modified Aldrete Recovery Scoring system (patient's activity, respiratory depth, circulation, consciousness, and oxygen saturation were scored).¹²

During anesthesia procedure, the time from the start of the anesthetic drug application to the last BoNT-A injection was recorded as the sedation period; the time interval from the completion of the first BoNT-A injection to the completion of the last injection was recorded as BoNT-A injection time; the time from the completion of the last BoNT-A injection to the time of the Modified Aldrete Recovery Score being ≥9 was recorded as recovery time; and the time from the entrance to the exit of the operating room was recorded as the total operating room time. Until the Modified Aldrete Recovery Score was ≥9, the amount of time patients were monitored in the operating room was recorded as the recovery time.

Bradycardia, hypotension, hypoxemia, apnea, bronchospasm, nausea, and vomiting, which could be observed during and after the procedure, were recorded as side effects.

Patients who did not undergo serial successive BoNT-A applications at least three times, which were performed within more than six months, those with irregular follow-ups were excluded from the study.

3 Statistical analysis

Statistical analysis was performed using SPSS version 21.0 (SPSS Inc, Chicago, Illinois, USA) with a confidence level of 95%. While frequency and percentage values were assigned for categorical variables, descriptive statistics, such as minimum, maximum, mean, and standard deviation, were assigned for numerical variables. The relationship between the categorical variables was analyzed using a Chi-square test, while an ANOVA test was employed to analyze the variability of a numerical variable compared to a categorical variable. The significance level was set at 0.05.

4 Results

320 Botulinum toxin A procedures administered to 75 children with cerebral palsy were evaluated. The number of cases consecutively performed at least three or more times as well as the demographic data are summarized in Table 1.

11 of the cases had GMFCS scores of 2; 34 had GMFCS scores of 3; 27 had scores of 4; and 3 had scores of 5 (Fig. 1).

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Fig. 1 Distribution of GMFCS scores.

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When the anesthesia methods were evaluated, it was found that 106 (33.1%) of the cases were administered sevoflurane with an anesthesia mask, 103 (32.1%) sevoflurane with a laryngeal mask, and 111 (34.6%) were observed to have been administered sedation-analgesia (Fig. 2).

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Fig. 2 Anesthetic management in procedures.

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Side effects developed in 10 of the 320 procedures performed. Vomiting complaints developed in eight cases, while bronchospasms developed in two cases. There was no significant difference between anesthesia types in terms of side effects (p > 0.05) (Table 2).

When evaluated in terms of GMFCS, 60 (80%) patients were seen to have exhibited two- or one-step improvements in terms of motor function after undergoing repeated BoNT-A application (p < 0.000*). Cerebral palsy children with GMFCS scores decreased by two or one as well as those with unchanged levels were not significantly different when compared in terms of age of BoNT-A first birth, birth weight, and gestational age (preterm, term) (p > 0.05). (Table 3).

When the anesthesia application times in the BoNT-A procedures were examined, it was seen that the total operating room and recovery times differed significantly depending on the procedures (p < 0.009, p < 0.016, respectively). Specifically, the total operating room and recovery times of those who had had six or more procedures were observed to be longer than those undergoing the same less than six times (Table 4).

When the recovery and total operating room times were compared during the first three BoNT-A procedures, it was found that they were significantly shorter in patients undergoing sedation, while the durations of recovery and total operating room were longer (p < 0.05). There was no difference in the anesthesia methods for those who had four or more procedures (Table 5).

5 Discussion

Today, BoNT-A applications have an important place in the treatment of cerebral palsy after two years of age. The physiological effects of BoNT-A cause reductions in muscle activity by preventing the release of acetyl choline in neuromuscular junctions. Thus, BoNT-A applications lead to relaxation in the muscles to which it is applied as well as a gradual decrease in spasticity.¹⁵

Bont-A application, which requires a multidisciplinary approach to providing treatment, should be performed at the appropriate age, target muscles, and times. Achieving progress in cases based on GMFCS and reaching the next motor milestone (especially standing up and walking) are the most important main targets of the treatment.¹⁶ In order to reach these main goals, it is important to successfully perform BoNT-A application under optimum conditions, the most convenient and safe of which is to use anesthesia.^1,8 Another outstanding key point in studies performed in the last decade is that it should be carried out in repetitive doses and at appropriate time intervals rather than in a single dose.¹⁷

Kahraman et al. (2016) found in a systematic review including 13 original studies, that the application of the procedure in the form of two first injections/one repeat particularly relieves spasticity when it is applied in children with spastic CPs, providing functional improvement in gross motor activities.⁴ Multiple studies have shown that repeat BoNT‐A application is a safe and effective approach; thus, it should be repeated at appropriate intervals.^18–20 For this reason, patients who underwent BoNT-A that was repeated at least three times were included in this study. Each procedure was performed under anesthesia to optimize the success rate of the application, and the safety and efficacy of each were evaluated.

When functional change was examined in our study, it was seen that repeat BoNT-A applications under regular anesthesia enabled significant functional improvement in the GMFCS steps of children with CP. However, there was no significant difference between the cases in which GMFCS 1 and 2 motor development progression was obtained in terms of age upon first BoNT-A application. In other words, the application of the procedure at an early age was not observed to cause any significant changes in GMFCS. Studies have shown that, with treatment initiated at an early age, motor development provides a greater potential for motor learning on the basis of neuroplasticity.^17,21

For behavioral purposes, various maneuvers performed by children with CP to achieve an early age aid in their achieving faster movements and improving their coordination.^17,21 Five motor milestones can be reached within the first two years of life. In recent studies, it has been observed that BoNT-A treatment, which is initiated before the age of two, prevents contractions reducing spasticity; however, there is a need for further evidence on this subject, as a special assessment is required for infants.^2,22 The GMFCS classification used for assessment is a validated tool for the measurement of motor function in children with CP. However, it may not be a sensitive enough method to detect minimal changes in a wide range of evaluations. Overall, we posit that BoNT-A treatment for motor development should be initiated at an early age.

Although the success of BoNT-A treatment in terms of motor development in children with CP is unquestionable, the factors that affect its success rate vary by patient. The functional improvements we observed in preterm children and those with low-birth weights were not different from those born via normal delivery and term delivery, which can be attributed to the increased spasticity observed in many studies due to the damage in the first motor neurons and the response of antispasmodic treatments given mainly to combat this damage rather than many other variables in the process.^16,23,24 Therefore, achieving more successful results in children with CP and functional deficits (GMFCS 1–2) illustrates that the effects of variables such as low-birth weight and preterm delivery are not significant, as in our study.^17,23,24

Irregular tooth structure and temporomandibular joint dysfunction observed in children with CP causes difficulties in airway management, chest wall deformities, physical limitations due to spasticity, and chronic obstructive and restrictive lung diseases, thus making anesthesia applications risky and difficult. Due to these risks, the difficulty of anesthesia increased in patients with high GMFCS. When we examined studies recommending intramuscular BoNT-A applications in children with CP under operating room conditions, Chow et al. reported that they experienced side effects in 6.6% of applications, while Louer et al. reported the same in 4.7% of applications.^7,8 We also observed that side effects such as bronchospasm, nausea, and vomiting unassociated with anesthesia type were observed in 3.12% of applications, and no serious side effects were seen. For this reason, in children with cerebral palsy, regardless of anesthesia type, BoNT-A was safely applied in the operating room, including in cases with high GMFCS.

It was observed that, as the repeat of the process increased in cases in which more than 3 BoNT-A applications were performed, the number of anesthetic drugs used, total operating time, and total recovery time also increased. Compared to other types of anesthesia, it was also observed that sedation application significantly reduced recovery time and total operating time in the first three applications. However, in any subsequent applications, it was observed that the duration of anesthesia was prolonged in patients who additionally underwent sedation, such as mask and LMA. It was thought that this situation, observed regardless of anesthesia type, might be related to drug tolerance. In repeat applications, drug tolerance is generally known to be due to receptor down regulation²⁵ but the presence of additional predisposing factors increasing this in children with CP is unknown. Oddo et al. highlighted the development of tolerance in sedation analgesia applied due to increased cerebral blood flow and increased cerebral metabolic rate following brain damage.²⁶ Gopisetti, on the other hand, stated that the development of tolerance is a common effect of Midazolam.²⁷

The safety and efficacy of the application performed with the sedation was observed in our study and in a study by Chow et al., but, in our study, it was observed that it did not shorten the anesthesia period in repeat applications of four or more.⁸ In patients undergoing four, five, and ≥ six procedures, GMFCS score and general loss of function (cases with severe functional deficit that benefit less from BoNT-A applications) may explain the long recovery period of patients in this sedation analgesia group due to more brain damages.

Repetitive doses of anesthesia are performed in order to perform repeated BoNT-A applications in children with CP. Studies on repetitive anesthesia have reported that depression, anxiety, sleep and attention disorder are encountered more frequently in these children than in others.^28,29 For these reasons, the increase observed in children's anxiety and existing spasticity arising due to the increased number of procedures makes anesthesia management more challenging.

In our study, it was observed that the mean recovery time of patients in the first three procedures was 5.61 min, and these patients were safely anesthetized. Following the fourth procedure, regardless of anesthesia type, recovery duration and the total operating room were seen to be prolonged. Drug resistance, children's fear, and spasticity in children may increase with age, and the fact that a large number of procedures are applied to relatively severe cases can be considered reasons for this situation. Thus, it was determined that the advantage of the short recovery time associated with the sedation application disappeared as the number of applications increased.

There are several limitations of our study that should be discussed, the most important of which is that it is retrospective. For this reason, only GMFCS was employed in the functional evaluation. Although it is a valid method in evaluating motor development, in addition to GMFCS, the modified Ashworth Scale, ROM of the hip, knee and ankle, the Gross Motor Function Measure (GMFM-66), and the Pediatric Evaluation of Disability Inventory (PEDI) could also have been employed while conducting the measurements.^22,30 Irregular follow-ups of patients also made it difficult to apply these evaluations. Additionally, a lack of randomized anesthesia method selection was another limitation. On the other hand, very few studies have evaluated functional data on repeated BoNT-A procedures or the effects and reliability of the anesthesia procedure. Contrary to the literature, this study reports results regarding the evaluation and reliability of functional and anesthetic methods applied for a high number of repeated procedures, including four, five, or even six (or more) applications.

In conclusion, the BoNT-A application, which will be applied to children with CP, can be applied safely and effectively under anesthesia in centers with sufficient and experienced teams. While the sedation analgesia application provided easier recovery than LMA and mask in the first three repeated applications compared to the general anesthesia, there was no difference between the types of anesthesia in four or more repeated applications. In repeated applications of sedation analgesia and other types of anesthesia, recovery has been shown to take progressively longer, and further studies on the causes of phenomenon are thus required.

Funding statement

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

Ethical statement

Ethical approval: Ethical approval for this study was granted by the research and ethics committee at the study centre. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Not required for this work.

Author contributions

MCS: Study design, Data acquisition, Manuscript preparation.

KES: Study design, Data acquisition, Manuscript preparation.

ICMJE Conflict of interest statement.

None declared

All authors read and approved the final version of the manuscript.