Daily salbutamol in young patients with SMA type II

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Abstract

The aim of this open pilot study was to establish the profile of tolerability and clinical response of salbutamol (albuterol) in a cohort of young children affected by type II spinal muscular atrophy (SMA). Twenty-three children between 30 months and 6 years of age were treated with salbutamol (2 mg three times a day) for 1 year. All children were longitudinally assessed using the Hammersmith motor functional scale 6 months before treatment started (T0), at baseline (T1) and 6 and 12 months later.

There was no significant change in function between T0 and T1 assessments, but the functional scores recorded after 6 and 12 months of treatment were significantly higher than those recorded at baseline (p = 0.006).

Our results suggest that salbutamol may be beneficial to SMA patients without producing any major side effect. Larger prospective randomized, double-blind, placebo controlled trials are needed to confirm these preliminary findings.

Introduction

Several studies have documented the effect of β-adrenergic agonists in animals [1], in human healthy volunteers [2], [3] and in subjects with muscle weakness due to acute or chronic conditions [4]. Evidence of a positive effect of salbutamol (albuterol) has also been reported in open pilot studies in patients with muscle disorders, such as facio-scapulo-humeral muscular dystrophy (FSH) or congenital myopathies, [5], [6], [7] though the only double blind placebo study, performed in FSH, has suggested that the positive effect was not maintained over time [8]. In 2001 a pilot study using salbutamol in patients with spinal muscular atrophy (SMA) type II and III reported a significant improvement in myometry and on DEXA scan scores between baseline and 6 months after treatment [5].

Following these encouraging results and in absence of any medication capable of improving the course of SMA, salbutamol has become part of clinical management of SMA patients in several centers. However the original pilot study had not been followed by a further randomized placebo controlled study that is considered to be the gold standard to establish the possible effect of a treatment. As the initial pilot study had been carried out in a relatively small and heterogeneous cohort, including both SMA type II and III patients with a wide age range, we reasoned that further information using appropriate disease-specific outcome measures in a more homogeneous cohort was needed before considering the effort of a larger randomized placebo-controlled study. We were also interested in establishing the possible effect of salbutamol in younger children compared to those studied in the original pilot study [5].

This paper reports the effect of salbutamol in 23 children with SMA type II, who started treatment before the age of 6 years.

Twenty-three consecutive children affected by SMA type II of age between 30 months and 6 years followed at three Italian Tertiary Referral centers, Catholic University and Bambino Gesù Children’s Hospital in Rome and Nigrisoli Hospital in Bologna were offered treatment with salbutamol between January 2005 and May 2006. All children had a diagnosis of SMA type II confirmed by genetic analysis with homozygous absence of SMN1. SMA II was classified according to the International Classification for SMA [9], based on age at disease onset and maximum function achieved (i.e. onset age over 6 months, and being able to sit unsupported but not to walk). None of children was taking part in any other pharmacological trial or was on any other concurrent medication. None had corrective surgery for scoliosis before or during the treatment with salbutamol.

The families were informed of the preliminary published results and of possible side effects of salbutamol, and agreed to treatment. Patients were started on oral salbutamol at an initial dose of 1 mg three times a day. After the first week, if the initial dosage was tolerated, it was increased to 2 mg three times a day. A 24 h electrocardiogram (ECG) was performed in all patients before starting treatment to exclude possible baseline tachycardia or other ECG abnormalities.

Each child was longitudinally assessed using the Hammersmith functional motor scale, that is part of our routine clinical assessment. The scale consists of 20 items, investigating the child’s ability to perform various activities. A total score can be achieved by summing the scores for each item. The total score, obtained by adding up the answers to all items, ranges from 0 (all items failed) to 40 (all items met) [10].

All 23 patients had at least one preliminary assessment 6 months before baseline (T0) and a baseline assessment immediately before beginning treatment (T1). Subsequently, they were evaluated 6 (T6) and 12 months (T12) after the start of the treatment.

Each child was always assessed by the same examiner, and the three examiners from the three centers had formal training sessions with the physiotherapist who developed the scale (MM). Interobserver reliability among the three examiners was formally assessed and the correlation coefficient was 0.96, showing similar results to the inter-rater reliability found in previous studies using the same scale [10], [11], [12].

All the children also had a detailed assessment of joint mobility in order to exclude possible deterioration in contractures as observed in the previously published pilot study on salbutamol in SMA [5]. Mean value was calculated for each measurement between sides at baseline and added subtracted to the mean value at 6 and 12 months (worsening symbolized with plus and improvement with minus).

Data were analyzed with the Stata package, version 9 [13]. Descriptive statistics (mean, median, range and centiles) of the Hammersmith score at T0, T1, T6, and T12 were computed. The variation of total score after treatment start was assessed through the Friedman test for non-parametric repeated measures comparisons [14]. To assess whether the child’s condition at preliminary assessment (T0) influenced the treatment effect, a multivariate regression analysis, clustered to allow for the repeated measurements carried out within the same child, was performed using the score values as dependent variable, and patient’s age, time of measurement (T1, T6 or T12) and preliminary score status (T0 < 18 versus ⩾18) as independent variables.

Section snippets

Results

All 23 children completed 12 months of treatment. On direct questioning, the parents of all patients reported some subjective improvement in strength and endurance and increased stamina. Three patients who had already been walking in calipers but had been stable for several months, succeeded to take a few steps without calipers after a few months of treatment.

Table 1 shows details of the scores at T0, T1, T6, and T12.

Median score values were 19 at baseline, 21 at 6 months and 22 at 12 months

Discussion

Our results suggest that salbutamol administered for 12 months in non-ambulant young SMA patients may improve muscle function without significant adverse effects. All the families of the young children who received treatment for 12 months reported an increase in stamina and function, and this was confirmed by our assessment showing an improvement on the functional scale in 21 of the 23 patients assessed. The peak of the improvement was noticed after 6 months of treatment, but further

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