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clinmed/2000030001v1 (March 21, 2000)
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The treatment of moderate to severe asthma in children with a combination of nebulized sodium cromoglycate and salbutamol

 

Kenshi Furusho1, Kiyoshi Nishikawa2, Sei Sasaki3, Toru Akasaka4, Masahiko Arita5, Alan Edwards6

 

1.     Kishiwada City Hospital, Kishiwada-shi, Osaka, Japan.

2.     Nishikawa Clinic, Zentsuji-shi, Kagawa, Japan.

3.     Osaka Medical College Takatsuki-shi, Osaka, Japan.

4.     National Morioka Hospital, Morioka-shi, Iwate, Japan.

5.     Arita Children's Clinic, Hiroshima-shi, Hiroshima, Japan.

6.     Southampton General Hospital, Southampton. UK.

 

Correspondence to:

Dr Alan M Edwards

7 Fallowfield Close

Caversham

Reading. RG4 8NQ

UK.                                                     

 

Tel: +44 118 947 6969

Fax: +44 118 946 4778

E mail: aedwards{at}vectis-allergy.com

Short title: Nebulised sodium cromoglycate and salbutamol in severe childhood asthma

Keywords: sodium cromoglycate, salbutamol, combination treatment, severe asthma, children, nebulised treatment.


ABSTRACT

Background:  The management of severe, intractable asthma in childhood still presents the clinician with difficult challenges despite the availability of modern drugs. Following reports of good results using the combination of nebulised sodium cromoglycate with Beta-2 agonists, the Severe Asthma Inhalation Research Committee of Japan organised a multicentre trial of this treatment in children with moderate to severe asthma.

Objectives: To investigate the relative efficacy, tolerability and safety of the combination of sodium cromoglycate and salbutamol in the treatment of moderate and severe childhood asthma.

Methods: Open, randomised, crossover trial of 12 weeks duration, comparing the combination of sodium cromoglycate and salbutamol with salbutamol alone and with sodium cromoglycate alone. All treatments administered twice daily by powered nebuliser. Main outcome measures were the change in asthma score, and the patient’s opinion of treatment.

Results: The change in asthma scores from baseline values significantly in favour of the combination. When compared to salbutamol, mean difference -7.5, 95% CI –11.70 to-3.29 ( p<0.0001). When compared to sodium cromoglycate, mean difference -8.53, 95% CI –14.03 to -3.25 (p <0.0001). Patient opinions also significantly in favour of combination treatment (p<0.001 v salbutamol; p <0.01 v sodium cromoglycate). Two patients reported adverse effects.

Conclusions: Regular twice daily inhalation of a combination of sodium cromoglycate and salbutamol gave better control of symptoms than previous treatments in patients with severe, intractable asthma. Few adverse effects with this therapy suggest it is extremely useful, safe and effective.


Introduction:

 

Despite the availability of new, potent bronchodilators, corticosteroids and anti-allergy drugs there are still children with moderate and severe asthma that are difficult to treat. Many of these require combinations of drugs, frequent hospital admissions and in some cases institutional care. Nishikawa et al [1], reported excellent results with the use of the regular inhalation of sodium cromoglycate combined with a Beta-2 agonist administered as a solution by powered nebuliser. The Severe Asthma Inhalation Research Committee of Japan organised a multicentre clinical trial to investigate the safety, efficacy and tolerability of this treatment.

 

Materials and methods:

Study design: The trial was to an open, randomized, crossover design in which the combination of SCG plus salbutamol was compared with salbutamol alone and with SCG alone.

Methods: After a 4-week baseline period, during which they continued on their existing treatment, patients were randomized to receive either the combination as first treatment with the single-drug comparator as second treatment (Groups A1 and B1), or the combination as second treatment and the comparator treatment first. (Groups A2 and B2). Each treatment was for 4 weeks and the total trial period for each patient was 12 weeks. The randomization was managed by a central controller who supplied each centre with numbered envelopes containing instructions for allocation to treatment groups A1, A2, B1 and B2. At each centre, the envelopes were opened from the lowest number as cases were admitted into the trial and were treated in accordance with the directions. Patients at any one centre could be allocated to any of the four treatment groups.

Subjects: Two hundred and fifty-seven patients were entered into the study from 40 hospital centres of whom 232 completed the trial and were included in the analysis. The mean age was 8.7 ±3.5 years. There were 150 males and 82 females. One hundred and forty-nine patients were classified as having severe asthma, and 81 as moderately severe. Seventy patients were in-patients, 157 out-patients and 17 in-and out-patients. The treatments being used before the trial were oral theophyllines (216 patients), oral Beta2 agonists (152), inhaled Beta2 agonists (83), inhaled corticosteroids (40), oral corticosteroids (40), injected corticosteroids (20).

Test treatment: Test treatments were given in addition to existing treatment The test treatments were 1). SCG: 2ml of a 1% aqueous solution of sodium cromoglycate. 2) Salbutamol: 2ml of physiological saline to which 0.1ml of a dose of a 5mg/ml aqueous solution of salbutamol nebuliser solution was added for children aged less than 6 years and 0.2ml/dose (1.0mg) for children 6 years and older. 3) Combination: 2 ml of 1% aqueous solution of sodium cromoglycate to which either 0.1ml or 0.2ml of salbutamol solution (5mg/ml) was added. Treatments were administered twice-daily using power operated nebulisers from Nippon Shoji. In most cases the nebulised cloud was inhaled through a mouthpiece except in the case of young children who used a facemask.

Concomitant treatments: Drugs used during the baseline period were continued throughout both test periods. The dose of these could be varied at the discretion of the investigator. The names, doses and number of doses of all concomitant drugs were recorded on the daily diary card.

Measurements: During the trial the patient or the parent recorded the severity of asthma symptoms daily using a 0 to 3 scale and also the treatment used that day. At the end of each treatment period the patient or patient’s guardian evaluated that period compared to the baseline period using the following scale; much better, better, slightly better, no change, worse, don’t know.

The investigator saw the patient each week and from the daily records derived an attack score, which reflected the severity of asthma for that week. A treatment score was derived using an agreed scoring system for the treatments used. By adding the attack and treatment scores an Asthma Score was derived. The cumulative 2-weekly Asthma Score was used as the primary measure of asthma severity.

Side effects: The type, degree, time of onset, duration and treatment of any side effect together with recovery and possible causal relationship to treatment were recorded by the investigator at the end of each treatment period.

Withdrawals: Patients could be withdrawn from the trial by the investigator if continuance was considered to be inappropriate. The time and reason for withdrawal were recorded. As far as possible patients were included in analyses up to the time of withdrawal.

Statistical Analysis: The primary variable of treatment efficacy was the changes in asthma score from the last 2 weeks of the baseline period and the last 2 weeks of each treatment period. These were compared using Wilcoxon Rank Sum tests. Between group comparisons of the patient/guardian opinions of treatment were made using chi-squared tests. All tests were two-tailed and a p value of less than 0.05 was regarded as significant.

Ethical approval:  All patients or parents/guardians gave informed consent and local ethical review committees gave approval for the trial.

 

Results.

Twenty-five patients were excluded from the analysis; 9 did not complete either the baseline or the treatment periods, 8 had inadequate records, 3 each had missing data or did not comply and 2 dropped out for unspecified reasons.

The primary variable of treatment efficacy was the change in asthma score from baseline. The mean (SD) baseline asthma scores for the last 2 weeks of the baseline period were 112.81 (77.81) in the combination/salbutamol comparison and 117.90  (72.05) in the combination/SCG comparison. These values are not significantly different.

The changes in mean asthma score together with the standard deviations and 95% confidence intervals, from the last 2 weeks of the baseline period to the last 2 weeks of each treatment and the differences between treatments are shown in Table 1. This shows that the combination of SCG and salbutamol produces a significantly greater improvement in Asthma Score than either salbutamol alone (p<0.0001) or SCG alone (p<0.0001).

The patient’s opinions of each treatment are shown in Table 2. The number of patients who report they are better or much better is significantly greater for the combination than for salbutamol alone (p<0.001) and for SCG alone (p<0.01).

Adverse events were reported in 2 cases. One case developed sneezing and nasal irritation with the combination treatment. This was of mild severity and treatment was not stopped. The second case developed nausea when switched to the combination. This was severe and treatment was stopped. When procaterol was substituted for salbutamol the problem did not recur.

Discussion:

In this study we compared the efficacy and safety of a combination of a solution of sodium cromoglycate and salbutamol administered twice daily by powered nebuliser with either salbutamol solution alone or sodium cromoglycate solution alone in children with moderate and severe asthma.

The trial design can be criticised, as it was neither placebo controlled, nor double blind and did not include a washout period between treatments. We did not consider it justified to use a placebo treatment or a washout period in this difficult group of patients who were liable to unpredictable severe attacks of asthma. To reduce the effects of these potential deficiencies in the study we used a strict randomisation procedure managed by an independent central controller. The trial wa conducted at 40 separate hospital centres. As the analysis of the characteristics of the 4 treatment groups shows that the randomisation was satisfactory and the groups were comparable, we do not believe that the lack of a placebo and blinding compromised the results.

There have been few recent trials of a combination of sodium cromoglycate and a bronchodilator. The first sodium cromoglycate product (Intal compound®) introduced into the United Kingdom in 1968 was a dry powder combination of sodium cromoglycate and the non-specific β-agonist, isoprenaline. This was shown to give excellent results in both adults and children with moderate to severe asthma [1,2]. The study by Silverman et al., which compared sodium cromoglycate +isoprenaline with isoprenaline alone in children with severe perennial asthma, found that 71% of the combination treated group were still well controlled compared to 24% in the isoprenaline group. Shapiro et al.[3] compared nebulised sodium cromoglycate, terbutaline and the combination of the two in a double blind cross over study in 27 children with mild to moderate asthma. Significant differences between treatments were found in 3 out of 12 variables. Two of these were in favour of the combination and one in favour of sodium cromoglycate alone. The patients in this trial had relatively mild asthma and this together with the fewer patient numbers would make it difficult to demonstrate differences between active treatments. 

It is normally recommended that SCG products have to be administered four times a day. The dosing schedule in this trial was twice daily and the results show that this is adequate. Whether improved efficacy could be achieved by increasing the dose frequency is uncertain, but the potential for reduced compliance because of the inconvenience of a four times a day schedule has to be taken into consideration. We believe that the efficacy demonstrated by the combination treatment is sufficient to recommend a twice daily dosing frequency for moderate to severe patients but that in severe cases dosing commences at four times a day.

Finally we would like to consider why this therapy is effective as compared to the components administered separately. In addition to its anti-inflammatory effects, sodium cromoglycate has been reported to potentiate and sustain the smooth muscle relaxing properties of isoproterenol, epinephrine and salbutamol [4]. The two components of this combination may therefore have a true synergistic effect on the symptoms of asthma.

The dose of SCG delivered to the lung can be calculated from the amount that appears in the urine 4 hours after an inhaled dose. Hirota [5] has shown in 16 asthmatic children aged 6 to 14 years that when salbutamol is added to SCG, the mean 24 urinary excretion is 1.53 times higher than with SCG alone. The mean excretion from SCG alone was 1.04%. in his group of patients. These figures suggest that the addition of salbutamol increases the mean dose of sodium cromoglycate entering the lungs from 0.5mg to 0.8mg. This may be important both in terms of absolute efficacy and in duration of activity. 

 Current international guidelines [6] recommend SCG alone only as in mild persistent asthma in children above and below 5 years of age. There are no recommendations as its use in more severe asthma and no consideration of its use in combination with other drugs apart from Japan. We suggest that the results of this trial justify considering its use in other countries in this difficult group of patients.


Acknowledgements:

The authors wish to acknowledge the following who provided and monitored patients in the trial.

Dr Yoshinori Wagatsuma,  Dr Norio Nemoto,  Dr Mataka Kudo,  Dr Namio Yano,

Prof Akihiro Morikawa,  Dr Akira Yoshizumi,  Dr Hideo Sugimoto,  Dr Itsuo

Suzuki,  Dr Toshiyuki Nishimuta,  Dr Kaneo Shimanuki,  Dr Yasuhiro Kabasawa,

Prof Yoji Iikura,  Dr Minoru Baba,  Dr Michie Honjo,  Dr Hiroshi Hayakawa,

Dr Takehiko Matsui,  Dr Hajime Watanabe,  Dr Toshihiko Nemoto,  Dr Yoshiaki

Teramichi,  Dr Hiroshi Suguro,  Dr Tomio Kondo,  Dr Yukinori Uchida,  Prof

Shoichiro Shike,  Dr Gaiji Nakamura,  Prof Haruki Mikawa,  Dr Takao Hirao,  Dr

Kyoichiro Toyoshima,  Dr Yukiaki Sanada,  Prof Takanobu Kurashige,  Dr

Hiroshi Kimura,  Dr Taketoshi Watanabe,  Prof Chuzo Mori,  Dr Sankei

Nishima,  Prof Yoshio Tsuji,  Dr Reiji Okazaki,  (Controller) Prof Shigeru

Matsukura.

 

This study was supported by grants from Fujisawa Co Ltd. and Fisons-Fujisawa Co Ltd.

 

Competing Interests.

Dr Alan Edwards was an employee of Fisons Pharmaceuticals Ltd. and is a consultant to Fisons-Fujisawa Co Ltd.


 

 

References

1.     Nishikawa K. The effects of regular inhalation of disodium cromoglycate (DSCG) and salbutamol in severe and intractacble asthma patients. Jap J Ped Allergy Clin Immunol 1988;2:60-68.

2.      Brompton Hospital/Medical Research Council Collaborative Trial. Long-term study of disodium cromoglycate in treatment of severe extrinsic or intrinsic bronchial asthma in adults. Br Med J ii:383 (1972).

3.     Silverman M, Connolly NM, Balfour L, Godfrey S. Long-term trial of Disodium cromoglycate and isoprenaline in children with asthma. Brit Med J 1972; 2:378-381

4.     Shapiro GG, Furukawa CT, Pierson WE, et al. Double-blind evaluation of nebulized cromolyn, terbutaline, and the combination for childhood asthma. J Allergy Clin Immunol 81(2): 449 (1988).

5.     Kitamura S, Ishihara Y, Takaku F. Effect of Disodium Cromoglycate on the Action of bronchoactive Agents in Guinea-pig Tracheal Strips Arzneim Forsch. 34 II (9): 1002 (1984).

6.     Hirota T. Efficacy and limitations of inhaled anti-allergic therapy in asthma. In Current Advances in Pediatric Allergy and Clinical Immunology. Shinomiya K editor). Churchill Livingstone Japan (1996) pp. 125-128.

7.     Third International Pediatric Consensus Statement on the Management of Childhood Asthma. (Warner JO, Naspitz CK, Cropp GJA editors). Pediatric Pulmonology 25:1 (1998).

 

 

 


 

 

 

 

 

 

 

 

 

 

 

 

Table 1:  Asthma Scores. Change in asthma scores from the last two weeks of the baseline period to the last 2 weeks of each treatment period.

 

Baseline

Mean

(SD)

{n}

Change from baseline

Mean 

(SD)

[95% CI]

Difference

Mean 

(SD)

[95% CI]

Wilcoxon P value

 

 

SCG + salbutamol

salbutamol

SCG + salbutamol

SCG

 

 

 

 

 

 

 

 

 

 

SCG + salbutamol v salbutamol

Groups A1/A2

112.81 (77.18)

{115}

-43.9

(39.87)

[-36.53 to –51.27]

-36.77 (43.01)

[28.78 to –44.75]

 

 

-7.5

(22.64)

[-3.29 to –11.70]

<0.0001

 

 

 

 

 

 

 

 

SCG + salbutamol v SCG

Groups B1/B2

117.90

(72.05)

(113)

 

 

-45.38

(7.20)

[-36.58 to-54.19]

-36.75

(45.62)

[-28.20 to –45.29]

-8.53

(28.52)

[-3.25 to –14.03]

<0.0001

 

 

 

 

 

 

 

 

 

SCG = sodium cromoglycate


    

 

 

 

                                                            Table 2. Final Opinion of  Patients of the effects of each treatment. Number of patients in each category.

 

SCG + salbutamol

v

salbutamol

SCG + salbutamol

v

SCG

 

SCG

+

salbutamol

Salbutamol

SCG

+

salbutamol

SCG

Much Better

57

29

56

35

Better

40

43

34

39

Slightly Better

11

21

16

21

No different

6

17

3

14

Worse

1

5

2

4

χ2

20.277

13.632

p-value

<0.001

<0.01

 

SCG = sodium cromoglycate

 

           

 





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Right arrow Articles by Edwards, A.
Related Collections
Right arrow Paediatrics:
Other Paediatrics

Right arrow Respiratory Medicine:
Asthma

Right arrow Statistics and Research Methods:
Randomised Controlled Trials: examples


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