Orig inal Ar t ic le

Salbutamol and/or Beclomethasone Diproprionate in Asthma

Sunita Sharma, 1 Preeti Godatwar 2 and L.R. KulkarnP

Departments of IPharmacology, 2Pediatrics and 3Preventive and Social Medicine, Indira Gandhi Medical College, Nagpur, India.

Abstract. Objective: Acute severe exacerbation of asthma is potentially life threatening and requires critical assessment and appropriate therapy. Now a days, steroids are often combined with bronchodilators for the treatment of bronchial asthma. Therefore, the present study was undertaken to compare effectiveness of beclomethasone diproprionate-salbutamol combination versus salbutamol alone by MDI (with or without spacer) in acute asthma. Methods : A total of 57 paediatric patients (5-12 years) with acute attack of bronchial asthma attending emergency department of Indira Gandhi Medical College and Hospital was randomised to receive salbutamol (100 pg/puff) alone or with BDP (50 I~g/puff) by metered dose inhaler with or without spacer. All baseline investigations were repeated one hour after the therapy. Results : Clinical parameters indicative of severity of asthma improved statistically in all treatment groups. The increase in PEFR was better with MDI-S+B with spacer as compared to other groups, though it failed to reach statistical significance. The fall in serum potassium level is significantly more with MDI-S+B group when spacer was not used. No serious adverse effects were observed in any of the treatment groups. Conclusions. Metered dose inhalation of BDP-salbutamol combination with spacer provides better recovery whereas fall in serum potassium with MDI-S+B suggests use of spacer and monitoring of serum potassium during treatment. [Indian J Pediatr 2003; 70 (2) : 129-132]

Key words : Bronchial asthma; Salbutamol; Beclomethasone diproprionate; Metered dose inhaler

Traditionally, symptomatic control of bronchoconstriction with ~2-agonist has been the mainstay of therapy. 1 However, with growing awareness that asthma is an inf lammatory condition, the paradigm of asthma medication is shifting to use of anti-inflammatory agents. Glucocorticoids are the most potent anti-inflammatory agents available for the treatment of asthma. Their efficacy is related to many factors including a diminution in inflammatory cell function and activation, stabilisation of vascular leakage, a decrease in mucus production, and an increase in beta adrenergic response. 2 Various authors 3,4-~,6 have reported that stat dose of steroids given to patients of acute bronchial asthma reduces the rate of hospitalisation. There have been studies reporting combination of corticosteroids with bronchodilators as more beneficial than bronchodilators alone. Similar, Taylor DR7et al (1992) documented potentiation of acute biochemical effects of ~-agonist on steroid pretreatment. Corticosteroids are said to restore the bronchial hyperresponsiveness by various mechanisms 8 and this suggests that a combination of drugs which relieves bronchospasm and controls inflammation might be more useful than single drug during the acute attack of asthma. 9

The present s tudy was under taken to compare effectiveness of beclomethasone diproprionate-

Reprint requests : Dr. Sunita Sharma, 371, Ashish Apartments, Ist floor, North Ambazari Road, Gandhi Nagar, Nagpur-440 010, Maharashtra. E-mail : drsmsin@hotmail.com

salbutamol combination against salbutamol alone by MDI with or without spacer.

MATERIALS AND METHODS

The inclusion criteria required patients (aged 5-12 years) presenting with history of cough, breathlessness associated with wheezing, and respiratory rate more than 30 brea ths /minute . Patients who had pulmonary tuberculosis of history suggestive of foreign body aspiration were excluded from the study. A total of 57 patients, attending casualty or outpatient department at Indira Gandhi Medical College and Hospital, Nagpur for acute exacerbations of bronchial asthma were enrolled for this randomised study. The permission to conduct the study was given by the institutional ethical committee and informed written consent was taken from parents of all patients. After baseline investigations patients were randomised to one of the four treatment groups. (i) Metered dose inhaler-salbutamol 2 puff (100 ~tg/

puff) (MDI-S) (ii) Metered dose inhaler-salbutamol 2 puffs (100 ~tg/

puff) with spacer. (MDI - S*) (iii) Metered dose inhaler - salbutamol (100 ~tg/puff) +

beclomethasone diproprionate (50 ~tg/puff) 2 puffs. (MDI-S+B)

(iv) Metered dose inhaler-salbutamol (200 ~tg/puff) and beclomethasone diproprionate (50 ~tg/puff) 2 puffs with spacer (MDI-S+B S*).

Indian Journal of Pediatrics, Volume 70--February, 2003 129

Sunita Sharma et al

If p a t i e n t s d id no t r e s p o n d , s a m e t r e a t m e n t w a s repea ted after 20 minutes for 2 more doses. All clinical p a r a m e t e r s (pulse , r e s p i r a t o r y rate, b l o o d p re s su re , wheez ing and retraction, peak expiratory flow rate) and laboratory parameters (blood glucose, serum sodium and potassium, arterial blood gases) were repeated one hour after the therapy.

Wheezing and retraction each were scored 1~ on a scale of 0-3 a n d p e r c e n t p r e d i c t e d v a l u e for PEER w a s calculatedY

All r e su l t s w e r e e x p r e s s e d as Mean+_SD. P a i r e d s tudent "t' test was used for statistical analysis within the group. The difference in response be tween the t reatment g roups was assessed b y analysis of variance (ANOVA). The differences were cons idered to be significant w h e n "p' value was less than 0.05.

R E S U L T S

Of the 57 patients of acute bronchial asthma, 29 (50.88%) w e r e ma les and 28 (49.12%) w e r e females as seen in Table1 . In the p r e s e n t s t u d y , p r e t r e a t m e n t m e a n wheezing and mean retraction scores were similar as seen in Table 2 and i m p r o v e d s ign i f ican t ly one h o u r after t h e r a p y in all the t r e a t m e n t g r o u p s . P r e t r e a t m e n t respiratory rate was h igher in all the t rea tment groups.

TABLE 1. Demographic Profile of Asthma Patients Participating in the Study

However, a significant (p<0.05) fall in respiratory rate was observed in all t reatment groups. There was decrease in pulse rate t h o u g h no t statistically signif icant bu t there was no change in either sytolic or diastolic blood pressure after therapy.

The PEFR i m p r o v e d in all the t rea tment g r o u p s one h o u r after t h e r a p y bu t there w a s h i g h l y s ign i f ican t ly improvement in PEFR as well as percent predicted PEFR (54.18) in MDI-S+SB* as shown in Table 3.

O n a p p l y i n g A N O V A m e t h o d it w a s f o u n d tha t parameters indicative of response to the t rea tment like wheez ing , chest retract ion and oxygen sa tura t ion were not significantly different f rom each other. A n d though the improvemen t in PEFR was better in MDI-S+S B* as compared to other groups, it could not achieve the level of statistical significance.

There was no significant change in b lood sugar levels and se rum sod ium levels, but a fall in se rum potass ium levels was observed in all t reatment groups as depicted in Table 4. The fall was statistically significant (p<0.05) for MDI-S+B g roup w i thou t spacer. Five (33.33%) pat ients h a d h y p o k a l e m i a w h e n M D I - S + B w a s u s e d w i t h o u t spacer as compared to 3 (21.42%) pat ients w h e n spacer w a s used . In MDI-S g r o u p 2 (14.28%) a n d 1 (7.14%) pa t i en t s h a d h y p o k a l e m i a w i t h o u t and w i t h space r respec t ive ly . A N O V A s h o w e d tha t the fall in s e r u m p o t a s s i u m level is s ignif icant ly m o r e (df=3,56 F=4.44,

TABLE 3. Effect of Treatment on Peak Expiratory Flow Rate

Treatment Number of Male Number of Total PEFR (L/min) PEFR (L/rain) group patients female patients Treatment Group Before treatment After treatment

(Age in years) (Age in years) I 92.00 127.43"

I 6 8 14 (MDI-S) _+34.99 • (MDI-S) (6.00 -+ 0.41) (8.00 _+ 4.07) U 100.71 137.43" 11 7 7 14 (MDI-SS*) _+49.64 • (MDI-SS*) (6.95 _+ 1.98) (8.38 _+ 2.222) III 92.13 129.00 III 8 7 15 (MDI-S+B) -+47.89 -+56.41 (MDI-S+B) (7.64 -+ 2.38) (13.00 _+ 4.18) IV 95.36 135.14"* IV 6 8 14 (MDI-S+BS*) _+14.94 -+35.14 (MDI-S+BS*) (5.80 _+ 0.75) (7.89 _+ 4.33) Total 29 28 57 S* denotes use of spacer

*p<0.05, ** p<0.01 S* denotes use of spacer

TABLE 2. Effect of Treatment on Wheezing and Reaction

Treatment Wheezing Wheezing Retraction Retraction Group Score before Score after Score before Score after

treatment Treatment Treatment Treatment

I 2.43 0.79*** 2.07 0.64*** (MDI-S) • 0.49 _+ 0.59 -+ 0.70 +_ 0.61 II 2.36 0.50*** 1.86 0.29 (MDI-SS*) -+ 0.61 _+ 0.50 + 0.64 _+ 0.45 III 2.20 0.53"** 1.93 0.47*** (MDI-S+B) _+ 0.65 _+ 0.60 -+0.77 _+ 0.50 IV 2.50 0.57*** 2.00 0.50*** (MDI-S+BS*) -+ 0.50 _+ 0.62 +- 0.76 -+ 0.63

S* denotes use of spacer *** P<0.001

TABLE 4. Effect of Treatment on Serum Potassium Levels

Treatment Serum potassium Serum (mEq/L) potasium (mEq/L)

Group Before treatment After treatment I 4.10 3.82 (MDI-S) -+0.35 _+0.44 II 4.34 4.03 (MDI-SS*) _+0.62 -+0.17 III 4.49 3.53***# (MDI-S+B) -+0.45 -+0.50 W 4.06 3.71 (MDI-S+BS*) _+0.30 -+0.72

S'denotes use of spacer ***p<0.01 . ANOVA # (df = 3,56 F=4.44, p<0.05)

130 Indian Journal of Pediatrics, Volume 70--February, 2003

Salbutamol Alone and with Beclomethasone Diproprionate in Asthma

p<0.05) with MDI-S+B group when spacer was not used. In arterial b lood gas analysis, though the mean pH,

PaO2 and PaCO2 were within normal limits both before and af ter d rug the rapy , p H and PaO2 t rend to be on higher side of normal and PaCO2 slightly decreased one hour after therapy. Mean oxygen saturat ion increased significantly (p<0.05) in all the treatment groups one hour after therapy. Bicarbonates and base deficit improved after t he r apy and there was no significant change in oxygen content, carbon dioxide content, alveolar arteriolar gradient and ratio.

No serious adverse effects were observed in any of the t reatment groups. Cough and vomit ing were seen in 2 (6.89%) children when spacer was used as compared to 6 (20.68%) when aerosol therapy was given without spacer.

DISCUSSION

The present s tudy was designed to investigate clinical efficacy of combination of BDP and salbutamol compared to salbutamol alone in patients of acute bronchial asthma. Mean wheezing and mean retraction scores improved s igni f icant ly (p<0.001) one hou r af ter t h e r a p y in all t r e a t m e n t g roups . This s u g g e s t s e f f ec t iveness of salbutamol in relieving bronchospasm. In a study, Hickey, RW 1~ et al (1994) also demonst ra ted that salbutamol by MDI is beneficial in children with acute wheezing.

Pre t rea tment resp i ra tory rate was higher in all the t r e a t m e n t g r o u p s b e c a u s e a s t h m a t i c pa t i en t s o f ten hyperventilate during acute attack. However, a significant (p<0.01) fall of r e s p i r a t o r y ra te was obs e rved in all treatment groups when assessed one hour after treatment. Kesten S 12 et al (1990) had similar observation in his study.

In all the t reatment groups the decrease in the pulse rate may be due to effective bronchodilation improving respiratory rate, thereby causing a decrease in pulse rate.

PEFR and p e r c e n t p r e d i c t e d PEFR inc reased significantly in MDI-S+B S* group compared to MDI-SS*. This observation is in agreement with Aldrey OE 13 et al confirming pharmacological control of both obstructive and inflammatory changes in patients with asthma.

In the p r e s e n t s t udy , the re w a s no s ta t i s t i ca l ly significant (p<0.05) change in blood sugar levels though Dawson, KP 14 et al (1995) had documented a significant increase in b lood g lucose levels b y sa lbu tamol , the probable reason being use of nebuliser in their s tudy as compared to use of MDI in the present study. The rise in b l o o d g lucose m i g h t be due to s t i m u l a t i o n of be ta receptors which lead to accumulation of cAMP. The dual effect of cAMP, to enhance convers ion of glycogen to glucose and to decrease the synthesis of glycogen f rom glucose, summate to increase the output of glucose from the liver2 s

Hypokalemia is less in patients using spacer suggests that use of spacer decreases the oropharyngeal deposition of the drug as the particles stay in the spacer and thereby, the fall in serum potass ium levels is to a lesser extent26

The stimulation of a-receptors in skeletal muscle leads to inc reased in t r ace l lu la r concen t r a t i on of cAMP and subsequen t s t imula t ion of m e m b r a n e b o u n d sod iu m p o t a s s i u m ATPase p r o b a b l y leads to fall in s e r u m potassium levels. 17

The exact mechanism of aggravation with addition of beclomethasone diproprionate is not clear, but it has been sugges t ed tha t cor t icos te ro ids res tore the b ronchia l hyperresponsivenes to beta adrenergic agonist in severe asthmatic patients and normal subjects 8. Similar decrease in serum potassium levels has been documented by other au thors . 17,t8,19, pH , PaO2, PaCO2 i m p r o v e d in all the t r ea tment g roups one hour after therapy. No serious adverse effects were observed in any of the t rea tment groups.

The present s tudy showed that PEFR improves best w i t h MDI-S+B w i t h space r w h e r e a s fall in s e r u m potassium is max imum with MDI-S+B when spacer was not used.

Thus, it can be concluded that metered dose inhalation of Beclomethasone diproprionate-salbutamol combina- tion with spacer provides better recovery in patients of acute exacerbation of bronchial as thma whereas fall in se rum po ta s s ium wi th MDI-S+B suggests that spacer should be used with MDI and serum potass ium levels shou ld be m o n i t o r e d whi le g iv ing b e c l o m e t h a s o n e diproprionate along with salbutamol.

REFERENCES

1. McFadden ER. Asthma. In Isselbacher KJ, Braunwald E, eds. Harrison's Principles of Internal Medicine, Vol. 2. 13th edn; MC Graw Hill Inc, 1994; 1167-1172.

2. Lemanske RF, Busse WW. Asthma. JAMA 1997; 278 : 1855- 1873.

3. Storr J, Barry W, Barrel E, Lenney W, Hatcher G. Effects of a single oral dose or prednisolone in acute childhood asthma. Lancet 1987; 1: 879-882.

4. Chapman KR, Verbeek PR, White JG, Rebuck AS. Effect of short course of prednisone in the prevention of early relapse after the emergency room treatment of acute asthma. N Engl J Med 1991; 324 (12) : 788-894.

5. Wolfson DH, Nypaver MM, Blaser M, Hogan A, Evans R 3rd, Davis AT. A controlled trial of methylpredniosolone in the early emergency department treatment of acute asthma in children. Paediatr Emerg Care 1994; 10 (6) : 335-338.

6. Connet GJ, Warde C, Wooler E, Lenney W. Prednisolone and salbutamol in the hospital treatment of acute asthma. Arch Dis Child 1994; 70 : 170-173.

7. Taylor DR, Wilkins GT, Herbison GP, Flannery FM. Interaction between corticosteroid and ~-agonist drugs. Biochemical and cardiovascular effects in normal subjects. Chest 1992; 102 (2) : 519-524.

8. Pauwels R. Effect of corticosteroids on action of sympatho- mimetics. Bull Eur Physiopathol Respir 1985; 21 (5) : 53-55.

9. Pedersen S, Hansen OR. Budesonide treatment of moderate and severe asthma in children : a dose-response study. ] Allergy Clin Immuno11995; 95 (1 Pt 1) : 29-33.

10. Hickey RW, Gochman RF, Chande V, Davis HW. Albuterol delivered via metered-dose inhaler with spacer for outpatient treatment of young children with wheezing. Arch Pediatr Adolesc Med 1994; 148 : 189-194.

Indian Journal of Pediatrics, Volume 70---February, 2003 131

Sunita Sharma et al

11. Taylor MRH Asthma : audit of peak flow rate guidelines for admission and discharge. Arch Dis Child 1994; 70: 432-434.

12. Kesten S, Maleki-Yazdi MR, Sanders BR, Wells JA, McKillop S1, Chapman KR et al. Respiratory rate during acute asthma. Chest 1990; 97 : 58-62.

13. Aldrey OE, Anez H, Deibis L, Tassinari P, Isturiz G, Bianco NE. A double blind, crossover study using salbutamol, beclomethasone, and a combination of both in bronchial asthma. J Asthma 1995; 32 (1) : 21-28.

14. Dawson KP, Penna AC, Manglick P. Acute Asthma, Salbutamol and hyperglycemia. Acta Paediatr 1995; 84 (3) : 305- 307.

15. Serafin WE. Drugs used in the treatment of asthma. In Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG, eds. Goodman and Gilman's-The Pharmacological Basis of

Therapeutics, 9th edn. Mc Graw Hill 1996; 659-682. 16. Ariyananda PL, Agnew JE, Clarke SW. Aerosol delivery

systems for bronchial asthma. Postgrad Med J 1996; 72 (845), 151-156.

17. Clifton GD, Hunt BA, Patel RC, Burki NK. Effects of sequential doses of parenteral terbutaline on plasma levels of potassium and related cardiopulmonary responses. Am Rev Respir Dis 1990; 141 : 575-579.

18. Dickens GR, McCoy RA, West R, Stapczynski JS, Clifton GD. Effect of nebulised albuterol on serum potassium and cardiac rythm in patients with asthma on chronic obstructive pulmonary disease. Pharmacotherapy 1994; 14 (6) : 729-733.

19. Singhi SC, Jayashree K, Sarkar B. Hypokalaemia following nebulised slbutamol in children with acute attack of bronchial asthma. J Paediatr Child Health 1996; 32 (6) : 495-497.

I II II II I

IJP TRAVEL GRANT FOR MEDICAL CONFERENCE 2 0 0 3

(Benefit for Subscribers)

1. Six grants are available. Only Pos tgradua te s tudents are eligible to apply.

2. G r a n t wi l l c o v e r t r a in j o u r n e y to a n d fro, r e g i s t r a t i o n fee a n d l i m i t e d local e x p e n s e s . Tota l expendi ture not to exceed Rs. 5000 per candidate.

3. Appl icant should submi t a copy of the research p a p e r to be p resen ted at the conference a long wi th the letter of acceptance b y the conference organizers.

4. The app l i ca t ion s h o u l d b e f o r w a r d e d t h r o u g h the H e a d of the D e p a r t m e n t a long wi th a le t ter certifying that the appl icant is not be ing suppor t ed b y any other source.

5. Appl icant should be a subscriber to the journal.

6. Appl icant should explain in 200 w o r d s w h y h e / s h e wou ld like to be considered for the grant.

For in fo rma t ion p lease wr i t e to :

Editor-in-Chief, The Indian Journal of Pediatrics, 125 (2nd Floor), G a u t a m Nagar , N e w Delhi-110049.

Post Box No. 3875, N e w Delhi - 110 049. Phones : 26568098. Telefax : 26857587 E-mail : i jp.journal.vsnl.net@vsnl.net

132 Indian Journal of Pediatrics, Volume 70--February, 2003