Original Article

Levosalbutamol vs Racemic Salbutamol in the Treatment

of Acute Exacerbation of Asthma
Ajay Punj, Ashish Prakash and Ashu Bhasin
Department of Pediatrics, Subharti Institute of Medical Sciences, Meerut, U.P. India

ABSTRACT
Objective. To compare efficacy and tolerability of levosalbutamol (Group 1) and racemic salbutamol (Group 2) for the
treatment of acute exacerbation of asthma in children age 5 to 18 yr.
Methods. A randomized double blind clinical study involving 60 children was undertaken between October 06 to
December 07.
Results. The following baseline clinical characteristic were recorded initially and after giving 3 nebulizations at 20 min
intervals in the Ist hour of presentation viz respiratory rate (RR), heart rate (HR), oxygen saturation in room air SPO2, PEFR
(peak expiratory flow rate), serum K+ level and asthma score. In Group 1 patients (levosalbutamol), there was significant
increment in SPO2 and PEFR (P<0.05) values with decrease in tachypnea and asthma score while no significant difference
was found in pre and post treatment HR & Serum K+ levels. In Group 2 patients although there was clinical improvement in
terms of SPO2, PEFR, RR and asthma score, it resulted in significant tachycardia and decrease in K+ levels.
Conclusion. Levosalbutamol appears to be more efficacious than racemic salbutamol in terms of improvement in PEFR,
SPO2 and asthma score while deleterious effects of tachycardia and fall in serum K+ were seen with racemic salbutamol.
[Indian J Pediatr 2009; 76 (11) : 1131-1135] E-mail: punj.ajay@yahoo.com

Key words
words: Levosalbutamol; Racemic Salbutamol; Asthma

Inhalation therapy is the cornerstone of asthma

management. Salbutamol, the most commonly used
bronchodilator, is a chiral drug with R and S Isomers
(also known as enantiomers). The commonly used
formulation is a racemic mixture that contains equal
amounts of both R and S isomers. 1,2 Levosalbutamol
(LEV) the R isomer is the therapeutically active isomer
and has all the 2 agonist activity. Until recently Ssalbutamol was considered inert filler in the racemic
mixture but animal as well as human studies have
shown that S- salbulamol is not inert, rather it may have
some deleterious effects. Formulation of salbutamol
containing only R-isomer (levosalbutamol) has been
available in international market for the last few years.
Although the drug is available for some time now and it
has been theoretically recommended in cases of acute
severe asthma but no clinical study is available in
Indian population till date to compare the efficacy
between levosalbutamol and racemic salbutamol.
Correspondence and Reprint requests : Dr. Ajay Punj,
Department of Pediatrics, Subharti Institute of Medical Sciences,
Meerut, U.P. India.
[DOI-10.1007/s12098-009-0245-4]
[Received July 02, 2008; Accepted October 8, 2008]

Indian Journal of Pediatrics, Volume 76November, 2009

Though salbutamol is an effective treatment of acute

exacerbations but its use is associated with undesirable
side effects like tachycardia and hypokalemia. Hunt for
a more effective drug with less side effect is still on. The
studies that have tried to resolve the issue have either
been done in adult3 or if in children, they have included
subjects starting from one yr of age which will also have
less than five yr old with reactive airway disease and
hence a heterogenous population.4 Others have used a
combination of levosalbutamol with ipratropium
bromide. 5 Some studies have done a head on
comparison of LEV with RAC but in chronic stable
asthma patients. 6 Hence to the best of our knowledge,
efficacy and tolerability of LEV have not been compared
with RAC in acute exacerbation asthma in Indian
children, which was the purpose of our study.

MATERIAL AND METHODS

A randomized double-blind clinical study involving 60
children was undertaken between October06 to
December07 in the Department of Pediatrics, Subharti
Medical College, Meerut, to compare the efficacy and
1131

Ajay Punj et al
tolerability of levosalbutamol and Racemic salbutamol
in acute asthma. Sixty consecutive children of either
sex between ages of 5 to 18 yr, known cases of asthma
and presented to the ED (emergency department) with
acute exacerbation of asthma and who were able to use
the peak flow meter were enrolled in the study. Those
children already on preventive therapy (steroids or
LABA), first episode of wheezing, known case of
hypersensitivity to salbutamol, cyanotic or uncorrected
CHD, cystic fibrosis and any other chronic lung disease,
were excluded from the study. Informed consent was
obtained from the parents.
The study medicines were salbutamol 2.5 mg and
levosalbutamol 0.63 mg, concealed in numbered
envelope and all the eligible patients were randomly
assigned. The total drug volume was 2.5 ml in
nebulizing chamber & nebulized over a period of 8-10

minutes and patient was instructed to inhale from his

mouth. PEFR was measured using MINI-WRIGHTS
peak flow meter. Child was made to use the flow meter
in a standing position 3 times and best of the three
values was taken. PEFR was replicable and
reproducible as only those patients were included in
the study who were able to perform the maneuver and
best of three values was recorded
The following baseline clinical characteristics were
recorded initially and after giving 3 nebulizations at 20
min. intervals in the 1 st hour of ED presentation viz.
respiratory rate (RR), Heart rate (HR) oxygen
saturation in room air (SPO2) , PEFR (peak expiratory
flow rate) & Serum. K + level. Severity of asthma was
numerically assessed using the following asthma
scores.7

ASTHMA SEVERITY ASSESSEMENT

ASTHMA SCORE

Resp. rate
2-3 yrs
4-5 yrs
6-12 yrs
> 12 yrs
O2 saturation (Room Air)
Ausculation
Retraction
Dyspnea

1 point

2 point

3 point

3 4
3 0
2 6
2 3
> 95%
No to mild end-expiratory
wheezing
None, or Intercostal

35-39
31-35
27-30
24-27
90-95%
Expiratory Wheezing

Speaks in sentences or
coos and babbles

Speaks in partial sentences,

or utters short cries

40
36
31
28
<90
Insp+Exp wheezing, or
Diminished BS
Intercostal, Substernal +
Supraclavicular
Speaks in single words or
short phrases, or grunts

Intercostal + Substernal

SEVERITY ASSESSMENT

Asthma Score
% Predicted Peak Flow

Mild

Moderate

Severe

5-7
> 70%

8-11
50-70%

12-15
<50%

The duration that the child was treated in ED was one hr. during which no steroids were given and further drug treatment of admitted
children was according to asthma treatment protocol of the department.

The study was double-blind and comparative in

nature to assess the effects of two drugs on the above
mentioned parameters. The allotment was done
using Tippets Random Number table. The efficacy
of blinding was checked by asking the resident
doctors to identify the respules of drugs
levosalbutamol and salbutamol respectively;
however no one could identify the difference between
the drugs.

into account in the present study. Approval for the

study was taken from the ethical committee of the
institute. Departmental review board approved the
protocol for study.

A sample size of 29 was required to detect the

difference of 15% in PEFR with power of 95 % in
between two groups LEV and RAC by using the
formula 4pq/L2 , (least permissible error = 0.0129); so
sample size of 60 patients (30 in each group) was taken

Data were recorded on a predesigned proforma and

managed on an excel spread sheet. All the values were
expressed as mean S.D for pre-treatment and post
treatment effects. Comparative analysis of baseline
parameters of two groups and within the group before
and after treatment and percentage of improvement
between these two groups and comparison of two
groups after treatment were done using unpaired t
test. All the statistical analysis was done by using SPSS
package(11.5) version.

1132

Indian Journal of Pediatrics, Volume 76November, 2009

Levosalbutamol v s Racemic Salbutamol in the Treatment of Acute Exacerbation of Asthma

RESULTS
Of 84 asthmatics aged 5 to 18 yr presenting in ED with
acute exacerbation, 60 patients were enrolled and
randomized to treatment with either LEV or RAC (Fig.
1). 24 patients were considered ineligible. Group 1 (n =
30) received levosalbutamol 0.63 mg per dose and
Group 2 (n=30) received salbutamol 2.5mg per dose.

All the values for pre and post treatment parameters

are expressed as mean SD. Comparison done by
using unpaired t test at 5% and 1% level of
significance ( =0.05) and ( =0.01).All the statistical
analysis was done by SPSS (11.5) version.
In Group 1 patients (LEV) there was significant
increment in SPO 2 and PEFR, values with decrease in
tachypnea & asthma score while no significant
difference was found in HR & Serum K + levels. In
Group 2 (RAC) patients although there was clinical
improvement in terms of SPO 2 , PEFR, RR, and asthma
score but it resulted in significant tachycardia &
decrease in K+ levels.
Pretreatment values for various parameters were
comparable between the 2 group (Table 3) P value being
insignificant (P>0.05) in all.
T ABLE 3. Baseline Profile of Patients Enrolled in Study
Group 1 (LEV)

Fig. 1. Patient flow

Baseline characteristics like age, sex, diagnosis,

duration of asthma were comparable between the two
groups. None of the patients were receiving preventive
therapy (steroids or LABA) before presenting to ED.they
were either lost to preventive therapy or never initiated
on preventive therapy (i.e., on intermittent therapy).
None was given steroids during their one hr stay at ED.
To judge the effect of drug, following parameters
were taken; both pre & post treatment in both groups
RR, HR, SPO2, PEFR. Serum K+ levels and Asthma score
(Tables 1 and 2).
TABLE 1. Pre Treatment Observations
Parameters

Levosalbutamol

RR (per minute)
HR (per minute)
SPO2 (%)
PEFR (L/min)
Serum K +(meq/l)
Asthma score

29.53 5.12
109 18.20
95.57 14.81
195.33 29.82
4.67 0.78
7.38 1.27

Salbutamol

P value

29.7 4.16
108.53 17.96
95.77 13.84
196 30.49
4.65 0.69
9.27 1.32

1.38(P>
1.62(P>
1.51(P>
1.40(P>
1.22(P>
1.31(P>

0.05)**
0.05)**
0.05)**
0.05)**
0.05)**
0.05)**

Group 2 (RAC)

Age (years) 9.57 3.60

10.77 4.05
Sex
Boys
15
19
Girls
15
11
ED visits (past 12 mths)
O
10
13
1
20
17
Hospitalization (past 12 mths)
O
24
25
1
6
5
Duration of illness (years mean SD)
3.15 2.17
3.45 2.54

P value
P>.05 (1.38) *
P>.05 (.6061)*

P>.05 (.6346)*

P>.05 (.1113)*

P>.05 (.7295)*

*Not significant

Same parameters were compared between the two

groups after giving treatment. There was statistically
significant change (P<0.05) noticed in all the above 6
parameters (Table 2) Also a significant difference was
observed for HR, SPO2 , PEFR, and serum K+ levels and
asthma score at 1% level of significance (P<0.01)
Hence there was
improvement in clinical
parameters in Group 1 (LEV) patients in relation to RR,
SPO 2 , PEFR values and the clinical side effects of
tachycardia and low K + level were less compared to
Group 2 (RAC).

DISCUSSION

*not significant
TABLE 2. Post Treatment Observations
Parameters

Levosalbutamol

RR (per minute)
HR (per minute)
SPO2 (%)
PEFR (L/min)
Serum K + (meq/l)
Asthma score

25.6 3.60
108.43 13.25
98.23 11.01
275 32.61
4.43 0.63
5.2 0.73

Salbutamol
26.37 3.82
123.07 15.04
97.73 7.22
273 30.38
3.64 0.52
6.7 0.69

P value
2.19 (P < 0.05)*
2.63 (P < 0.05)*
2.73 (P < 0.05)*
2.92 (P < 0.05)*
3.01 (P < 0.05)*
8.17 (P < 0.05)*

Indian Journal of Pediatrics, Volume 76November, 2009

Results of this double blind randomized trial suggest

that administration of levosalbutamol by nebulizer in
children between the ages of 5 to 18 yr presenting with
acute exacerbation of asthma causes statistically
significant greater improvement in terms of PEFR, SPO2,
RR, and asthma score, as compared to salbutamol
inhalation. There was no increase in heart rate or fall in
K+ levels with levosalbutamol.
1133

Ajay Punj et al
Salbutamol is the most commonly used 2 agonist for
the treatment of asthma. Synthetic 2 agonist
bronchodilators including salbutamol are developed,
based on the structure of the epinephrine and thus are
supposed to mimic their bronchodilating action.
However, endogenous epinephrine produced in
human body is a pure single isomer R-epinephrine
whereas most of the 2 agonist drugs including
salbutamol are racemic drugs containing mixture of
50%-50% of R (Levo) and S (Dextro) optical isomers
(also known as enantiomers). Only R-isomer fits into
three-dimensional conformation of 2 adrenoceptor
proteins.1,2
LEV has approximately 2 fold greater affinity than
racemic salbutamol (RAC) for the 2 adrenergic receptor
and approximately 100 fold greater binding affinity
than S-salbutamol. LEV elevates intracellular
concentration of cyclic AMP (cAMP) by activating
adenyl cyclase. In the airways, increased concentration
of cAMP relaxes bronchial smooth muscle by reducing
intracellular calcium and prevents contraction of
hyperresponsive airways. Increased concentration of
cAMP also inhibits the release of inflammatory
mediators from mast cells and eosinophils.1,8
Recently, it has been established that regular and
excessive use of RAC induces paradoxical reactions in
some subjects with asthma. 9 This has led to
development of safer and therapeutically active agents
of the available 2 agonists. Consequently,
Levosalbutamol was approved by FDA (Food and
Drug Administration) in 1999 as a purified singleisomer for clinical use in asthma patients.
S-salbutamol causes bronchial hyperresponsivenes
by a cholinergic dependent 2 adrenergic independent
mechanism. 10 It has been observed that when Ssalbutamol or LEV is exposed to isolated human
bronchus, S-salbutamol enhances and LEV inhibits the
contractile response to histamine and leucotriene
C4. 11,12 These pharmacologic actions, if translated
clinically, suggest that in the absence of LEV induced
smooth muscle relaxation, S-salbutamol has the
potential to induce bronchoconstriction in asthmatic
patients.13
S-salbutamol may promote airway obstruction by
increasing mucus secretion by airway epithelial cells
and interfering with mucociliary clearance.14,15 Airway
mucus plugging and increased number of neutrophils
and cytotoxic T cells in the lung have been associated
with fatal exacerbation in asthma patients.16
Airway inflammation is an important feature of
asthma and S-salbutamol has been shown to promote
the synthesis and release of numerous inflammatory
mediators from esinophils, mast cells, T-lymphocytes
and airway epithelial cells. It also induces
1134

morphological changes in neutrophils and

granulocytes that are associated with recruitment and
activation of these cells.17,18,19,20
We compared LEV to RAC in acute exacerbation of
asthma because the available study which has
compared LEV to RAC in pediatric population has
been done in settings of chronic stable asthma patients.6
although they have also shown that LEV (0.63mg)
produces greater percent change in FEV1 immediately
post nebulization (18%) than (2.5mg) RAC (15.6%)
Studies assessing the efficacy of LEV in acute
exacerbation of asthma have been done in adults.21,3 but
none in children. One study has compared LEV with
RAC but has included children population starting
from 1 yr which will include less than 5 yr old with
reactive airway disease and hence a heterogeneous
population. 4 This study has only assessed
hospitalization as outcome measure which was less
with LEV. Hence though this outcome measure is not
same as in the present study, its points towards
usefulness of LEV similar to the present results. In this
study there was no demonstration of reduction of side
effects like tremors and tachycardia but then they had
used a higher dose of LEV (1.25 mg). In the present
study using a lesser dose of LEV (0.63mg), there was
reduction in side effects while therapeutic efficacy
remained better than RAC. The authors calculated the
extra cost burden of using LEV, it was only Rs.2.10 per
therapy (3 respules). The lower dose of LEV used in the
present study has offset the cost disadvantage of LEV
usage shown in other studies.4
Another study has compared LEV with a
combination of salbutamol and ipratropium bromide
(IB) in children between 6-18 yr presenting with acute
asthma and reported that LEV was associated with less
tachycardia but had shown no other advantage over
RAC with IB. 5 In the present study also tachycardia
was less. Hypokalemia was also significantly less with
LEV in the present study, this issue has not been
addressed in any of the previous studies.
The present study had some limitations, one was
that FEV1 was not assessed. Though this has
demonstrated higher sensitivity and more optimal
baseline reproducibility compared to PEFR22. We used
PEFR instead of FEV1 as an index of airway
obstruction, given the limitations of PEFR we obtained 3
PEFR measurements for each patient at baseline and
after treatment and recorded the highest PEFR of the 3
measurements. Other studies have also assessed the
PEFR as the spirometric indices are not used to make a
decision regarding hospital admission or discharge 5,
hence PEFR was thought to be of better practical utility.
Rate of admission to the hospital from the ED was not
chosen to be an outcome measure due to the large
Indian Journal of Pediatrics, Volume 76November, 2009

Levosalbutamol v s Racemic Salbutamol in the Treatment of Acute Exacerbation of Asthma

1. Penn RB, Frielle T, McCullough FR, Aberg G, Benovic J.

Comparison of R-, S- and RS-albuterol interaction with
human 1-and 2 adrenergic receptors. Clin Rev Allergy
Immunol 1996;14: 37-45.
2. Clive P, Jhon M. Contrasting properties of albuterol
stereoisomers. J Allergy Clin Immuno 1999; 104 : S31-41.
3. Nowak RM, Emerman CL, Schaefer K, Disantosterfano RL,
Vaickus L, Roach JM. Levalbuterol compared with racemic
albuterol in the treatment of acute asthma: results of a
polot study. Am J Emerg Med 2004; 22 : 29-36.
4. Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison
of racemic albuterol and levalbuterol for treatment of acute
asthma. J Pediatr 2003; 143: 731-736.
5. Ralston ME, Euwema MS, Knecht KR, Ziolkowski TJ,
Coakley TA, Cline SM. Comparison of levalbuterol and
racemic albuterol combined with ipratropium bromide in
acute pediatric asthma: a randomized controlled trial. J

Emerg Med 2005; 29 : 29-35.

6. Milgrom H, Skoner CP, Bensch G, Kim KT, Claus R,
Baumgartner RA. Low-dose levalbuterol in children with
asthma: safety and efficacy in comparision with placebo
and racemic albuterol. J Allergy Clin Immunol 2001; 108:
938-945.
7. Qureshi F, Pestian J, Davis P et al. Effect of neubulised
ipratropium on hospitalisation rates on children with
asthma. NEJM 1998; 339: 1030-1035.
8. Canning B. Pharmacological properties of S-albuterol in
human airway smooth muscle preparations. Am J Resp Crit
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9. Van Essen-Zandvliet EE, Hughes MD et al. Effects of 22
months of treatment with inhaled salbutamol lung function,
airway responsiveness, and symptom in children with
asthma. Am Rev Resp Dis 1992; 146: 547-554.
10. Keir S, Page C, Spina D. Bronchial hyper-responsiveness
induced by chronic treatment with albuterol: role of sensory
nerves. J Allergy Clin Immunol 2002; 110: 388-394.
11. Templeton AGB, Chapman ID, Chilvers E, Morley J,
Handley DA. Effects of (S)-albuterol on isolated human
bronchus. Pulm Pharmacol 1998; 11 : 1-6.
12. Mazzoni L, Naef R, Chapman ID, Morley J. Hyperresponsiveness of the airway to histamine following
exposure of guinea pigs to racemic mixtures and distomers
of 2 selective sympathomimetics. Pulm Pharmacol 1994; 7:
367-376.
13. Cockcroft DW, Swystun VA. Effect of single doses of SSalbutamol, R-Salbutamol, racemic salbutamol, and
placebo on the airway response to methacholine. Thorax
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14. Chang MM, Zhao YH, Chen Y et al. S-albuterol but not other
2 agonist isomers, has stimulatory effects on mucin
secretion and changes in gene expression on airway
epithelium. Am J Resp Crit Care Med 2001; 161 : A 144
15. Perterson BT, Miller EJ, Effect of enatiomers of albuterol on
lung epithelial permeability. Am J REsp Crit Care Med 2000;
161: A 416
16. OSulivan S, Cormican L, Faul JL, Ichinohe S, Johnston SL et
al. Activated, Cytotoxic CD8 + T Lymphocytes contribute
to the pathology of asthma death. Am J Resp Crit Care Med
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effects of 2 adrenergic agonist on eosinophil response to IL5. J Allergy Clin Immunolo 1998; 111 : S35.
18. Cho SH, Haartleroad JY, Oh CK. S-albuterol increases the
production of histamine and IL-4 in mast cells. Int Arch
Allergy Imunolo 2001; 124: 478-484.
19. Friere M, Pergolizzi R, Millon C, Dominguez PJ. Cytokine,
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20. Kwong CC, Chung QN, Choi SS et al. Effects of isomers of
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1843-1849.

Indian Journal of Pediatrics, Volume 76November, 2009

1135

number of enrolled subjects that would be required to

detect a significant reduction in admission rate between
the two groups.
In summary in a sample of children aged 5-18 yr
presenting to the ED with acute exacerbation of asthma
with initial mean PEFR < 80% of predicted, nebulized
LEV (0.63mg) demonstrated efficacy in terms of
significant improvement in SpO2, PEFR and asthma
score (P<0.01) and better tolerability in terms of less
tachycardia and less hypokalemia compared to RAC
(P<0.01)

CONCLUSION
LEV offers health care provider and patients a safe, well
tolerated and efficacious bronchodilator. LEV appears
to be more efficacious than RAC in terms of PEFR, SPO2
and asthma score while deleterious effects of
tachycardia and fall in Serum K+ levels were seen with
RAC and the total cost of therapy remained comparable.
Hence levosalbutamol should be considered as first line
therapy in situations in which a short acting beta
agonist is warranted.
Contributions: Dr. Ajay initiated and designed the study
directed the data analysis and wrote the manuscript; he will act as
the gurantor of the paper Dr. Ashish helped in designing the
study discussed the core ideas, analysed and edited the
manuscript. Dr. Ashu helped in data collection and analysis and
edited the manuscript.
Conflict of Interest: None
Role of Funding Source: Departmental Funding

REFERENCES