Hospital treatment of asthma: lack of benefit from theophylline given in addition to nebulized albuterol and intravenously administered corticosteroid

doi:10.1016/S0022-3476(05)83442-0

The Journal of Pediatrics

Volume 122, Issue 3, March 1993, Pages 464-469

https://doi.org/10.1016/S0022-3476(05)83442-0 Get rights and content

Study objective: To determine the efficacy of theophylline when given in addition to nebulized albuterol and intravenously administered corticosterold to children hospitalized with mild to moderate asthma.

Design: Randomized, prospective, placebo-controlled, double-blind trial.

Setting: Tertiary-care children's hospital.

Patients: Twenty-nine patients with asthma between the ages of 2 and 16 years completed the study. The treatment and placebo groups were similar in age, gender, race, illness severity, and emergency department treatment.

Interventions: All patients received intravenously administered methylprednisolone and nebulized albuterol. The treatment group received intravenous theophylline therapy and the placebo group dextrose in water. When intravenously administered medications were discontinued, therapy continued with oral administration of theophylline (or placebo) and of prednisone.

Measurements and main results: Twice-daily assessments of clinical asthma symptoms were made by using a scoring system consisting of respiratory rate, inspiratory/expiratory ratio, wheeze, and accessory muscle use. Time required to reach study discharge criteria (asthma score≤2) (30.4±16.8 vs 27.0±10.3 hours; p=0.51) and the rate of improvement of the clinical asthma score (−0.10±0.05 unit/hr vs−0.11±0.09 unit/hr; p=0.88) were not significantly different between the theophylline and placebo groups. The number of albuterol aerosol treatments required and the adverse effects experienced were not significantly different between groups.

Conclusion: When the combination of systemically administered corticosteroid and inhaled albuterol is used in the treatment of children hospitalized with mild to moderate asthma, addition of theophylline may not be justified.

References (21)

SelfTH et al.
Inhaled albuterol and oral prednisone therapy in hospitalized adult asthmatics: does aminophylline add any benefit?
Chest
(1990)
FantaCH et al.
Emergency room treatment of asthma: relationships among therapeutic combinations, severity of obstruction and time course of response
Am J Med
(1982)
FantaCH et al.
Treatment of acute asthma: is combination therapy with sympathomimetics and methylxanthines indicated?
Am J Med
(1986)
RobertsonCF et al.
Response to frequent low doses of nebulized salbutamol in acute asthma
J Pediatr
(1985)
FantaCH et al.
Glucocorticoids in acute asthma: a critical controlled trial
Am J Med
(1983)
CockcroftDW et al.
Theophylline does not inhibit allergen-induced increase in airway responsiveness to methacholine
J Allergy Clin Immunol
(1989)
HendelesL et al.
Theophylline: a “state of the art” review
Pharmacotherapy
(1983)
SelfTH et al.
Is theophylline use justified in acute exacerbations of asthma?
Pharmacotherapy
(1989)
PiersonWE et al.
Double-blind trial of aminophylline in status asthmaticus
Pediatrics
(1971)
BeckerAB et al.
The pulmonary index: assessment of a clinical score for asthma
Am J Dis Child
(1984)

There are more references available in the full text version of this article.

Cited by (68)

Aminophylline infusion for status asthmaticus in the pediatric critical care unit setting is independently associated with increased length of stay and time for symptom improvement
2014, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
To our knowledge this is the first study to suggest a significant correlation between the use of aminophylline for treatment of severe asthma in the PCCU setting and increased LOS and time to symptom improvement. Interestingly, several studies of the pediatric asthma population have shown a slight trend toward increased LOS or increased time to symptom improvement with the administration of aminophylline or theophylline [19–22]. These results suggest the use of aminophylline and other methylxanthines in children with severe asthma exacerbations may be associated with increased morbidity.
The role of aminophylline in the treatment of severe acute asthma in the pediatric critical care unit (PCCU) is not clear. We sought to examine the association of aminophylline treatment with PCCU length of stay and time to symptom improvement.
Patients with severe acute asthma who were admitted to our PCCU and received aminophylline infusion were retrospectively compared with similar patients who did not receive aminophylline. The primary outcome measure was functional length of stay (i.e. time to which patients could be transferred to a general pediatric ward bed). A secondary outcome was time to symptom improvement.
Adjusted functional length of stay was longer for subjects who received aminophylline (n = 49) than for the patients who did not (n = 47) (hazard ratio 0.396, p < 0.001), as well as the time for symptom improvement (hazard ratio 0.359, p < 0.001). In the group of subjects receiving aminophylline, those with a serum theophylline level ≥ 10 mcg/ml (therapeutic) (n = 31) had longer functional length of stay (hazard ratio 0.457, p = 0.0225) and time to symptom improvement (hazard ratio 0.403, p = 0.0085) than those with levels < 10 mcg/ml (sub-therapeutic) (n = 18).
The addition of aminophylline to therapy with corticosteroids and inhaled β-agonists was associated with statistically and clinically significant increases in functional length of stay and time to symptom improvement in the PCCU. This potential morbidity supports the National Asthma Education and Prevention Program guideline proscribing aminophylline use in acute asthma.
Early administration of two intravenous bolus of aminophylline added to the standard treatment of children with acute asthma
2008, Respiratory Medicine
Citation Excerpt :
We did not observe any significant difference between the two groups related to the length of stay in the observation room, the length of oxygen use, the number of beta agonist nebulizations and/or the MDI puffs administered the destination of these patients (admission to the ward or to the PICU and/or discharge from PER). These findings are in accordance with other previous studies enrolling older children.10–12 Some systematic reviews evaluating the use of aminophylline compared to placebo in children with acute asthma attack, demonstrated an improvement in lung function tests in the intervention group.13
Evaluate the efficacy of adding two intravenous bolus of aminophylline to the standard treatment of acute asthma episode in children admitted to the pediatric emergency room (PER).
Between March 2001 and February 2002, 60 children (2–5 years old), admitted to the PER at Hospital de Clínicas de Porto Alegre (Brazil), due to an episode of acute asthma, refractory to conventional therapy (an oral dose of steroids and at least three doses of inhaled albuterol, associated or not with oxygen) were enrolled in a randomized, double blind, placebo controlled clinical trial. The randomization was performed in blocks of 10 patients, who received a “bronchodilator solution” (either saline or aminophylline), in two doses: on arrival at the PER and again 6 h later. The intervention group received aminophylline 5 mg/kg/dose diluted in normal saline (NS) solution up to a 20 mL volume, while the placebo group received plain NS, both in an infusion rate of 1 cc/min. The main outcomes were total length of hospital stay, length of supplemental oxygen use, number of bronchodilator nebulizations and/or aerosol inhalations performed and patient destination. The groups were compared using the Students t-test, Mann–Whitney test and Chi-Square test, accepting p<0.05 as significant.
Comparing the main outcomes, we did not find differences between the placebo and aminophylline groups: 29.0±14.7 versus 26.2±13.4 beta-agonist nebulizations per patient (p=0.46); 2.4±10.6 versus 5.6±14.2 aerosol inhalations per patient (p=0.32); 24.7±30.0 versus 26.0±25.2 h for oxygen supplement (p=0.86); 43.2±30.0 versus 43.6±23.7 h for length of hospital stay (p=0.95). We also did not find differences between the two groups related to the blood pressure, heart rate, respiratory rate and oxygen saturation.
In children aged 2–5 years admitted to a PER with asthma, two intravenous doses of 5 mg/kg of aminophylline given 6 h apart did not change the length of stay in hospital, the number of nebulizations given or the duration of oxygen therapy required. We are unable to tell whether there would be benefit with higher doses of aminophylline designed to give levels in the usual therapeutic range.
Emergency department management of pediatric asthma
2004, Clinical Pediatric Emergency Medicine
For the physician providing acute care for children, knowledge of optimal management of pediatric asthma is essential. Asthma is one of the most common diseases of childhood, with a prevalence rate of 5.4% in the pediatric population, accounting for 17% of pediatric encounters in US emergency departments.
Asthma is characterized by bronchial hyperreactivity, airway inflammation, and reversible airway obstruction. New developments in the understanding of the underlying physiology and pharmacologic treatment of pediatric asthma have occurred in recent years. Although inhaled beta-adrenergic agonists remain the initial treatment of choice for acute bronchospasm in asthma, there is increased understanding of the importance of inflammation in the disease process. There is also recognition of the role of cholinergic-mediated airway obstruction.
This review focuses on the clinical applications of these concepts in the emergency management of pediatric asthma, the role of newer treatment modalities, and the value of implementing an emergency department management protocol.
Contemporary approach to the emergency department management of pediatric asthma
2002, Emergency Medicine Clinics of North America
Efficacy of IV theophylline in children with severe status asthmaticus
2001, Chest
Citation Excerpt :
Furthermore, controlled studies incorporating a variety of clinical scoring tools for gauging asthma severity have been unable to document an influence of methylxanthines on the rate of improvement or time to achieve a predetermined severity score.2223252627 However, the generalization of these results to severe status asthmaticus has been limited by the exclusion of patients who could not perform standard pulmonary function testing,23 had a Pco2 > 50 mm Hg,23scored > 5 on the CAS,24 failed to improve within 6 h,2327 or required PICU admission.22242526 Yung and South38 conducted a large, randomized, controlled trial of combination therapy in children with severe, acute asthma that, for the first time, was inclusive of patients who were poorly responsive to β-agonists, in impending respiratory failure, or admitted to the PICU.
To determine whether adding IV theophylline to an aggressive regimen of inhaled and IV β-agonists, inhaled ipratropium, and IV methylprednisolone would enhance the recovery of children with severe status asthmaticus admitted to the pediatric ICU (PICU).
A prospective, randomized, controlled trial. Asthma scoring was performed by investigators not involved in treatment decisions and blinded to group assignment.
The PICU of an urban, university-affiliated, tertiary-care children's hospital.
Children with a diagnosis of status asthmaticus who were admitted to the PICU for ≤ 2 h and who were in severe distress, as indicated by a modified Wood-Downes clinical asthma score (CAS) of ≥ 5.
All subjects initially received continuous albuterol nebulizations; intermittent, inhaled ipratropium; and IV methylprednisolone. The theophylline group was also administered infusions of IV theophylline to achieve serum concentrations of 12 to 17 μg/mL. A CAS was tabulated twice daily.
Forty-seven children (median age, 8.3 years; range, 13 months to 17 years) completed the study. Twenty-three children received theophylline. The baseline CASs of both groups were similar and included three subjects receiving mechanical ventilation in each group. All subjects receiving mechanical ventilation and theophylline were intubated before drug infusion. Among the 41 subjects who were not receiving mechanical ventilation, those receiving theophylline achieved a CAS of ≤ 3 sooner than control subjects (18.6 ± 2.7 h vs 31.1 ± 4.5 h; p < 0.05). Theophylline had no effect on the length of PICU stay or the total incidence of side effects. Subjects receiving theophylline had more emesis (p < 0.05), and control patients had more tremor (p < 0.05).
Theophylline safely hastened the recovery of children in severe status asthmaticus who were also receiving albuterol, ipratropium, and methylprednisolone. The role of theophylline in the management of asthmatic children in impending respiratory failure should be reexamined.
The effectiveness of high-dose inhaled budesonide therapy in the treatment of acute asthma exacerbations in children
2001, Annals of Allergy, Asthma and Immunology
International guidelines recommend the use of systemic steroids for the treatment of acute asthma attack if it has not been resolved within 24 to 36 hours of home management with regular β₂ mimetic inhalation. Such therapy for infrequent exacerbations is unlikely to have serious systemic effects. Unfortunately, many patients receiving frequent courses are potentially at risk for corticosteroid-induced side effects such as adrenal suppression, depression of linear growth, and osteoporosis.
To decrease the use of frequent oral corticosteroid courses in children, this study was designed to evaluate the efficacy of high-dose inhaled steroids in comparison with oral steroids, in the therapy of acute asthma exacerbations in children.
Sixty children who have experienced an acute exacerbation of asthma unresponsive to home management with regular use of inhaled β₂ mimetics, yet not severe enough to hospitalize, were randomized to be treated with either high-dose inhaled budesonide (1600 μg daily) or oral methylprednisolone (1mg/kg daily) plus medium-dose inhaled budesonide (800 μg daily, both in addition to inhaled terbutaline, 2000 μg daily). Pre- and posttreatment pulmonary index scores, forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), FEV₁/FVC and forced expiratory flow 25% to 75% (FEF_25%-75%) were evaluated.
The mean number of decrease in pulmonary index score was 2.61 ± 1.12 in the high-dose budesonide-receiving group (group I) and 1.90 ± 1.08 in the oral steroid-receiving group (group II). There was a statistically significant difference between the two groups, in favor of group I (P = .038). No statistically significant difference was detected between the two groups with respect to the increase in lung function test measurements (FEV₁, FEV₁/FVC, FEF_25%-75%; P = .790, .959, .819, respectively).
Short-term high-dose budesonide therapy can be considered an alternative for children who are experiencing an acute asthma attack that is unresponsive to home management with regular use of an inhaled β₂ mimetic, yet who are not severe enough to hospitalize.

View all citing articles on Scopus

^**: Supported in part through a grant from the Central Ohio Lung Association.

^*: Now at the Department of Emergency Medicine, Children's Hospital Medical Center, Cincinnati, OH 45229-2899.

View full text

Hospital treatment of asthma: lack of benefit from theophylline given in addition to nebulized albuterol and intravenously administered corticosteroid**

Chest

Am J Med

Am J Med

J Pediatr

Am J Med

J Allergy Clin Immunol

Theophylline: a “state of the art” review

Pharmacotherapy

Is theophylline use justified in acute exacerbations of asthma?

Pharmacotherapy

Double-blind trial of aminophylline in status asthmaticus

Pediatrics

The pulmonary index: assessment of a clinical score for asthma

Am J Dis Child