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Meta-Analysis
. 2005 Apr 18;2005(2):CD001276.
doi: 10.1002/14651858.CD001276.pub2.

Intravenous aminophylline for acute severe asthma in children over two years receiving inhaled bronchodilators

A Mitra  1 , D Bassler, K Goodman, T J Lasserson, F M Ducharme
Affiliations
Meta-Analysis

Intravenous aminophylline for acute severe asthma in children over two years receiving inhaled bronchodilators

A Mitra et al. Cochrane Database Syst Rev. .

Abstract

Background: Since the advent of inhaled beta2-agonists, anticholinergic agents and glucocorticoids, the role of aminophylline in paediatric acute asthma has become less clear. There remains some consensus that it is beneficial in children with acute severe asthma, receiving maximised therapy (oxygen, inhaled bronchodilators, and glucocorticoids).

Objectives: To determine if the addition of intravenous aminophylline produces a beneficial effect in children with acute severe asthma receiving conventional therapy.

Search strategy: The Cochrane Airways Group register of trials was used to identify relevant studies. The latest search was carried out in December 2004

Selection criteria: Randomised-controlled trials comparing intravenous aminophylline with placebo in addition to usual care in children met the inclusion criteria.

Data collection and analysis: Two reviewers independently assessed studies and extracted data. Disagreement in the selection of trials was resolved by consensus. Attempts were made to contact authors to verify accuracy of data.

Main results: Seven trials met the inclusion criteria (380 participants). Methodological quality was high. All studies recruited children with acute severe asthma and requiring hospital admission. Six studies sought participants who were unresponsive to nebulised short-acting beta-agonist and administered systemic steroids to study participants. In two studies where some children were able to perform spirometry, baseline FEV1 was between 35 and 45% predicted. The addition of aminophylline to steroids and beta2-agonist significantly improved FEV1% predicted over placebo at 6-8 hours, 12-18 hours and 24 hours. Aminophylline led to a greater improvement in PEF% predicted over placebo at 12-18 hours. There was no significant difference in length of hospital stay, symptoms, frequency of nebulsations and mechanical ventilation rates. There were insufficient data to permit aggregation for oxygenation and duration of supplemental oxygen therapy. Aminophylline led to a three-fold increase in the risk of vomiting. There was no significant difference between treatment groups with regard to hypokalaemia, headaches, tremour, seizures, arrhythmias and deaths.

Authors' conclusions: In children with a severe asthma exacerbation, the addition of intravenous aminophylline to beta2-agonists and glucocorticoids (with or without anticholinergics) improves lung function within 6 hours of treatment. However there is no apparent reduction in symptoms, number of nebulised treatment and length of hospital stay. There is insufficient evidence to assess the impact on oxygenation, PICU admission and mechanical ventilation. Aminophylline is associated with a significant increased risk of vomiting.

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Conflict of interest statement

None known.

Figures

1.1
1.1. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 1 FEV1 ‐ Change in % Predicted FEV1 within 4hrs of enrolment.
1.2
1.2. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 2 FEV1 ‐ Change in % Predicted FEV1 6‐8 hrs after enrolment.
1.3
1.3. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 3 FEV1 ‐ Change in % Predicted FEV1 at 12‐18hrs after enrolment.
1.4
1.4. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 4 FEV1 ‐ Change in %Predicted FEV1 at 24hrs after enrolment.
1.6
1.6. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 6 Peak Flow ‐ Change in PEF at 6‐8hrs after enrolment (SMD).
1.7
1.7. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 7 Peak Flow ‐ Change PEF at 12‐18hrs after enrolment (SMD).
1.8
1.8. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 8 Peak Flow ‐ Change PEF at 24 hrs after enrolment (SMD).
1.22
1.22. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 22 Change in symptom scores 6‐8hrs after enrolment ‐ SMD (Standardised Mean Difference).
1.23
1.23. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 23 Change in symptom scores 12‐18hrs after enrolment ‐ SMD (Standardised Mean Difference).
1.24
1.24. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 24 Change in symptom scores 24hrs after enrolment ‐ SMD (Standardised Mean Difference).
1.25
1.25. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 25 Number of nebulisers required in 24hours.
1.26
1.26. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 26 ICU Admission Rates.
1.27
1.27. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 27 Rates of Patients Mechanically Ventilated in ICU.
1.28
1.28. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 28 Length of Hospital Stay.
1.29
1.29. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 29 Vomiting.
1.30
1.30. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 30 Headache.
1.31
1.31. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 31 Tremor.
1.32
1.32. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 32 Seizures.
1.34
1.34. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 34 Arrhythmias.
1.35
1.35. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 35 Blood pressure.
1.38
1.38. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 38 Death.
1.40
1.40. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 40 Withdrawal due to adverse health events.
1.41
1.41. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 41 Withdrawal due to poor asthma control.
1.43
1.43. Analysis
Comparison 1 Aminophylline + ß2‐agonists & systemic steroids versus placebo + ß2‐agonists & systemic steroids, Outcome 43 Withdrawal (any cause).
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Bien 1995 {published data only}
    1. Bien JP, Bloom MD, Evans RL, Specker B, O'Brien KP. Intravenous theophylline in pediatric status asthmaticus. A prospective, randomized, double‐blind, placebo‐controlled trial. Clinical Pediatrics 1995;34(9):475‐81. [MEDLINE: ; UI: 96072999] - PubMed
Carter 1993 {published data only}
    1. Carter E, Cruz M, Chesrown S, Sheih G, Reilly K, Hendeles L. Efficacy of intravenously administered theophylline in children hospitalised with severe asthma. Journal of Pediatrics 1993;122(3):470‐6. [MEDLINE: ; UI: 93180095] - PubMed
Di Giulio 1993 {published data only}
    1. DiGiulio GA, Kercsmar CM, Krug SE, Alpert SE, Marx CM. Hospital treatment of asthma: lack of benefit from theophylline given in addition to nebulized albuterol and intravenously administered corticosteroid. Journal of Pediatrics 1993;122(3):464‐9. [MEDLINE: ; UI: 93180094] - PubMed
Needleman 1995 {published data only}
    1. Needleman JP, Kaifer MC, Nold JT, Shuster PE, Redding MM, Gladstein J. Theophylline does not shorten hospital stay for children admitted for asthma. Archives of Pediatrics & Adolescent Medicine 1995;149(2):206‐9. [MEDLINE: ; UI: 95152717] - PubMed
Nuhoglu 1998 {published data only}
    1. Nuhoglu Y, Dai A, Barlan IB, Basaran MM. Efficacy of aminophylline in the treatment of acute asthma exacerbation in children. Annals of Allergy, Asthma, & Immunology 1998;80(5):395‐8. [MEDLINE: ; UI: 98270772] - PubMed
Strauss 1994 {published data only}
    1. Strauss RE, Wertheim DL, Bonagura VR, Valacer DJ. Aminophylline therapy does not improve outcome and increases adverse effects in children hospitalized with acute asthmatic exacerbations. Pediatrics 1994;93(2):205‐10. [MEDLINE: ; UI: 94167167] - PubMed
Yung 1998 {published and unpublished data}
    1. Yung M, South M. Randomised controlled trial of aminophylline for severe acute asthma. Archives of Disease in Childhood 1998;79(5):405‐10. [MEDLINE: ; UI: 99209332] - PMC - PubMed

References to studies excluded from this review

Baba 2002 {unpublished data only}
    1. Baba K, Taniguchi H, Noda Y, Arai T, Suzuki K, Takagi K, et al. Treatment with NKH477, a water soluble forskolin derivative for acute exacerbation of asthma: comparison with clinical effects of aminophylline. Chest (www.abstracts‐to‐view.com). 2002:S181.
Evans 1979 {published data only}
    1. Evans WV, Monie RDH. Aminophylline, salbutamol and combined intravenous infusions in acute severe asthma [abstract]. British Journal of Diseases of the Chest 1979;73:423‐4. - PubMed
Hambleton 1979 {published data only}
    1. Hambleton G, Stone MJ. Comparison of IV salbutamol with IV aminophylline in the treatment of severe, acute asthma in childhood. Archives of Disease in Childhood 1979;54(5):391‐2. - PMC - PubMed
Kato 2004 {published data only}
    1. Kato M, Masago K, Kawashita H, Miyamoto N, Hirata T. Combination therapy with systemic corticosteroid and theophylline is more effective for the treatment of acute exacerbation of asthma [Abstract]. American Thoracic Society 100th International Conference, May 21‐26, Orlando. 2004:A37 Poster J77.
Matsubara 1998 {published data only}
    1. Matsubara Y, Shimada T. The effects of aminophylline infusion in the treatment of children with acute asthma exacberation ‐ Evaluation with (81m)Kr ventialtoin scintigraphy. Jikeikai Medical Journal 1998;45(3):75‐84.
Nakano 2006 {published data only}
    1. Nakano J, Yano T, Yamamura K, Yoshihara H, Ohbayashi O, Yamashita N, Ohta K. Aminophilline suppress the release of chemical mediators in treatment of acute asthma. Respiratory Medicine 2006;100(3):542‐50. - PubMed
Pierson 1971 {published data only}
    1. Pierson WE, Bierman CW, Stamm SJ, Arsdel PP Jr. Double‐blind trial of aminophylline in status asthmaticus. Pediatrics 1971;48(4):642‐6. - PubMed
Ream 2001 {published data only}
    1. Ream RS, Loftis LL, Albers GM, Becker BA, Lynch RE, Mink RB. Efficacy of IV Theophylline in Chidlren with Severe Status Asthmaticus. Chest 2001;119:1480‐1488. - PubMed
    1. Ream RS, Loftis LL, Albers GM, Becker BA, Lynch RE, Mink RB. The efficacy of intravenous theophylline in children with severe status asthmaticus. Critical Care Medicine 1998;26(Suppl):114A. - PubMed
Roberts 2003 {published data only}
    1. Roberts G, Newsom D, Gomez K, Raffles A, Saglani S, Begent J, et al. Intravenous salbutamol bolus compared with an aminophylline infusion in children with severe asthma: a randomised controlled trial. Thorax 2003;58(4):306‐10. - PMC - PubMed
Tomac 1996 {published data only}
    1. Tomac N, Saraclar Y, Tuncer A, Adiliougulo G, Cengizlier R. Efficacy of intravenously administered theophylline in children with moderate asthma attacks. Cocuk Sagligi Ve Hastalikari Dergisi 1996;39(3):423‐30.
Wang 2004 {published data only}
    1. Wang CZ, Wang Y, Lin KX, Wang JP, Zao ZQ. Comparison of inhaled corticosteroid combined with theophylline and double dose inhaled corticosteroid in moderate‐severe persistent asthma [Abstract]. European Respiratory Journal 2004;24(Suppl 48):127s.
Yamauchi 2005 {published data only}
    1. Yamauchi K, Kobayashi H, Tanifuji Y, Yoshida T, Pian HD, Inoue H. Efficacy and safety of intravenous theophylline administration for treatment of mild acute exacerbation of bronchial asthma. Respirology 2005;10(4):491‐6. - PubMed

References to studies awaiting assessment

Whig 2001 {published data only}
    1. Whig J, Puri S, Mahajan R, Chopra SC, Mittal N, Malhotra S. Placebo controlled evaluation of intravenous aminophylline in acute asthma. Lung India 2001;19(4):97‐100.

References to ongoing studies

Torero 1999 {published data only}
    1. Torero L, Maggi JC. Use of aminophylline in the pediatric patient with moderate and severe status asthmaticus. Pediatrics 1999;104(Suppl 3):680‐1.

Additional references

Becker 1984
    1. Becker AB, Nelson NA, Simons ER. The Pulmonary Index Assessment of a Clinical Score for Asthma. American Journal of Diseases of Children 1984;138(June):574‐6. - PubMed
Ben Zvi 1982
    1. Zvi Ben‐Zvi, et al. Inhaled beta 2 and subcutaneous adrenaline are not equivalent: An Evaluation of the Initial Treatment of Acute Asthma. Pediatrics 1982;70(3):348‐53. - PubMed
Bishop 1992
    1. Bishop J, Carlin J, Nolan T. Evaluation of The Properties and Reliability of a Clinical Severity Scale for Acute Asthma in Children. Journal of Clinical Epidemiology 1992;45(1):71‐6. - PubMed
BTS 2003
    1. British Thoracic Society. British Guidelines on Asthma Management. Thorax 2003;58(Supplement 1).
Chalut 2000
    1. Chalut DS, Ducharme FM, Davis GM. The Preschool Respiratory Assessment Measure (PRAM): a responsive index of acute asthma severity. Journal of Pediatrics 1996;137(6):744‐6. - PubMed
Conrad 1981
    1. Conrad KA, Prosnitz EH, Conrad KA, Prosnitz EH. Cardiovascular effects of theophylline. Partial attenuation by beta‐blockade. European Journal of Clinical Pharmacology 1981;21(2):109‐14. - PubMed
Emerman 1990
    1. Emerman CL, Devlin C, Connors AF. Risk of toxicity in patients with elevated theophylline levels. Annals of Emergency Medicine 1990;19(6):643‐8. - PubMed
Jadad 1996
    1. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds JM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Controlled Clinical Trials 1996;134(17):1‐12. - PubMed
Matthews 1996
    1. Matthews JNS, Altman DG. Statistics Notes: Interaction 2: compare effect sizes not P values. British Medical Journal 1996;313(7060):808. - PMC - PubMed
May 1974
    1. May C. History of the introduction of theophylline into the treatment of asthma. Clinical Allergy 1974;4:211‐7. - PubMed
Wanke 1994
    1. Wanke T, Merkle M, Zifko U, Formanek D, Lahrmann H, Grisold W, et al. The effect of aminophylline on the force‐length characteristics of the diaphragm. American Journal of Respiratory & Critical Care Medicine 1994;149(6):1545‐9. - PubMed
Wolfe 1978
    1. Wolfe JD, Tashkin DP, Calvarese B, Simmons M. Bronchodilator effects of terbutaline and aminophylline alone and in combination in asthmatic patients. New England Journal of Medicine 1978;298(7):363‐7. - PubMed
Wood 1972
    1. Wood DW, Downes JJ, Leeks HI. A Clinical Scoring System for the Diagnosis of Respiratory Failure. American Journal of Diseases of Children 1972;123(March):227‐8. - PubMed