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Three Part Question

In [patients with moderate to severe asthma resistant to inhaled beta-2-agonists] does [IV aminophylline or IV salbutamol] result in [quicker relief with less side effects]?

Clinical Scenario

A 20-year-old male is brought to the Emergency Department in acute respiratory distress with asthma. He has a history of poor compliance with unstable asthma and several hospital admissions in the past. His old notes are available and you notice whenever IV treatment has been commenced he has been given aminophylline. You feel that the best drug is a beta-2 agonist and that if it is not getting to the receptors via the airways then IV is the next best route. There is some dismay among the nursing staff when you formulate an IV regime. They say they have never given it before. You wonder whether your approach is evidence-based.

Search Strategy

Medline 1966-10/03 using the OVID interface.
[(exp albuterol/ OR salbutamol.mp) AND intravenous.mp] AND [exp asthma/ OR exp bronchial spasm/ OR exp bronchoconstriction/ OR bronchoconstriction.mp] AND [exp aminophylline/ OR aminophylline.mp OR exp theophylline/ OR theophylline.mp] LIMIT to human AND English.

Search Outcome

Altogether 71 papers found of which 62 were considered irrelevant or of insufficient quality for inclusion. The remaining 9 papers are shown in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Beswick K et al, 1975, UK	20 patients in GP setting with acute bronchospasm	Single blinded randomised trial of IV slabutamol or aminophylline	Vital signs	Same	Small non-ED study (majority treated at home)
			PEFR FEV1 FVC	Difference favouring salbutamol at 10 and 20 mins but not significant
			Side effects	Significantly worse profile for aminophylline
Williams SJ et al, 1975, Wales	20 acute asthmatics with peak flow < 25% predicted, PaO2 < 68mmHg	DBRCT One hour infusion of either 500gm aminophylline or 500mcgm salbutamol	Peak flow	Increased but not significant for salbutamol	Small numbers
			Pulse	More tachycardia (significant) with salbutamol
			BP	Fall in diastole
			Side effects	Less tremor, nausea, no difference in plasma [K+]
Tribe AE et al, 1976, Australia	23 acute asthma patients	DBRCT of IV aminophylline vs salbutamol	Spirometry	Non-significant benefit and peak effect of aminophylline	Sub-optimal dose of salbutamol Variable pre-trial treatment
			ABG	Quicker improvement in oxygen tension with salbutamol
Femi-Pearse D et al, 1977, Nigeria	50 patients with peak flow < 165l/min	Single and double blinded trials of salbutamol and aminophylline	5 minutely pulse and peak flow measures	Significant benefit in peak flow at 5 mins(p<0.005) and 20 mins (p<0.05) for single blinded trial only for salbutamol. No difference in pulse rate	Small trial Low dose of salbutamol
Johnson AJ et al, 1978, UK	39 of 62 acute asthmatics unresponsive to initial IV 10 min aminophylline infusion and nebulised salbutamol	Single blinded RCT Either 1mg/min aminophylline or 10mcgm/min salbutamol	Peak expiratory flow	Non-significant benefit of aminophylline	All received IV aminophylline initially No initial bolus of salbutamol Variable used of nebulised salbutamol acutely Not blinded to physicians Variable background preventive treatment
			FEV1	Non-significant benefit of salbutamol
			FVC	Non-significant benefit of aminophylline
			Arterial gases	No difference
			Pulse & BP	Significant tachycardia in salbutamol group
Evans WV et al, 1980, UK	21 acute asthma patients	Single blinded RCT comparing aminophylline, salbutamol or combined IV	Spirometry	Non-significantly quicker time to improvement with aminophylline and combined infusion	Small numbers Variable baseline severity Sub-therapeutic salbutamol dosing
Sahay JN et al, 1984, UK	20 adults with FEV1<70% predicted	Double Blinded RCT crossover of aminophylline, turbutaline and salbutamol	Spirometry	All produced significant improvement, salbutamol significantly better than aminophylline to 30 mins post dose then no difference with better peak effect.	Small group, not acutely unwell
			Vital signs and side effects	Salbutamol significantly more tachycardia and palpitations which return to no difference at 90 mins
Sharma TN et al, 1984, India	30 known asthmatics with acute bronchospasm	RCT of aminophylline, salbutamol or turbutaline	Spirometry	Salbutamol significantly better FEV1	Blinding not clear Salbutamol 250mcgm given as 1 min. bolus
			Side effects	Significantly more palpitations with salbutamol
Grief J et al, 1985, Israel	21 patients (mean age 38 years) with acute on chronic asthma	Single Blinded crossover 20 min infusion of salbutamol or aminophylline	% increase in peak flow	Salbutamol shows significant benefit to 30 mins (p<0.01) and 45 mins (p<0.05) post infusion	Small study Not fully blinded
			Pulse rate	Tachcardia with salbutamol
			BP	No difference
			Plasma [K+]	Average drop of 0.6 mmol/l
			Tremor	More in salbutamol group

Comment(s)

Multiple small trials of reasonable quality show IV salbutamol to be as good if not better at reversing obstructive airflow in asthmatics. Those studies which were equivocal used drug regimes that could be considered sub-therapeutic or confounded. Side effects, although present appear to be well tolerated. Recent or high-powered trials comparing the two drugs do not exist.

Clinical Bottom Line

IV salbutamol should be considered a first line agent in the acute management of severe asthma in adults.

References

1. Beswick K, Davies J, Davey AJ. A comparison of intravenous aminophylline and salbutamol in the treatment of severe bronchospasm. Practitioner 1975;214:561-66.
2. Williams SJ, Parrish RW, Seaton A. Comparison of intravenous aminophylline and salbutamol in severe asthma. BMJ 1975;4(5998):685.
3. Tribe AE, Wong RM, Robinson JS. A controlled trial of intravenous salbutamol and aminophylline in acute asthma. Med J Australia 1976;2:749-52.
4. Femi-Pearse D, George WO, Ilechukwu ST et al. Comparison of intravenous aminophylline and salbutamol in severe asthma. BMJ 1977;1(6059):491.
5. Johnson AJ, Spiro SG, Pidgeon J et al. Intravenous infusion of salbutamol in severe acute asthma. BMJ 1978;1(6119):1013-5.
6. Evans WV, Monie RD, Crimmins J et al. Aminophylline, salbutamol and combined intravenous infusions in acute severe asthma. Br J Dis Chest 1980;74(4):385-9.
7. Sahay JN, Bell R, Chatterjee SS et al. Comparative study of effects of intravenous administration of aminophylline, salbutamol and terbutaline in patients suffering from reversible airways obstruction. Curr Med Res Opin 1984;9(1):1-6.
8. Sharma TN, Gupta RB, Gupta PR et al. Comparison of intravenous aminophylline, salbutamol and terbtaline in acute asthma. Indian J Chest Dis & All Sci 1984;26(3):155-58.
9. Grief J, Markovitz L, Topilsky M et al. Comparison of intravenous salbutamol (albuterol) and aminophylline in the treatment of acute asthmatic attacks. Ann Allergy 1985;55(3):504-6.