Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

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Randomized controlled trial of aminophylline for severe acute asthma.

Yung M, South M.

Arch Dis Child 1998;79:405-410. [full-text until July 1999] [abstract]

Reviewed by Girish Deshpande, MD, Kathleen Meert, MD, Children's Hospital of Michigan

Review posted July 2, 1999

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I. What is being studied?:

The study objective:

To determine whether children with severe acute asthma unresponsive to frequent doses of inhaled salbutamol, ipratropium, and steroids are conferred any further benefits by the addition of aminophylline given intravenously.

The study design:

Randomized, double blind, placebo controlled study.

The patients included:

Children (aged 1-19 years) with severe acute asthma who were unresponsive to three nebulized doses of 5 mg salbutamol.

Severe asthma was defined by: asthma severity score (ASS) of > 6, spirometry (where possible) of < 50% predicted, or the patients obviously being sick and admitted to the intensive care unit. Unresponsiveness to nebulized salbutamol meant no improvement in an ASS of > 1, or spirometry of > 15%.

The patients excluded:

Exclusion criteria were: pregnancy, other chronic respiratory disease, significant disease of other organ systems, a known adverse reaction to theophylline, previous enrollment, and administration of theophylline (by mouth or intravenously) in the previous 24 hours.

The interventions compared:

The treatment group consisted of 81 patients who received IV aminophylline infusions as a loading dose of 10 mg/kg infused over one hour, followed by a continuous infusion of 1.1 or 0.7 mg/kg/hour for patients < 10 years, and > 10 years, respectively. Patients randomized to the placebo group were given sterile water at the same volumes and rates. The duration of the infusion was determined by the medical staff giving the treatment and not by the investigators.

Comment: This dosage schedule was intended to achieve concentrations in high therapeutic range. The medical staff determining the duration of infusion could have led to inconsistencies in management.

The outcomes evaluated:

Primary outcome: the length of stay in hospital.

Secondary outcomes:

• FEV1, forced vital capacity, maximum mid-expiratory flow, and peak flow expressed as percentages predicted for age and measured at baseline, 6 hours, 12-18 hours, 18-24 hours, and daily thereafter.
• SpO2 after breathing in room air for 10 minutes, measured every 6 hours.
• ASS score every 6 hours
• Heart rate and respiratory rate
• Duration of supplemental oxygen.
• Total dose of salbutamol
• For mechanically ventilated patients: the duration of mechanical ventilation, and the area under the peak-pressure-time curve.
• Adverse effects including nausea, vomiting, headaches, irritability, tremor, and seizures, were recorded every 6 hours.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Sequentially numbered boxes were randomly assigned to contain either aminophylline or placebo using a computer generated code with randomly permuted blocks of different sizes (two, four or six subjects) such that the balance between the treatment arms was maintained every 12 subjects. Subjects were further stratified by age as older and younger than 6 years.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. One patient in the placebo group and 3 in the aminophylline group did not receive their allocated treatment, but they were not withdrawn from the study, and they were analyzed as intention to treat.

Out of 83 subjects older than 6 years, 48 subjects were able to perform pulmonary function test at baseline and 42 were able to perform tests both at baseline and at six hours. Sixty-two subjects in each group completed all five measurements of SpO2 at different times. Eight subjects had missing data for their ASS score at enrollment, as they were intubated before randomization.

Were patients analyzed in the groups to which they were randomized?

Yes. There were no crossovers between the treatment groups.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. The principal investigator, the medical and nursing staffs carrying out the treatment, and the subjects and his or her family were blind to the treatment group. Blinding was maintained throughout the period of hospital admission and to the end of the study. Only the statistician, the pharmacist and the second investigator were aware of the assignment, none of whom were directly involved in the care of the patients.

4. Were the groups similar at the start of the trial?

Baseline characteristics such as age, pulmonary function tests, SpO2, ASS, heart rate and respiratory rate, past history, use of other medications like inhaled beta-2 agonists, cromoglycate, inhaled and oral steroids, were similar in both the groups.

5. Aside from the experimental intervention, were the groups treated equally?

No. Seventy-one subjects were admitted in the ICU; 30 belonged to the aminophylline group and 41 to the placebo group. Forty-one subjects received intravenous salbutamol, of which 15 subjects were in the treatment group and 26 were in the placebo group. The placebo group received intravenous salbutamol for significantly longer duration (16 hours vs 8.8 hours), and at higher total dose (3.19 mg/kg vs 1.0 mg/kg) than the aminophylline group. There is no mention of the criteria for the use of intravenous salbutamol. Fourteen subjects underwent endotracheal intubation and mechanical ventilation, of these 9 were intubated before randomization (3 in the treatment group and 6 in the placebo group) and 5 after randomization; all of which were in the placebo group. Again, the indications for intubation, in patients who required intubation after randomization, are not specified.

III. What were the results?

1. How large was the treatment effect?

a) The geometric mean length of stay for the placebo group was 2.87 days and 2.69 days for the aminophylline group. The ratio aminophylline length of stay to placebo length of stay was 0.94.

b) Pulmonary function tests:

• FEV1 at 6 hours: 14.1% improvement from baseline (aminophylline group) vs 3.7% improvement from baseline (placebo group). Difference 10.4%.
• MMEF at 6 hours: 13.3% improvement from baseline (aminophylline group) vs -0.4% improvement from baseline (placebo group). Difference 13.7%.
• PEFR at 6 hours: 14.8% improvement from baseline (aminophylline group) vs -0.3% improvement from baseline (placebo group). Difference 15.1%.

c) SpO2: Statistically significantly higher in the aminophylline group for up to 30 hours, however difference not of clinical significance.

d) ASS score at 6 hours: decreased by 2.04 in aminophylline group and 1.32 in placebo group. Difference 0.72.

e) No difference in ICU length of stay between the two groups.

f) Only five subjects required intubation after randomization, all of which belonged to the placebo group. Nine patients were intubated before randomization of which 3 were randomized to aminophylline group and 6 to the placebo group.

	Necessity for intubation after randomization
	Intubated	Not intubated	Totals
Aminophylline	0	78	78
Placebo	5	71	76
Totals	5	149	154

Using this data we calculated an absolute risk reduction (ARR) of 7% [the difference in the proportion of patients requiring intubation in each group]. The number needed to treat (NNT) to avoid one intubation is 14.2 patients.

g) There was a trend towards reduction in the duration of intubation between groups (aminophylline 8.25 hours vs placebo 34.0 hours), and in the median area under the curve of peak inspiratory pressure vs time (aminophylline 123 h-cm H2O, placebo 867.5 h-cm H2O).

h) Adverse effects: 26 of 81 aminophylline treated patients had adverse effects severe enough to require discontinuation of infusion, whereas only 4 of 82 placebo treated patients required discontinuation.

	Adverse event	No adverse event	Totals
Aminophylline	26	55	81
Placebo	4	78	82
Totals	30	133	163

Using this data we calculated an ARR of -27%. The negative value for ARR indicates an absolute risk increase. NNT is -3.7. The negative value indicates the number needed to harm. The RR for adverse events is 666%. The RRR is -540%.

2. How precise was the estimate of the treatment effect?

a) The 95% confidence interval for the ratio of aminophylline length of stay to placebo length of stay was 0.77 to 1.14. Thus aminophylline could have reduced the length of stay by as much as 23%, or increased it by as much as 14%.

b) Pulmonary function tests:

• FEV1 at 6 hours: 95% CI for the difference in improvement from baseline: 4.2 to 16.6%.
• MMEF at 6 hours: 95% CI for the difference in improvement from baseline: 4.3 to 15.7%.
• PEFR at 6 hours: 95% CI for the difference in improvement from baseline: 6.5 to 23.7%.

c) SpO2: Only median SpO2 provided for each time point; no indicator of variability given.

d) ASS score at 6 hours: 95% CI for the difference in the decrease in ASS score is 0.22 to 1.22.

e) No difference in ICU length of stay between the two groups.

f) Risk of intubation post-randomization:

	95% Confidence Interval
ARR	1.3% to 12.7%
NNT	7.8 to 77

The CI for the "incidence of intubations post-randomization" can be calculated using the rule of 3's which states that when the numerator is zero, we can be confident (with 95% certainty) that the true incidence is no more than 3/n. Hence, we can calculate the upper limit for the incidence as = 100 X 3/78 = 3.8%.

g) Adverse effects requiring discontinuation of infusion:

	95% Confidence Interval
ARR	-38% to -16%
NNT	-6.3 to -2.6

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Yes. The study patients were similar to the population of patients cared for in our pediatric ICU. However, the results are confounded by the failure to standardize the use of intravenous salbutamol.

2. Were all clinically important outcomes considered?

No. The study demonstrated the efficacy of aminophylline in improving pulmonary functions, but other physiologic indicators of airway obstruction such as PCO2 were not evaluated.

3. Are the likely treatment benefits worth the potential harms and costs?

In the present study, authors tried to achieve theophylline concentrations in the upper end of the therapeutic range, which probably explains the higher incidence of adverse effects. About 62% of patients in this study had initial theophylline level > 80 µmol/L (14.5 mg/L). Prevalence of adverse effects exceeds 65 to 70% as the theophylline concentration exceeds the upper limit of the therapeutic range (>110 µmol/L or 20 mg/L)(1). More than 90% of patients with serum theophylline concentrations greater than 165 µmol/L (30 mg/L) demonstrate signs of toxicity. Considering that the authors did demonstrate the beneficial effect on the early pulmonary function, sustained improvement in oxygen saturation, and reduced the risk of intubation with aminophylline, it is worthwhile to consider using aminophylline for acute severe asthma, keeping a close watch on the theophylline concentration

References

1. . Shannon MW. Theophylline and caffeine. In: Clinical Management of Poisoning and Drug Overdose, 3rd ed. Haddad LM, Shannon MW, Winchester JF (Eds). WB Saunders Company, Philadelphia, 1998, pp 1093-1106.

Comments

I want to reinforce the problem areas that the reviewer identified. While this article will influence my practice toward increased use of aminophylline, I remain unconvinced. Is aminophylline really as effective as the article makes it seem? Is all the literature published over the last 10 - 15 years regarding the lack of benefit from aminophylline to discarded? The last paper that I know of to show an effect was Pierson et al's from 1971 (Pediatrics;48,642) in which the addition of aminophylline to q4h isoproterenol nebs was shown to be beneficial. I suspect that the treatment and placebo groups were not as similar as the baseline characteristics table suggests. Asthma severity scores are notoriously subjective in their assessment. How was the scoring standardized? Pulmonary function tests could only be performed on a minority of patients. Blood gas data was not presented as part of the baseline characteristics. The two groups had one major pre-entry difference; the placebo group had twice as many intubated patients enrolled in it as the treatment group. An appropriate conclusion from the article might be that the risk of requiring intravenous salbutamol and of intubation were reduced.

Without a rigid protocol for directing care decisions one can not truly conclude this. Moreover, when in relation to the time of study entry did these interventions occur? If they were shortly after randomization they may be more of a reflection of pre-entry illness severity than of the impact of aminophylline on illness severity. The lack of data on how treatment decisions regarding salbutamol dosing and administration were made hampers the comparison of the two groups. One of the primary issues regarding the role of aminophylline is whether or not it use adds to the efficacy of treatment sufficiently to justify the added toxicity. As we cannot tell whether the Beta agent was used in an optimal fashion (given the lack of heart rate change between baseline and treatment state I suspect that the salbutamol dosing was low) we cannot conclude that aminophylline use is warranted in the PICU setting where maximal beta agents are in use or whether one would have seen such an impact of aminophylline had higher doses of salbutamol been in use in these patients. Nevertheless, as I said already this paper will influence my treatment of patients and I appreciate the major effort the authors have made to conduct what was undoubtedly a difficult study to perform. Thanks for the opportunity to comment.

Peter Trinkaus
PT142@columbia.edu

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