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

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Article Reviewed:

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A Pilot Prospective, Randomized, Placebo-Controlled Trial of Bilevel Positive Airway Pressure in Acute Asthmatic Attack.

Soroksky A, Stav D, Shpirer I.

Chest 2003;123 1018-1025 [abstract]

Reviewed by Keith Lewis MD, Loma Linda University, Loma Linda, CA

Review posted August 26, 2004

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I. What is being studied?:

The study objective:

The objective of this study is to compare conventional asthma treatment alone, with bilevel pressure ventilation (BPV) plus conventional asthma treatment in adult patients with severe asthmatic attacks admitted to the emergency department.

The study design:

This study is a prospective, randomized, placebo-controlled pilot study.

The patients included:

33 patients with severe asthma attacks as defined by the study entry criteria. These criteria were:

1. FEV1 < 60% of predicted by age, height, and gender.
2. Respiratory rate > 30 breaths/min.
3. History of asthma of at least 1 year
4. Duration of current asthma attack of < 7 days

The 33 patients included were recruited from a among the 124 asthmatic patients age 18 to 50 years that were seen in the emergency department with an acute asthma attack during the study period.

The interventions compared:

This study compares the use of hourly nebulized salbutamol 2.5 mg and ipratropium 0.25mg, IV corticosteroids and oxygen (to maintain oxygen saturation > 95%) with "sham" BPV nasal mask to the use of the same treatments with the addition of "real" BPV administered through a nasal mask for 3 hours. The BPV was begun at pressures of 8/3 and titrated up to a maximum of 15/5 or until the respiratory rate was < 25.

The outcomes evaluated:

The primary outcome that was evaluated was improvement in a lung function test during the stay in the emergency department. This was defined as an increase of at least 50% in FEV1 compared to baseline on ED arrival or an improvement to > 60% of predicted value. Secondary endpoints evaluated were the need to hospitalize and the occurrence of respiratory failure with the need for mechanical ventilation.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, the screened patients that met the inclusion criteria were randomized to either receive conventional treatment combined with BPV or conventional treatment plus sham BPV. The specific technique of randomization was not specified.

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

Was followup complete?

Yes, all the patients that were screened were accounted for. All of the patients that started the study were accounted for, but two patients from the treatment group and 1 from the control group were withdrawn from the study as they could not tolerate the mask; these patients were included in the final intent to treat analysis of the secondary outcome variable (need to hospitalize). 33 patients entered the study and 30 completed the study, and they were all accounted for.

The patients were followed for 1 month following discharge for the emergency department and the readmission rate to the emergency department or to the hospital was recorded. The follow up for the patients that were admitted to the hospital is not addressed.

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

Yes, there was no cross-over between groups.

Secondary questions:

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

Yes and no. In the discussion section the authors indicate "the study was blinded to patients and the attending physician, but they did not succeed in blinding it from the investigating team". (Although unless the machine was covered, anyone walking by could see pressure changes displayed, or the lack thereof.)

The authors attempted to blind personnel to the treatment by having the control group utilize a sub-therapeutic BPV (sham BPV) with inspiratory and expiratory pressures set at 1cm of water as opposed to the treatment group that received therapeutic pressures through their BPV devices. The therapeutic pressures administered to the treatment group were titrated according to clinical symptoms during the course of the study. This was not done for the control group.

Also, four large holes were made in the tubing connecting the sham BPV apparatus and nasal mask. This was done to minimize the therapeutic effect the low pressures delivered could have and to allow unlimited airflow to the control group patients. It is not clear whether study personnel or patients were blinded to this difference.

Additionally, the control group patients were not instructed to breath solely through their nasal mask and were encouraged to breathe orally as well. This was done to minimize the side effects that a subtherapeutic nasal mask could have. By contrast the treatment group patients were specifically instructed to breathe only through the mask and breathing through the mouth was discouraged in this group.

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

Yes, there were no statistically significant differences in demographic or physiologic parameters at the start of the trial. The initial mean FEV1 was similar in both groups with a mean of 37.27 ± 10.7% of predicted for the BPV group and 33.8 ± 10.2% in the control group. Also FVC was similar between the two groups at the start of the trial 48.27 ± 11.87% in the BPV group and 48.6 ± 16.05% in the control group. Blood gas analysis was similar in both groups, with both showing mild hypocarbia and slightly reduced oxygen tension. Heart rate, respiratory rate, and blood pressure were also similar between the two groups at the start of the trial.

In terms of patient demographics the two groups were similar in terms of age, sex, duration of asthma attack, and duration of asthma, and prior episodes of respiratory failure. There were no significant differences between the two groups in terms of permanent use of inhaled corticosteroids, systemic steroids, or inhaled beta agonist.

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

Yes there were no statistically significant differences in the standard treatments between the two groups, including the number of respiratory treatments and steroid use. However, differences in the amount of oxygen given are not reported.

III. What were the results?

1. How large was the treatment effect?

80% of the patients in the treatment group reached the primary endpoint of an increase in FEV1 > 50% compared to admission baseline. By comparison only 20% in the control group achieved this. The mean (± SD) FEV1 % predicted for the treatment group after 3 hours was 56.1 ± 16.3%, or a percentage improvement from baseline of 51.1 ± 19.3% For the control group it was 42.3 ± 15.9% or a percentage improvement from baseline of 24.1 ± 23.6% .

The secondary endpoint of need to hospitalize was reached by 17.6% (3 of 17 patients) of the treatment group as compared to 62.5% 10 of 16 patients) of the control group. This represents a relative risk reduction (RRR) of 71.84% when calculated as follows:

Risk without therapy: X = 10/16 = 0.625
Risk with therapy: Y = 3/17 = 0.176 .
Absolute risk reduction: (X-Y) = 0.625 - 0.176 = 0.449
Relative risk: Y/X = 0.176/0.625. = 0.2816
Relative risk reduction: [(X-Y)/X] x 100= 71.84%
Calculated RRR confidence boundaries 49 - 82%
Number needed to treat: 2.2

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

The confidence interval around the 71% relative risk reduction is 14% to 91%. These calculated upper and lower RRR confidence boundaries tell us, with 95% confidence, the true RRR lies within this range. The range is very wide because the numbers of patients studied was so small.

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

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

Perhaps. The study sample was drawn from an adult population of patients presenting to an emergency department with acute asthma attacks. From this population those with severe attacks were selected by using objective criteria. A large proportion of asthmatic patients with a severe attack would likely meet the inclusion criteria of this study and could be expected to experience similar benefits. However, the applicability of these data to children, particularly young children, is unknown.

2. Were all clinically important outcomes considered?

Yes, the authors of this study use a substitute endpoint of change in FEV1 for the outcome of change in respiratory status in the asthmatic patients studied. They also looked at the need for hospitalization and need for mechanical ventilation as secondary outcomes.

Clearly the most important clinical outcome is the dramatic reduction in need for hospitalization, although the decision regarding hospitalization was not independent - they state it was based on the FEV change, as well as "clinical judgment." No adverse events or side effects were reported, but certainly any event relating to barotrauma would need to be investigated in future studies.

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

There were no significant side effected or harmful effects identified in this study in either group. Cost was not specifically addressed. The additional intervention (BPV) would add additional cost. However, the potential benefit of improve respiratory status and decrease in need for hospitalization in these patients would likely offset this additional cost and possibly lead to an overall savings. In terms of the calculated ARR, the calculated number needed to treat to prevent one hospitalization is 2.2 . This tends to support the treatments benefits.

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