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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Intravenous magnesium therapy for moderate to severe pediatric asthma: Results of a randomized, placebo-controlled trial.

Ciarallo, L, Sauer, AH, Shannon, MW.

J Pediatr 1996; 129: 809-14. [abstract]

Reviewed by Barry Markovitz

Review posted May 27, 1997

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I. What is being studied?:

The study objective:

To evaluate the efficacy of intravenous magnesium (IVMg) therapy for moderate to severe asthma exacerbations in pediatric patients

The study design:

Randomized, double-blind, placebo-controlled trial

The patients included:

31 patients 6 to 18 years of age with an asthma exacerbation whose peak expiratory flow rate (PEFR) was less than 60% predicted after three ß2-agonist nebulizer treatments (and "the medical team concluded that intravenous access was necessary for further management").

Patients were excluded with a temperature > 38.5°C, systolic blood pressure < 25th %ile for age, recent use of theophylline, history of cardiac, renal, or pulmonary disease, and pregnancy.

The interventions compared:

Intravenous magnesium sulfate, 25 mg/kg (max 2 gm) in 100 ml normal saline (given over 20 minutes), vs. saline alone, administered in the emergency department.

The outcomes evaluated:

The primary outcome variables assessed were indices of pulmonary function (PEFR, FEV1, FVC) over 110 minutes following treatment. Secondary measures included rates of hospital admission and length of stay of inpatients (see III-2 below).

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. A block randomization scheme was employed to ensure equal group assignment during the seasons when asthma was more prevalent.

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

Was followup complete?

Apparently. The authors state that 31 patients "completed the study," but they do not note if any additional patients were enrolled.

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

Yes. There was no cross-over of patients between groups.

Secondary questions:

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

Yes. The magnesium or placebo solutions were prepared in the pharmacy and coded. 100 ml of saline was used to reduce the chance for a patient detecting the warm sensation that can accompany magnesium infusion.

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

Almost. Age, gender, vital signs, SaO2%, time of nebulized ß2-adrenergic or corticosteroid therapy were the same in both groups. PEFR and FVC were similar between the groups at study entry, but FEV1 was significantly less in the Mg-treated group (33.1 ± 11.4 vs. 45.1 ± 12.2 % predicted, p = 0.01). The lower FEV1 in the Mg-treated patients could have offered more "room for improvement," thus potentially exaggerating the impact of IVMg.

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

Yes. There was no difference between groups in the number of additional nebulized treatments given during the study period, or in the number of patients receiving intravenous corticosteroids just upon study entry.

III. What were the results?

1. How large was the treatment effect?

Reported as percent improvement from baseline, the PEFR of the IVMg group increased after 80 minutes by 46%, compared to only 16% in the placebo group (p= 0.05). FEV1 improved significantly in the treated patients by 50 minutes (34% vs. -1%, p=0.05). The percent improvement in PEFR and FEV1 remained significantly higher in the IVMg patients throughout the study duration (110 minutes). However, FVC change only reached significance at 80 minutes; percent changes are not reported.

If assessed as the number of patients with PEFR's better than 60% predicted (the study's entry criterion) at the end of the observation period, 11 of 15 (73%) of the IVMg patients achieved this goal, vs. only 5 of 16 control patients (31%); Relative Risk = 2.35 (95% CI 1.07, 5.16). Four of 15 IVMg patients had the decision to admit be reversed, compared to none of the control patients. This represents an absolute risk (of admission) reduction (ARR) of 27%. Alternatively, the relative "risk" (RR) of reversing the decision to admit in the IVMg group was 9.56 (95% CI 0.56, 163.82). (See notes for an example of these calculations.)

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

Confidence intervals for the pulmonary function test results are not reported, but the absolute risk reduction (ARR) of hospitalization provided by IVMg was 27%, with 95% CI's from 5 to 49%. We can be 95% certain that the reduction in hospitalization provided by this therapy is between 5 and 49%. Although the lower confidence interval for the RR of cancelling admission crosses one, the RR of 9.56 represents a very strong trend.

Though not required for study entry, physicians caring for all the study patients (treated and controls) had decided to admit them prior to enrollment in the study. Patients discharged from the emergency department instead involved having the decision to admit be reversed. It is not clear from the report whether the rate of discharge from the ED was intended to be investigated in the trial's design. Such a post hoc analysis reduces the strength of the conclusions.

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

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

Perhaps for patients in the Emergency Department. Asthma is an enormous problem in pediatrics, and represents the single largest diagnosis for which children are admitted to the hospital. The patients in this study appear typical of urban patients with asthma who fail to respond to initial therapy. Having an alternate therapy to administer in the ED that is effective in reducing hospitalization rates would be welcome.

It is difficult to extrapolate these results with confidence to PICU patients with severe status asthmaticus at this time.

2. Were all clinically important outcomes considered?

Yes. The investigators' primary intent was to assess the impact of IVMg on pulmonary function. Although perhaps more objective than clinical symptoms or appearance, the patient's disposition quite often relies on these clinical signs as well.

Given that hospitalization rates were a secondary consideration, and that the sample sizes were small, caution is warranted in overinterpreting the results of this study.

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

There were no complications (e.g., hypotension, weakness) detected from IVMg from the dosage employed. If larger studies confirm these results, it would indeed be safe and very cost-effective to treat such patients in an effort to avoid hospitalization.

The clinically useful parameter of NNT (number needed to treat) in this study - to avoid hospitalization - is 4. In other words, 4 patients with a moderate to severe asthma exacerbation who had not responded to ß2-agonists would need to be treated with IVMg to avoid one hospitalization. (See notes for an example of these calculations.)

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