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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Efficacy of IV Theophylline in Children With Severe Status Asthmaticus

Ream RS, Loftis LL, Albers GM et al.

Chest 2001;119:1480-1488. [abstract; full-text for subscribers]

Reviewed by Mara Chavolla MD, Washington University School of Medicine, St. Louis Children's Hospital

Review posted December 13, 2001

I. What is being studied?:

The study objective:

To determine whether adding intravenous (IV) theophylline to an aggressive regimen of inhaled or IV Beta agonist, inhaled ipratropium and IV methylprednisolone would enhance the recovery of children with severe status asthmaticus admitted to the pediatric intensive care unit (PICU).

The study design:

Prospective, randomized, single blinded controlled trial.

The patients included:

Children with status asthmaticus (n=47) admitted to the PICU for more than 2 hr and who were in severe distress (Clinical Asthma Score 5). The analysis was focused on the 41 patients who were not intubated.

The patients excluded:

Patients were excluded for known allergy or hypersensitivity to any methylxanthine, beta-agonist or anticholinergic medication; a serum theophylline level 3 mcg/ml in the emergency department; underlying cardiovascular disease, pregnancy or failure to obtain consent. Intubated asthmatics were not excluded, but were analyzed separately (n=6).

The interventions compared:

Subjects in the experimental group were loaded with aminophylline (bolus dose 7 mg/kg), followed by an infusion of theophylline in 5% dextrose at rates adjusted for age and theophylline level target of 12 to 17 micrograms/ml.

The outcomes evaluated:

Response to therapy was determined by changes in the subjects CAS. The authors examined the time to reach a Clinical Asthma Score 3, considered compatible with an intensity of illness safely managed outside the PICU. A secondary outcome was the time required to meet predetermined criteria for discharge from the PICU (discontinuation of IV terbutaline, beta-agonist inhalations no more than every 2 h, and an FiO2 of less than 0.5%.

II. Are the results of the study valid?

1. Is there a strong, independent, consistent association between the surrogate end point and the clinical end point?

No. In an effort to quantify the severity and predict outcomes of acute asthma an array of multivariate clinical scores have been described in the literature. The Clinical Asthma Score (CAS) was first described by Woods et al and since then has been used for assessment of asthma severity, to predict outcomes of an attack or to evaluate treatment efficacy (1). Several papers have demonstrated the lack of predictive value of asthma scores for long term outcomes such as length of stay, ED disposition, or complications (2, 3, 4). However, the CAS has been useful to monitor the severity of asthma and clinical decision making and has been generally accepted as a valid outcome measure for therapeutic trials (2). A recent publication demonstrated the CAS to correlate well with the probability of long duration of bronchodilator therapy and hospitalization in children with acute asthma (5), although it was most useful when combined with other predictors. The clinical asthma score could therefore, be used to assess the improvement of the respiratory status in response to an asthma medication.

2. Is there evidence from randomized trials in other drug classes that improvement in the surrogate end point has consistently led to improvement in the target outcome?

Yes, the asthma score has been frequently used when comparing the efficacy of different classes of beta-agonist and the time to improve from impending respiratory failure status (CAS < 5). Secondary outcomes in several of these studies have been hospital stay and the intensity of respiratory therapy at bedside; both of them showed to decrease with improvement of the CAS (6, 7). The CAS has been used in most studies investigating the response to therapy, but the secondary outcomes have not always been predicted by CAS changes. Nevertheless, it is obviously an inexact science of determining the severity of asthma illness and the CAS provides the most consistently reported and intuitively appropriate score to use.

3. Is there evidence from randomized trials in the same drug class that improvement in the surrogate end point has consistently led to improvement in the target outcome?

No, there are several trials that studied the efficacy of IV theophylline in children with status asthmaticus that showed no significant differences in CAS, forced expiratory volumes and duration of hospital stay (8, 9, 10). Furthermore, there were significantly more adverse effects associated with the use of theophylline (9). These studies were done on patients with mild to severe acute asthma exacerbation. Only one randomized, double blind, placebo controlled trial of aminophylline in severe status asthmaticus showed improvement at six hours, using a different asthma score, favoring the aminophylline group (11). No significant differences were found at any other time or in the total PICU time or duration of hospital stay.

IIa. Validity Questions for Therapy Articles:

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Patients were randomly assigned to control or experimental groups by means of a computer generated random number series.

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

Was followup complete? and were patients analyzed in the groups to which they were randomized?

Although not specified, all of the patients who entered the trial were presumably followed until their PICU and hospital discharge. The patients were analyzed in the groups to which they were assigned. However, there is a discrepancy of the number of observations in the graph of percent change in respiratory rate. It is unclear why there are so few observations later in the hospitalization, perhaps by this time many patients had reach the goal of a CAS 3. They decided to analyze separately intubated patients from their primary analysis. They would have had significant changes in relevant clinical outcomes if they had included them. It is unclear why they decided to analyze them separately; they did not need to do this since it was not part of their pre-determined exclusion criteria and fits with their goal of studying the effects of theophylline in sick, PICU admitted patients.

Secondary questions:

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

No. The PICU attending and resident team, and presumably the patients and their families were aware of the subject group assignment. The physician investigator performing the CAS evaluations was blinded to group assignment. With the need for blood levels, dose adjustment and the parental concern for repeated blood sampling, blinding of the patients and caretakers becomes difficult. However the lack of blinding in this case is a significant problem.

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

Yes, there were no significant differences between the theophylline and control groups regarding age, sex, home medications, previous use of hospital resources, origin (ED vs. ward), ED treatment, or time of admission. Respiratory rate, pH, PC02, CAS and PRISM scores were not different.

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

Yes, subjects in both groups were administrated beta-agonist, inhaled ipratropium and IV methylprednisolone. The dose and mode of administration of the beta-agonist were titrated by the PICU team. There was a discrepancy in the use of IV terbutaline. Only 6 patients in the theophylline group vs. 11 in the control group received IV terbutaline, but apparently the difference in treatment was not statistically significant.

III. What were the results?

1. How large, precise, and lasting was the treatment effect? (Effect should be large, precise, and lasting to consider a surrogate trial as possible basis for offering patients the intervention.)

Theophylline was associated with a significant decrease in the time to reach a CAS < 3 among 20 experimental patients who were not receiving mechanical ventilation. The time to achieve a CAS < 3 was 18.6 +/- 2.7 hours (mean +/- SEM) in the experimental group vs. 31.4 +/- 4.5 hours in the control group (p < 0.05). Theophylline did not significantly influence the time to meet PICU discharge criteria among patients not receiving mechanical ventilation.

Interestingly, the very few patients receiving mechanical ventilation (n=6) and IV theophylline (n=3), required less time to reach a CAS < 3 and required less time to meet discharge criteria than the control group patients receiving mechanical ventilation (n=3), around 100 hours less for both outcomes (p < 0.05). Presumably, patients in the theophylline group were extubated faster than the control group. The authors also allude to the possibility that the theophylline may have prevented intubation in some patients, but it is difficult to make any kind of interpretation of the analysis of the 6 intubated patients.

Side effects were frequent. An increased incidence of emesis was reported in the theophylline group, and tremor was more frequently reported in the control group (p < 0.05 for both). Four patients had elevations in the CK levels but only one of them was in the theophylline group. The three control patients with elevations in CK levels were receiving both inhaled albuterol and IV terbutaline. These elevations were not statistically significant.

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

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

Perhaps. While the reduction of the time needed to achieve a CAS of < 3 in the theophylline group, most remarkably for intubated patients, is appealing, the size of the sample and the increased incidence of side effects in the theophylline group (p < 0.05), cautions against this addition to the acute asthma therapy. Important outcomes such as duration of PICU and hospital stay were not different for patients not receiving mechanical ventilation, but were significantly decreased for the intubated patients in the theophylline group. Although the number of patients is too small, larger studies in intubated asthmatics may show a definitive role for theophylline in the treatment of the most severe asthma exacerbations.

2. Were all clinically important outcomes considered?

Yes. Measures of CAS, respiratory rate, use of mechanical ventilation, length of stay in the hospital and the PICU, as well as side effects were considered. However, there is still a lack of understanding in the interactions between methylxanthines and other drugs, particularly the beta-agonists as there is a theoretical risk of an additive cardiotoxic effect of combined therapy.

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

No, The evidence so far suggests that theophylline does not have a significant impact on the duration of hospital and ICU stay and that it increases the incidence of side effects in the asthmatic patients. However, the addition of theophylline may show definitive benefits in larger studies in the more severe asthma exacerbation, requiring mechanical ventilation.

References

1. Werner H. Status asthmaticus in children. Chest 2001; 119:1913-1929 [abstract]
2. Parkin P, Macarthur C, et al. Development of a Clinical Asthma Score for use in hospitalized children between 1 and 5 years of age. J Clin Epidemiol 1996; 49:821-825 [abstract]
3. Van der Windt D, Nagelkerke A, et al. Clinical scores for acute asthma in preschool children. A review of the literature. J Clin Epidemiol 1994; 47:635-646 [abstract]
4. Baker MD. Pitfalls in the use of clinical asthma scoring. Am J Dis Child 1988; 142:183-185 [abstract]
5. Keogh KA, Macarthur C. Predictors of hospitalization in children with acute asthma. J Pediatr 2001; 139:475 Ð 480 [abstract]
6. Papo MC, Frank J, et al. A prospective, randomized study of continuous versus intermittent nebulized albuterol for severe status asthmaticus in children. Crit Care Med 1993; 21:1479-86 [abstract]
7. Moler FW, Herwitz ME, et al. Improvement in clinical asthma score and PaCO2 in children with severe asthma treated with continuous nebulized terbutaline. J Allergy Clin Immunol 1998; 81:1101-09 [abstract]
8. Carter E, Cruz M, Chesrow S. Efficacy of IV administered theophylline in children hospitalized with severe asthma. J Pediatr 1993; 122:470-6 [abstract]
9. Bien JP, et al. Intravenous theophylline in pediatric status asthmaticus. A prospective, randomized, double blind, placebo-controlled trial. Clin Pediatr 1995; 34:475-81 [abstract]
10. Vieira SE, et al. Efficacy of IV aminophylline as supplemental therapy in moderate broncho-obstructive crises in infants and preschool children. Pulm Pharmacol Thera 2000; 13:189-194 [abstract]
11. Yung M, South M. Randomized controlled trial of aminophylline for severe acute asthma. Arch Dis Child 1998; 79:405-10 [abstract]

     

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