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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A randomized comparison of helium-oxygen mixture (heliox) and racemic epinephrine for the treatment of moderate to severe croup

Weber JE, Chudnofsky CR, Younger JG, et al.

Pediatrics. 2001 Jun;107(6):E96. [abstract] [full-text]

Reviewed by Mehrengise Cooper MD, The Children's Hospital, Boston MA

Review posted November 13, 2001

I. What is being studied?:

The study objective:

This was to compare the effect of a mixture of Helium and Oxygen (Heliox 70:30) to racemic epinephrine on croup scores.

The study design:

A prospective, randomized double-blind trial set in an Emergency department and intensive care unit of an urban level I trauma center.

The patients included:

These were randomly assigned consecutive children with moderate to severe croup, aged between 6 months and 3 years, who had received treatment with humidified oxygen and steroids. Moderate or severe croup was defined as the presence of hoarseness, barking cough and stridor in a patient with an upper respiratory infection less than seven days duration and a Modified Taussig Croup Score of 5; if the patients scored 3 in any category with a total Modified Taussig Croup Score of 5, inclusion criteria were met. Twenty-nine patients were successfully studied, out of a total of thirty-three who were enrolled.

The patients excluded:

Exclusion criteria included a history of congenital heart disease, tracheal stenosis, bronchopulmonary dysplasia; or signs and symptoms suggestive of an alternative cause of stridor, for instance: epiglottitis, bacterial tracheitis, retropharyngeal or peritonsillar abscess, reactive airways disease or supraglottic foreign body. Others excluded were those where protocol violations occurred, or where rescue doses of racemic epinephrine was administered.

If the patient's oxygen saturation was < 90% following second dose of racemic epinephrine or placebo, or they were unable to tolerate facemask or tent house, or if there was any clinical deterioration.

The interventions compared:

Patients were assigned to receive 70:30 Heliox mixture or racemic epinephrine via similar blinded delivery systems and data was collected over 4 hours. This data included vital signs, oxygen saturation and croup scores.

The outcomes evaluated:

Reductions in croup score.

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?

The surrogate end-point used in this study is the croup score. These scores are useful as tools to demonstrate disease severity at a single point in time and then follow the score through the course of an illness, for example a decreasing score is an objective measure of clinical improvement. The Modified Taussig Croup Score (1) - one of several clinical scoring systems used in the management of croup - assesses patient colour, anxiety, retractions, stridor, and level of consciousness with equal importance whilst classifying disease as severe if there is a maximal score in any of the above. This is relevant when looking at stridor and retractions as these have both been shown to be inversely related to the tracheal diameter.

To clinically assess patients with croup, knowledge of clinically important events is important, notably intubation, and data on length of hospital stay. There appears to be little published data correlating croup scores with clinical endpoints; it appears that most studies using croup scores generally follow patients for a short period of time, 4 hours seems to be a maximal time period.

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. Other drugs have been used in the management of croup and these have used croup scores as the surrogate end-point. The mainstay of drug treatment has been with steroids - intramuscular dexamethasone (2), oral dexamethasone and nebulized budesonide (3). These generally are of benefit for children with mild-moderate croup. Oral administration may be the best option as it is easy to administer, easily available and lower cost.

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?

Studies using croup scores as a surrogate end-point have been used in studies where independently racemic epinephrine and Heliox have been shown to improve the work of breathing and objectively reduce croup scores.

Westley et al showed that in comparing the use of nebulised racemic epinephrine against saline was significantly more effective as shown by improvement in clinical scores (4). Another study comparing the effectiveness of Helium-oxygen mixture in reducing post-extubation stridor, compared with oxygen-supplemental room air, used a clinical stridor scoring system, and showed improved scores with the use of Heliox mixture (5).

However, there are no available trials evaluating the effect of either of these agents on a true clinical endpoint.

IIa. Validity Questions for Therapy Articles:

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, via a computer-generated randomized method.

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?

No. Four patients were excluded because of protocol violations, and two others for requiring rescue doses of racemic epinephrine.

Children, who were included, were followed for the 240 minutes as outlined in the study design. Yes, they were analyzed in the groups to which they were randomized.

Secondary questions:

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

Not all were blind to the treatment. A respiratory therapist knew which protocol the patient was receiving, but was not involved with patient recruitment or data collection.

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

Yes. Comparing the baseline data of the four groups - enrolled, nonenrolled, heliox, and racemic epinephrine - were similar for sex, and initial severity (croup scores 5 to 9, heart rate, respiratory rate and arterial oxygen saturation).

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

Yes. During the 240 minutes of the study and observation period the groups were treated equally. All patients received treatment with humidified oxygen and steroids. Oxygen flow meters were calibrated in advance to correct for the differences in physical properties of the two gases. In addition, children who received Heliox received 3 hours of continuous gas therapy with nebulized saline administered as a placebo.

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.)

The treatment effect was for a duration of 240 minutes. This was deemed a safe enough period of time for treatment and one-hour observation to ensure patient safety from previously published data.

No differences were noticed between the groups of the two study arms with regards to croup scores over time or clinical outcome (with the only clinical outcome reported being intubation - no patient in either group was intubated). Improvements in the measured parameters over time were seen in both groups - p < 0.01 in each group. The most rapid rate of improvement was seen in the first 30 minutes of treatment followed by a slower rate of improvement. Overall there was no difference seen in croup scores between the groups at the end of the observation period (p = 0.13), when analysis was performed with repeat-measure analysis of variance. There were no statistical differences between the treatment groups in other measured severity parameters (heart rate, respiratory rate and oxygen saturation).

Of note, the minimum sample size was calculated at 14 patients per group to produce an 80% power to detect a change of 2 in the croup score, and a power of 90% to detect a change of 3 between the two groups, suggesting that the study is underpowered.

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

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

Children are frequently admitted to the Pediatric Intensive Care Unit with croup requiring close observation where airway compromise is a large risk and so all these treatment options can be considered.

2. Were all clinically important outcomes considered?

All clinically important outcomes were considered. No children required intubation, as airway compromise leading to exhaustion and respiratory failure is the most serious outcome in a patient with croup. Analyzing any data on the 29 children who met the inclusion criteria but were not included within the study would have been useful; especially with regards to clinically important outcomes.

It would be essential to look at these patients over a longer time period including information on admission rates, length of hospital stay, and if there were any potential life-threatening events in order to assess treatment effect, when comparing this with the physiological measure of a croup score.

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

This study shows that there is an improvement in the croup scores when patients are treated with cool humidified oxygen, steroids, and either Heliox mixture or racemic epinephrine. However, the study has limitations; the power was not adequate to detect a small difference between the two groups of children unwell enough to require aggressive management. In addition, if a third group had been included of cool mist oxygen and steroids alone, the possibility of an incremental benefit seen in the Heliox group may have been attributable to the use of cool oxygen. There is no information reviewing any harms or costs involved in this study.

Heliox has been used in other different situations and hypoxia has been reported Ð this would be a clear contraindication to its use.

More work is needed to evaluate the effectiveness of Heliox in the management of croup.

References

1. Taussig LM, Castro O, Beaudry PH, Fox WW, Bureau M. Treatment of laryngotracheobronchitis (croup). Use of intermittent positive-pressure breathing and racemic epinephrine. Am J Dis Child. 1975 Jul;129(7):790-3.[abstract]
2. Klassen TP. Croup. A current perspective. Pediatr Clin North Am 46(6):1167-1178. 1999 [abstract]
3. Godden CW, Campbell MJ, Hussey M, Cogswell JJ. Double blind placebo controlled trial nebulized budesonide for croup. Arch. Dis. Child. 76:155-158, 1997. [abstract]
4. Westley CR, Cotton EK, Brooks JG. Nebulized Racemic Epinephrine by IPPB for the Treatment of Croup. Am J Dis Child 132:484-487, 1978. [abstract]
5. Kemper KJ, Ritz RH, Benson MS, Bishop MS. Helium-oxygen mixture in the treatment stridor in pediatric trauma patients. Crit Care Med 19:356-359, 1991 [abstract]

    

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