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:

Please visit the new Evidence Based Journal Club Reviews

Ribavirin in ventilated respiratory syncytial virus bronchiolitis. A randomized, placebo-controlled trial.

Guerguerian AM, Gauthier M, Lebel MH, Farrell CA, Lacroix J.

Am J Respir Crit Care Med 1999;160:829-34. [abstract] [full-text for subscribers]

Reviewed by P. Chalikonda MD, Lutheran General Children's Hospital, Park Ridge, IL

Review posted February 8, 2000

---

I. What is being studied?:

The study objective:

Effectiveness of ribavarin in previously healthy infants with RSV bronchiolitis who needed mechanical ventilation.

The study design:

Randomized, prospective, double blind, placebo-controlled study.

The patients included:

All consecutive infants < 1yr age mechanically ventilated for respiratory distress secondary to RSV bronchiolitis were considered. The inclusion criteria required the presence of:

1. First episode of bronchiolitis diagnosed clinically with the presence of tachypnea, chest retraction, prolonged expiratory time, pulmonary rales or wheezing and hyperinflation on chest x ray.
2. Mechanical ventilation instituted for respiratory distress manifested by one or more of the following: extreme fatigue, impending respiratory arrest, severe apnea if preceded by significant respiratory distress, uncompensated respiratory acidosis (pH < 7.30 and pCO2 > 60 mm Hg) , Hypoxia (Pao2 < 60 mm Hg or SpO2 < 93% with FiO2 > or equal to 0.6 and
3. Proven RSV etiology.

The patients excluded:

1. Cyanotic congenital heart disease or congenital heart disease under medication or associated with pulmonary hypertension.
2. Chronic respiratory diseases including BPD, Cystic fibrosis, chronic aspiration, pulmonary hypoplasia, neuromuscular disease.
3. Central hypoventilation or altered airway protection
4. Primary or secondary immune deficiency states, Chronic liver and kidney disease
5. Previous treatment with ribavarin or mechanical ventilation for > 24 hrs prior to starting ribavarin.
6. Failure to prove RSV etiology by rapid diagnostic test
7. Initiation of mechanical ventilation for apnea without significant respiratory distress as defined in inclusion criteria
8. Nosocomially acquired RSV ( after 7 days of hospitalization)
9. Failure to obtain consent rapidly enough to permit initiation of aerosol therapy within 24 hrs of beginning mechanical ventilation.

The patients were excluded a posteriori if they were discovered to be having any of the aforementioned underlying conditions during the same hospital stay, if the aerosol therapy was administered for less than 18 hrs. or if any virus other than RSV is identified on cultures drawn.

The interventions compared:

6 grams of Ribavarin diluted with sterile water to make a total volume of 300 ml vs. 300 ml of sterile 0.9 NaCl, were administered by the SPAG 2 aerosol generator over 18 hrs every 24 hrs for a maximum of 7 days or until extubation, whichever came first. All patients were ventilated in the IMV mode with continuous flow, time cycled ventilation.

The outcomes evaluated:

Primary: Length of ventilation. However the criteria for extubation were not well defined.

Secondary: length of ICU stay, length of oxygen therapy required to maintain SpO2 > 93% and the length of hospitalization

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. The patients were assigned randomly by table of random numbers and pharmacy assigned aerosol according to the predetermined order of randomization.

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

Was followup complete?

Yes, all patients were followed completely throughout their hospital course.

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

Yes. Patient data was processed based on intent to treat analysis. Patient characteristics were compared using the unpaired Students t test for continuous variables and the chi square test for categorical variables. The evolution of ventilatory settings was compared by analysis of variance.

Secondary questions:

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

The patients, health workers and study personnel were blinded to the study. Although the standard precautions for aerosol administration were followed for both the groups there was a possibility the health professionals could discover which patient got the ribavarin because of its propensity to cause particle deposition on the endotracheal tube and on the ventilator tubing. The treating physicians were asked not to try to find out which group got the ribavarin.

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

No differences in age, weight, sex, length of symptoms prior to ICU admission, length of hospitalization pre-ventilation, length of ventilation pre-aerosol treatment, ventilator settings pre-aerosol or blood gases pre-aerosol were noted.

The only difference between the two groups is that children born at < 37 weeks gestation constituted 52% of the placebo group and 30% of the treatment group with a Chi square test 0.1>p>0.05

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

The authors state that both the groups were similar with respect to number of patients who received sedation, paralysis, aerosolized intermittent albuterol, corticosteroids and antibiotics.

III. What were the results?

1. How large was the treatment effect?

No statistically significant effects of treatment were seen as compared with the placebo treatment group.

	Ribavarin	Placebo	p value
Length of aerosol therapy	59.87 ± 29.15	70.57 ± 37.12	0.31
Length of ventilation	102.16 ± 65.26	126.28 ± 78.72	0.29
Length of ICU stay	140.20 ± 80.87	161.45 ± 86.06	0.42
Length of oxygen therapy	185.24 ± 102.94	208.20± 87.89	0.44
Length of hospitalization	255.85 ± 124.93	294.95 ± 124.40	0.32

all numbers are hours (mean ± SD)

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

The group studied was not a very big one. According to a retrospective calculation by the authors, if the sample size was 290, a difference in duration of ventilation of 24 hrs (given a standard deviation of 71.5 hrs for the total sample and a mean of 102.16 hrs in the ribavarin group and of 126.28 hrs in the placebo group) could be detected. It is not clear why the authors determined the sample size based on an expected reduction in mechanical ventilation time by 50% (*)

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

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

The results can be applied to my patient care and will not change my practice. However, a larger study may confirm the trend shown by this study.

2. Were all clinically important outcomes considered?

Yes. All the clinically important outcomes were considered in the study.

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

No. Ribavarin is an expensive medication not without harmful effects. In some cases, it may even block the endotracheal tube.

As per this study, there are no statistically significant positive effects of ribavarin in mechanically ventilated RSV bronchiolitis children less than 1 yr age. Hence the likely treatment benefits of ribavarin are not worth the potential harms.

Footnote

Our calculations reveal that with an alpha error of 0.05, beta of 0.2, proving a significant reduction in ventilatory support duration by 24 hours would require 390 patients per group. (Hulley SB, Cummings SR: Designing Clinical Research. Baltimore MD, Williams and Wilkins, 1988) [return to text]

Comments

Back to the EB Journal Club Index