INTRODUCTION

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Respiratory syncytial virus (RSV) is the most common cause of respiratory tract infection in children. The majority of infants infected with the virus have a benign and self-resolving course of respiratory symptoms. Some children, however, suffer a more severe course of infection and require ventilatory support (1, 2). Initial publications claimed that ribavirina guanosine analog with in vitro activity against RSVbenefited patients suffering from RSV bronchiolitis (3). Further trials failed to reproduce the initial benefits, and this prompted the American Academy of Pediatrics to modify its initial positive recommendations (7, 8). Currently, the Academy's guidelines state that certain risk groups, and severely ill patients, may benefit from aerosolized ribavirin in RSV respiratory disease.

We undertook a prospective, double-blind, placebo-controlled trial to resolve the question of the clinical effectiveness of ribavirin in previously well infants without underlying illnesses who require ventilatory support for respiratory distress secondary to a first episode of RSV bronchiolitis.

	METHODS

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Population Characteristics

From March 1, 1994 to April 1, 1997 all consecutive infants < 1 yr of age who were mechanically ventilated for respiratory distress secondary to RSV proven bronchiolitis in the intensive care unit (ICU) of Sainte-Justine Hospital, a tertiary care pediatric institution, were considered eligible for this study. Patient participation in the study was approved by the institution's Medical Ethics Committee on Research, and informed written parental consent was obtained before randomization. The inclusion criteria were: (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 radiograph; (2) mechanical ventilation instituted for respiratory distress manifested by one or more of the following: (i) extreme fatigue, or impending respiratory arrest, or severe apnea if preceded by significant respiratory distress; (ii) uncompensated respiratory acidosis (pH < 7.30 and PCO₂ > 60 mm Hg); (iii) hypoxia (Pa_O2 < 60 mm Hg or pulse oxymetry saturation [Sp_O2] < 93% with fraction of inspired oxygen [FI_O2]  0.6); and (3) proven RSV etiology.

The exclusion criteria were: (1) cyanotic congenital heart disease, congenital heart disease under medication or associated with pulmonary hypertension; (2) chronic respiratory disease associated with bronchopulmonary dysplasia, cystic fibrosis, chronic aspiration, pulmonary hypoplasia, or neuromuscular disease; (3) central hypoventilation syndrome or altered airway protection; (4) primary or secondary immune deficiency; (5) chronic liver disease or renal failure; (6) previous treatment with ribavirin; (7) mechanical ventilation for > 24 h prior to the start of the aerosol treatment; (8) failure to prove RSV etiology by rapid diagnostic test; (9) initiation of mechanical ventilation for apnea without significant respiratory distress as defined previously; (10) nosocomial acquired RSV infection as defined by Hall and coworkers (after 7 d of hospitalization) (9); (11) failure to obtain parental informed consent rapidly enough to permit initiation of aerosol therapy within 24 h of the beginning of mechanical ventilation. The a posteriori exclusion criteria were: (1) patient discovered to have one or more of the aforementioned underlying conditions during the same hospital stay; (2) aerosol administered for less than 18 h; (3) a viral pathogen other than RSV identified on viral cultures sampled before or during mechanical ventilation. The end of the study was the time of discharge from hospital or death.

Identification of RSV and Other Pathogens

The presence of RSV was necessary for the patient to be considered eligible for the study; this was proved by two methods of detection. First, for quick evaluation of patients, a rapid antigen detection test (Immediate Care Diagnostics In Vitro RSV Antigen Test Pack; Abbott, Chicago, IL) was performed in the ICU on nasopharyngeal secretions. The diagnosis was then confirmed by a second test (Kallestad Pathfinder RSV EIA Kit; Sanofi Diagnostics Pasteur, Chaska, MN) performed by the microbiology laboratory, on nasopharyngeal and/or endotracheal secretions. Viral cultures were performed on endotracheal secretions to exclude the presence of other pathogens on initiation of mechanical ventilation. Bacterial cultures were done on endotracheal secretions sampled on initiation of mechanical ventilation and twice a week, or more often if superinfection was suspected.

Randomization, Time Zero, and Baseline Data

Randomization was done with a table of random numbers. The pharmacy assigned the aerosol according to the predetermined order of randomization. Time zero was the beginning of the administration of the study drug. Baseline data were collected relative to time zero.

All data were collected upon admission to the pediatric ICU, and prospectively during the study, by a staff critical care physician or fellow not involved in patient care. Patient characteristics studied included gender, race (white, black, Asian, Native Canadian), gestational age at birth in weeks, postnatal age in days at the beginning of mechanical ventilation, and weight. A clinical history was obtained from parents to identify any conditions excluding the infant a priori. A family history of reactive airway disease and allergies was noted. Duration of symptoms (cough, nasal discharge, wheezing, and fever) preceding the ICU admission was noted. The time of admission to hospital was considered to be the time of admission to a ward (general or ICU). Length of hospitalization before ventilation and length of ventilation before the beginning of the study drug were noted. Reasons for intubation and mechanical ventilation were also noted. The beginning of ventilation was considered to be the hour at which mechanical ventilation was started in the ICU with a ventilator.

Administration of Ribavirin and Blinding

Ribavirin vials (ICN Pharmaceuticals Inc., Montreal, PQ, Canada) and placebo vials were both prepared by the hospital pharmacy. According to the manufacturer's recommendation, one 6-g vial of ribavirin was diluted with sterile water to a volume of 300 ml to achieve a concentration of 20 mg/ml. The placebo was 300 ml of sterile NaCl 0.9%. The study aerosol (ribavirin or NaCl 0.9%) was incorporated in the administrating device (SPAG 2; ICN Pharmaceuticals Inc.) by the pharmacy. Consequently, in accordance with blinding precautions, the premixed, diluted and ready-to-use solutions were not directly manipulated by any caregivers. The study drugs were administered by the aerosol generator, SPAG 2, which produces small particles that have been described to attain the lower respiratory tract (10, 11). Respiratory therapists were responsible for the installation of the SPAG 2 generator with the ventilator circuit, as well as for ventilator maintenance. Precautions previously described were used and adapted to avoid ribavirin deposition and aerosol-related complications: (1) Tygon ventilator tubing (Baxter, Pointe-Claire, PQ, Canada) was used to connect the patient to the ventilator; (2) one-way valves were inserted between the SPAG circuit and the ventilator circuit; (3) double filters were used in the expiratory circuits; (4) filters proximal to the patient were removed and discarded every 8 h; (5) the endotracheal tube was suctioned every 2 h or more frequently if necessary. Physicians were asked not to try to discover which treatment was being administered to their patient. Standard precautions (12) used to protect personnel from aerosol exposure were used for all patients. The aerosol was administered over 18 h every 24 h for a maximum of 7 d or until extubation, whichever came first.

Comaneuvers: Ventilation and Treatment Strategies

All patients were ventilated by intermittent mandatory positive pressure ventilation with continuous flow, time-cycled, Sechrist IV-100B Infant Ventilators (Sechrist Industries, Anaheim, CA). Ventilator management was under the responsibility of one of the four staff pediatric intensivists, and all decisions with regard to mechanical ventilation were made and prescribed by the attending physician, not by respiratory therapists or nurses. Mechanical ventilation was initiated with a rate (intermittent mandatory ventilation Mi]) of 25 to 30 cycles/min; an inspiratory ratio of 1:2 or 1:3; a peak inspiratory pressure (peak PI) of 20 to 30 cm H₂O to achieve adequate chest expansion; a positive end-expiratory pressure (PEEP) of 3 to 5 cm H₂O; and a FI_O2 sufficient to maintain a Sp_O2  93%. For all patients, the ventilator flow rate was 8 to 16 L/min, the flow rate of the aerosol generator was 8 to 9 L/min, and its pressure was set at 40 mm Hg. All airway pressures were measured at the endotracheal tube adapter. Ventilator settings were adjusted to maintain pH > 7.35, Sp_O2  93% or Pa_O2  65 mm Hg, and capillary PCO₂  55 mm Hg. If the patient worsened (respiratory acidosis, increased chest retractions and/or tachypnea), the ventilatory rate was increased to 35 cycles/min, or the peak PI was modified by increments of 3 to 5 cm H₂O to a maximum of 40 to 45 cm H₂O. If the FI_O2 used to maintain oxygenation was  0.6, PEEP was increased by increments of 2 cm H₂O to a maximum of 8 cm H₂O. As the patient improved, the FI_O2 was lowered below 0.6, then the PEEP was lowered to initial levels, the peak PI to 20 to 25 cm, and the rate (Mi) decreased, until the patient was breathing spontaneously with a continuous positive airway pressure (CPAP) of 3 to 5 cm H₂O. Extubation was carried out when the patient maintained adequate blood gases under minimal ventilation. End of ventilation was noted as the time of extubation. Supplemental oxygen was continued to maintain Sp_O2  93%.

Additional treatments (sedation, paralysis, inhaled albuterol [salbutamol], steroids, antibiotics, and chest physiotherapy) were left to the discretion of the attending ICU physician. Hydration and nutrition were provided through enteral nasogastric feedings and/or the intravenous route, as considered appropriate.

Outcomes and Monitoring

The primary outcome measured in this study was the length of ventilation. Secondary outcomes measured were the length of ICU stay, the length of oxygen therapy to maintain Sp_O2  93%, and the length of hospitalization. Occurrence of adverse events such as barotrauma and pulmonary superinfection was also documented.

Usual ICU cardiorespiratory monitoring was provided for all patients, including pulse oxymetry. Hourly ventilatory settings (Mi, peak PI, PEEP, FI_O2) and respiratory rate were noted. Capillary blood gases, which accurately reflect arterial pH and PCO₂ in children (13), were monitored before intubation, 30 min after beginning of mechanical ventilation, before starting the study aerosol, within 1 h of start of study aerosol, and every 6 h until extubation. Daily chest radiographs were monitored. Any other investigation believed to be necessary by the attending physician was carried out. All complications were noted.

Analytic Methods

The total number of patients required to detect a reduction in length of ventilation of 50% was determined before the beginning of the trial, using a formula provided by Lachin (14) and our previous published mean length of ventilation (4.4 d) for severe bronchiolitis (15). We found that a total of 42 patients was needed. Data were entered on a spreadsheet program (Excel 4.0; Microsoft, Redmond, WA). All registered data were verified at least twice before the analysis was performed. Results of descriptive statistics are expressed as absolute numbers and percentage of the population group, and as mean ± SD. After completion of the study, data were processed by an "intent to treat" analysis. Patient characteristics were compared using the unpaired Student's t test for continuous variables, and the chi-square test for categorical variables (software: Statsview 4.5; Abacus Concepts, Inc., Berkeley, CA). The evolution of ventilatory settings was compared by analysis of variance (ANOVA) (Software: SAS, release 6.12; SAS Institute Inc., Cary, NC).

	RESULTS

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Baseline Data

During the 3-yr period of the study, 51 cases of proven RSV bronchiolitis in patients with no other underlying disease were admitted to the pediatric ICU of Sainte-Justine Hospital and required mechanical ventilation. Of these 51 eligible patients, 42 patients were randomized to receive ribavirin or placebo NaCl 0.9% aerosol. Inability to obtain parental consent within the desired deadline prevented the inclusion of nine patients who had baseline characteristics that were comparable to those of the randomized patients (data not shown). One patient was excluded after central hypoventilation (Leigh syndrome) was diagnosed after failure to wean from mechanical ventilation even though lung disease had resolved. Forty-one patients were used for "intent to treat" outcome analysis. Twenty patients received ribavirin and 21 received NaCl 0.9%. Both groups were similar with respect to most baseline data (Table 1). The only difference between the two groups was in the distribution of infants of less than 37 wk gestation at birth: there were six in the 20 (30%) ribavirin patients, and 11 in the 21 (52%) NaCl 0.9% treated patients. The blood gas parameters (pH, PCO₂) before the start of the study drug, as well as the FI_O2, the inspiratory Mi rate, and the peak PI, were not statistically different. Bacterial pathogens were sought by culture of endotracheal secretions sampled during the hours that followed intubation and preceded administration of the aerosol. In the group randomized to ribavirin, five patients had positive cultures (Escherichia coli [2], Haemophilus influenzae non-b [1], Moraxella catarrhalis [2]); in the placebo group, one patient had a positive culture for Staphylococcus aureus. No viruses other than RSV were identified.

Outcomes

There was no statistically significant difference in length of ventilation between the two groups (Table 2). After the study was completed, we estimated its power with the actual results: we found that a total of 290 patients would be required to detect a difference in duration of ventilation of 24 h, with a p value < 0.05 and a  < 0.2, given a standard deviation of 71.5 h for the total sample, and a mean of 102.16 h in the ribavirin group and of 126.28 h in the control group (14). The higher number of preterm infants in the control group should bias the data in favor of ribavirin, but no differences were found.

There were also no statistical differences in the secondary outcomes measured, namely length of aerosol therapy, length of ICU stay, total length of oxygen therapy, and length of hospitalization (Table 2).

By comparing the mechanical ventilation management and gas exchange between the two groups, we found similarities not only in the length of support, but also in the type of ventilation required. FI_O2 (p = 0.48), Mi (p = 0.1), peak PI (p = 0.79), spontaneous breathing rate (p = 0.99), pH (p = 0.83), and PCO₂ (p = 0.82) did not differ between the ribavirin and placebo groups for the first 5 d of mechanical ventilation (120 h) (Figure 1).

View larger version (27K): [in this window] [in a new window]   Figure 1.   Clinical parameters in the ribavirin and the control groups. Ventilatory settings of each patient were monitored hourly. Every 6 h (time 0, 6, 12, 24), measurements recorded during the previous 4 h were used to calculate the mean of the setting. Blood gases were drawn every 6 h. Means ± SD of FIO2, Mi rate, and pH of all patients in the ribavirin (square and full line) and placebo (diamond and dotted line) groups are plotted for the first 120 h. No significance difference was found.

Additional treatments were used in many patients. Both groups were similar with respect to the number of patients who received sedation, paralysis, aerosolized intermittent albuterol, corticosteroids, and antibiotics (Table 3).

All 41 patients survived and were discharged home. The administration of the study drug was completed in 40 patients, all of whom tolerated it well. One patient developed early severe lung disease compatible with acute respiratory distress syndrome. As a result, the study drug was stopped after 34.3 h at the request of the treating physician, who suspected a left pneumothorax (never confirmed) and felt that the aerosol did not permit adequate ventilatory management. The identity of the aerosol (ribavirin) was not revealed until the final data analysis. The patient eventually received nitric oxide (NO) as rescue therapy, was discharged from the ICU on Day 16, and went home on Day 26 of hospitalization. If this patient is excluded and the data reanalyzed, there remains no statistical difference between the two treatment groups, with a length of ventilation of 90.9 h in the ribavirin group and a p value of 0.09.

No pneumothorax or pneumomediastinum was detected on the daily chest radiographs done on all patients. One patient (who received the placebo) developed a right lobar pneumonia on Day 3 of ventilation and Staphylococcus aureus grew on culture of endotracheal secretions; this patient's course did not differ from that of the other patients. No mechanical or ventilator dysfunction was noted during the whole study.

	DISCUSSION

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Effectiveness of Aerosolized Ribavirin

It is clear that ribavirin is active against RSV in vitro, but its effectiveness in RSV bronchiolitis in producing significant changes in clinical outcomes such as the length of mechanical ventilation, of ICU stay and of hospital stay, is still a matter of debate (7, 16).

Only two prospective, randomized, placebo-controlled trials of children mechanically ventilated for RSV bronchiolitis have been conducted so far to assess the impact of ribavirin on the duration of mechanical ventilation, and they have delivered conflicting results.

The earlier trial (5), which involved a total of 28 patients, demonstrated a decreased duration of mechanical ventilation in patients treated with ribavirin. This study has been criticized for the long mean duration of ventilation in the placebo group (10 d), which was almost twice as long as the expected time of ventilation for this disease: in four other studies, the length of mechanical ventilation among patients with RSV bronchiolitis who did not receive ribavirin was much shorter [median of 5.5 d (17); averages of 4.4 d (15), 8.2 d (2), and 5.0 d (18)]. It is suspected that the placebopure waterused in this trial worsened the patients' clinical condition by inducing bronchospasm (2, 19).

A second trial, also conducted on 41 ventilated infants, did not demonstrate a decreased duration of mechanical support with ribavirin (2). This study used an aerosolized saline placebo, but included infants with various underlying conditions that are known to modify the severity of the illness. Although the patients studied were stratified according to these conditions, this obviously decreased the number of infants available for analysis in each subgroup. Furthermore, although it is crucial for the assessment of the effectiveness of ribavirin in shortening the course of ventilation that its administration be initiated early, the mean time from the onset of ventilation to the start of aerosol in this study was more than 24 h.

Other studies have also reported the ineffectiveness of ribavirin in mechanically ventilated infants, but they were not randomized placebo-controlled. A prospective multicenter cohort study (18) failed to demonstrate ribavirin to be effective in decreasing length of ventilation. A historical cohort study (20) did not show ribavirin to have a positive effect on either ventilated or nonventilated patients. A multicenter review of hospitalized children with RSV infection demonstrated by multivariate analysis that ribavirin treatment was associated with an increase in duration of hospital stay (21).

This clinical trial intentionally focused on a homogeneous group of infants to avoid possible interference from diverse risk factors. The course of mechanical ventilatory support and the treatment of patients randomized in the study were comparable to those described in recent papers (17, 18, 22). We report a lack of effectiveness of aerosolized ribavirin in reducing the length of ventilation, length of oxygen therapy, length of ICU stay, and total length of hospitalization in infants with no underlying illness ventilated for respiratory distress secondary to RSV bronchiolitis. These data suggest that there is no indication for the use of aerosolized ribavirin in mechanically ventilated patients with RSV bronchiolitis and no underlying illness.

Questions may arise with respect to these results, in particular regarding the nature of the blinded assessment and the statistical power.

Despite specific precautions to avoid ribavirin accumulation, it is actually very difficult to hide completely the deposits that aerosolized ribavirin may cause in endotracheal tubes and ventilator circuits. This problem is indeed unavoidable in every trial on this drug when given by aerosol therapy. In order to optimize blinding of physicians in our study, respiratory therapists and nurses regularly cleaned the outer surface of the equipment to eliminate any visible precipitates of ribavirin. They were also specifically asked to keep the medical team in charge of the patients unaware of treatment assignment, in the event that the presence of ribavirin deposits was suspected.

Statistical power is always a concern when interpreting the results of a negative clinical trial. According to Pon and Notterman (23), only a multi-institutional study with a very large sample size would have sufficient power to determine that there is no difference between ribavirin and placebo in mechanically ventilated children with RSV bronchiolitis. We calculated that a total of 290 patients would be needed to find a statistically significant difference in duration of ventilation, given the results of our study; whether it is appropriate to undertake a clinical trial requiring such a large sample size to prove efficacy remains a matter of debate.

Usefulness of Aerosolized Ribavirin

Although one positive study (5) suggested that aerosolized ribavirin may be useful, our data and the results of other clinical studies (2, 18, 20, 21) reported no clinically important differences with the use of ribavirin. A treatment must be cost-effective to be useful. Thus, side effects, adverse events, and costs must also be taken into account. Adverse events have been described with the use of aerosolized ribavirin in mechanically ventilated children. Englund and colleagues (24) and Hicks and colleagues (25) both reported that aerosolized ribavirin can completely plug an endotracheal tube, with serious results for the patient. Some data also suggest that aerosolized ribavirin increases maximal peak PI (10), which may increase the resistance in the ventilator circuit and the risk of barotrauma (26). Aerosolized treatment was discontinued without breaking the code in one patient of this study at the request of the attending physician because he felt that the aerosol treatment was harmful; it was disclosed after the data were analyzed that the patient was receiving ribavirin. Ribavirin is also quite expensive (27). Thus, data from the literature also suggest that the usefulness of aerosolized ribavirin for shortening the duration of mechanical ventilation in normal infants is not clinically significant, if it even exists.

Conclusion

The 1996 recommendations of the American Academy of Pediatrics (8) and the 1997 recommendations of the Canadian Paediatric Society (28) on ribavirin stated that prospective randomized placebo-controlled trials were still needed to determine the effectiveness of this drug. The need to investigate specific groups of patients at risk has also been expressed (22, 29, 30). Our trial which attempted to decrease the risk of flawed results by initiating rivabirin therapy early and using normal saline as the placebo clearly suggests that aerosolized ribavirin is not an effective treatment in children without underlying diseases requiring mechanical ventilation for RSV bronchiolitis. Published surveys show that critical care physicians and infectious disease specialists, both in North America and in Europe, have little faith in ribavirin for RSV-associated respiratory disease (31, 32). It is possible that a very large clinical trial on ribavirin would succeed in detecting a statistically significant difference with respect to important outcomes like the length of mechanical ventilation, but the clinical relevance of such a trial is questionable, and it is difficult to foresee great enthusiasm for its organization. Intravenous ribavirin, which may avoid any increase in airway resistance, bronchospasm, and endotracheal tube plugging associated with aerosolized ribavirin, may be a better way to treat severe RSV bronchiolitis, but there are no hard data to support this hypothesis. The focus of interest has now shifted to the development of preventive strategies for RSV bronchiolitis, and vaccines as well as immune modulation with immunoglobulins are presently being studied (33, 34). These may prove to be better methods of decreasing the morbidity associated with this widespread infection.