Original Article
A Controlled Trial of Aerosolized Ribavirin in Infants Receiving Mechanical Ventilation for Severe Respiratory Syncytial Virus Infection
N Engl J Med 1991; 325:24-29July 4, 1991
- Abstract
- Abstract
Background.
Although the antiviral agent ribavirin improves the course of lower respiratory tract disease in spontaneously breathing infants with respiratory syncytial virus infection, it is not known whether ribavirin can benefit infants with severe respiratory syncytial virus disease who require mechanical ventilation.
Methods.
We conducted a randomized, double-blind, placebo-controlled evaluation of ribavirin (20 mg per milliliter) administered continuously in aerosolized form to infants receiving mechanical ventilation for respiratory failure that was caused by documented respiratory syncytial virus infection.
Results.
Of the 28 infants (mean [±SD]age, 1.4±1.7 months) enrolled, 7 had underlying diseases predisposing them to severe infection (mean age, 3.0±2.6 months), and 21 were previously normal (mean age, 0.8±0.9 month). Among the 14 infants who received ribavirin, the mean duration of mechanical ventilation was 4.9 days (as compared with 9.9 days among the 14 who received placebo; P = 0.01), and the mean length of supplemental oxygen use was 8.7 days (as compared with 13.5 days; P = 0.01). The mean length of the hospital stay was 13.3 days after treatment with ribavirin and 15.0 with placebo (P = 0.04). When only the 21 previously normal infants were considered, the mean length of the hospital stay was 9.0 days for the ribavirin recipients and 15.3 days for those who received placebo (P = 0.005).
Conclusions.
In infants who require mechanical ventilation because of severe respiratory syncytial virus infection, treatment with aerosolized ribavirin decreases the duration of mechanical ventilation, oxygen treatment, and the hospital stay. (N Engl J Med 1991; 325:24–9.)
Media in This Article
Figure 1
Percentage of Infants in the Ribavirin (□) and Control (■) Groups Requiring Mechanical Ventilation after Aerosol Therapy Began.Figure 2
Percentage of Infants in the Ribavirin (□) and Control (■) Groups Requiring Supplemental Oxygen after Aerosol Therapy Began.Article Activity
- Article
RESPIRATORY syncytial virus is the most important respiratory pathogen causing lower respiratory tract infection in infants and young children. Ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a synthetic nucleoside with inhibitory activity against a variety of viruses, including respiratory syncytial virus.1 2 3 The Food and Drug Administration approved the licensure of aerosolized ribavirin for the treatment of respiratory syncytial virus infection in December 1986. Approval was limited to use in infants who were breathing spontaneously and was based on the beneficial effect demonstrated in three controlled clinical trials.4 5 6 Two of these trials involved previously normal infants, and one involved infants with underlying diseases known to predispose patients to severe illness. The trials have been criticized for their limited numbers of subjects, their lack of objectivity in defining entry criteria and improvement in respiratory function, and their statistical methods.7 Furthermore, none demonstrated significant effects on mortality, duration of treatment or hospitalization, or need for supportive therapy, including oxygen, mechanical ventilation, and intensive care.
Ribavirin is not approved for use in infants requiring assisted ventilation because precipitation of the drug in the respiratory equipment may interfere with safe and effective ventilation of the patient.8 We developed a system that permits simultaneous mechanical ventilation and delivery of ribavirin to infants.9 We then designed and completed a randomized, double-blind, placebo-controlled evaluation of aerosolized ribavirin in infants with respiratory syncytial virus infection who require mechanical ventilation.
Methods
Patients
Infants who had clinical symptoms and findings on chest radiography that were compatible with lower respiratory tract infection were eligible for the study if a specimen of their respiratory secretions was positive for respiratory syncytial virus by direct immunofluorescent antibody stain and if they required mechanical ventilation because of respiratory failure. Infants requiring ventilatory support because of apnea, those who were already receiving ribavirin when mechanical ventilation began, and those with concurrent infection with other organisms were excluded. For children without chronic lung disease, respiratory failure was defined as a partial pressure of arterial carbon dioxide (PaCO2)≥8 kPa, a partial pressure of arterial oxygen (PaO2)≤8 kPa and a fraction of inspired oxygen (FiO2)≥0.6 (a ratio of oxygen tension to inspired oxygen ≤13.3), or respiratory arrest (preceded by severe respiratory distress) with absent or ineffective respirations accompanied by cyanosis or bradycardia. For children with chronic lung disease, respiratory failure was defined as an increase in the PaCO2 sufficient to cause respiratory acidosis (pH ≤7.30).10
The study protocol was reviewed and approved by the Medical Committee for the Protection of Human Subjects in Research at Stanford University. Informed consent was obtained from the parents or guardians of the study subjects before their entry into the study.
Randomization and Drug Administration
Before randomization, the infants were stratified into two groups according to the presence of underlying diseases known to predispose children to severe infection with respiratory syncytial virus.11 The infants were assigned by a pharmacist independent of the investigators to receive either ribavirin or placebo. The assignment was accomplished under double-blind conditions with a random table. The table assigned equal numbers of infants to the treatment and control groups for each 10 patients enrolled.
The ribavirin solution for aerosol delivery was prepared by a pharmacist in a concentration of 20 mg per milliliter.9 The placebo was an identical volume of sterile water. The ribavirin and placebo solutions were delivered in the aerosol-generating chamber to the respiratory therapist. Our technique for administering ribavirin during mechanical ventilation has been described previously.9 Ribavirin or placebo was administered continuously for seven days or until the infant was extubated, whichever came first. The aerosol generator was turned off during periods of suctioning and chest-percussion therapy. A record of each infant's time on the aerosol generator was maintained.
In order to ensure the blinding of nurses and physicians, the respiratory therapists cleaned the outer surfaces of the equipment with isopropyl alcohol. The adapter connecting the ventilator to the patient was rinsed in sterile water and reinserted. These procedures, designed to eliminate any visible precipitation of ribavirin, were performed every two hours. Infants were removed from the study if they required an FiO2≥0.6 for 96 hours or more.
Ventilatory Support
Our technique for the ventilatory support of infants with severe bronchiolitis has been described previously.12 In brief, our goal was to maintain a PaCO2 of 5.3±0.7 kPa using a ventilatory rate of 10 to 15 breaths per minute and a tidal volume of 15 ml per kilogram of body weight, or whatever peak inspiratory pressure was required to achieve adequate chest excursion. If the PaCO2 rose to ≥6 kPa, we increased the ventilatory rate to 20 breaths per minute when volume-limited ventilation was used or when chest excursion was adequate on pressure-limited ventilation. If chest excursion was inadequate on pressure-limited ventilation, we increased the peak inspiratory pressure before increasing the ventilatory rate. If the PaCO2 was ≤4.7 kPa, we lowered the tidal volume to 10 ml per kilogram, the peak inspiratory pressure to 2.5 kPa (25 cm of water), and finally the ventilatory rate. Our goal was to maintain a PaO2 of 10.0±1.3 kPa using an end-expiratory pressure of 0.4 kPa (4 cm of water) plus supplemental oxygen. If the FiO2 required to maintain adequate oxygenation was ≥0.6, increased expiratory pressure was tried. If the PaO2 was ≥11.3 kPa, the FiO2 was first decreased to 0.6, then the expiratory pressure was lowered to 0.4 kPa (4 cm of water), and finally the FiO2 was further decreased. Mechanical ventilation was discontinued and the trachea was extubated when the patient was able to maintain a PaO2 ≥9.3 kPa and a PaCO2 ≤6 kPa with the expiratory pressure ≤0.4 kPa (≤4 cm of water), the FiO2 ≤0.4, and the ventilatory rate ≤4 breaths per minute. Supplemental oxygen was administered after mechanical ventilation until the infant could maintain a fractional oxyhemoglobin saturation ≥0.95 while breathing room air. All decisions regarding changes in ventilator settings and the administration of oxygen were made by pediatric house officers under the direct supervision of the attending physician in the intensive care unit.
Chloral hydrate, narcotic agents, or benzodiazepine drugs were prescribed for sedation, as needed. Neuromuscular relaxants were given if a peak inspiratory pressure of 3.9 kPa (≥40 cm of water) was required or if the patient was agitated and resistant to mechanical ventilation despite the administration of sedative agents. Intravenous aminophylline in doses adequate to maintain serum concentrations of 10 to 20 μg per milliliter was used in all patients. Aerosolized bronchodilators were used at the discretion of the attending physicians. Suctioning of the endotracheal tube was performed every one to two hours, and chest percussion every two to four hours. Intravenous antibiotics were used until cultures of blood obtained at the time of hospital admission had remained negative for three days. Corticosteroids were not administered.
Airway pressure during ventilation was measured in the proximal airway (Ventilator Monitor 00120, Bunnell, Salt Lake City) and recorded every hour along with the ventilatory rate and the FiO2. Arterial blood gases were measured every two to six hours, depending on the patient's clinical status. The alveolar oxygen tension was calculated according to a standard equation, with a respiratory quotient of 0.8. The ratio of arterial to alveolar oxygen tension was then calculated. The ventilatory-efficiency index relates the ventilatory input to the alveolar ventilation of the infant and was calculated from the ventilatory rate, the pulmonary distending pressure, and the corresponding PaCO2.13 The airway pressure, arterial blood gas data, calculated ratio of arterial to alveolar tension, and ventilatory-efficiency index were averaged for eight hours after enrollment and before the aerosol treatment began. These variables were evaluated at 24-hour intervals after entry into the study; specific values were determined by averaging recordings that started 4 hours before and ended 4 hours after the end of each 24-hour period.
Cost of Hospitalization
Data on the cost of hospitalization of the infants were obtained from the Department of Patient Financial Services (the hospital bills) and the Faculty Practice Program (the physicians' bills) of the Stanford University Medical Center.
Statistical Analysis
All variables selected for statistical evaluation were identified before unblinding and analysis of the results. Results in the treatment and control groups were compared with use of the unpaired, two-tailed Student's t-test and the Mann—Whitney rank-sum test. The frequencies of survival and of meeting the exit criteria were compared in the treatment and control groups by the two-tailed Fisher's exact test. The ventilatory and blood gas data were analyzed by linear regression to allow us to compare the rate of change in each of these variables in the treatment and control groups.13 We obtained the intercept and slope for each infant, using the data collected immediately before aerosol treatment began and at the defined 24-hour intervals until mechanical ventilation was discontinued. We compared the mean values of the intercept and slope for the treatment and control groups with the unpaired, two-tailed Student's t-test.
Results
Enrollment
During the 30-month period from November 1987 to May 1990, 36 infants had virologically documented lower respiratory tract infections caused by respiratory syncytial virus and met our entry criteria. Of the 36 infants, 28 (78 percent) were enrolled in the trial. Of the remaining eight, five were excluded because of parental refusal, one because of earlier treatment with ribavirin, one because of mixed infection documented by bronchoalveolar lavage, and one because of treatment with ribavirin at the request of the attending physician. Of the 28 infants enrolled, the diagnosis of respiratory syncytial virus infection was confirmed in 26 by a positive direct-immunofluorescence antibody test performed on specimens obtained from nasopharyngeal swabs, and in 2 by a positive direct-immunofluorescence antibody test performed on specimens of lung effluent obtained by bronchoalveolar lavage. Fourteen infants were randomly assigned to receive ribavirin and 14 to receive placebo.
Description of Subjects
Of the 28 infants, 21 had no known underlying disease, and 7 did (5 with bronchopulmonary dysplasia, 1 with congenital heart disease, and 1 with hypotonia due to neuromuscular disease). The mean (±SD) age of the infants, as corrected for preterm birth, was 1.4± 1.7 months (range, —0.7 to 8.0). (A negative value results when an infant's gestational age plus his or her postnatal age is less than 40 weeks.) The mean age of the infants without underlying disease was 0.8±0.9 month (range, —0.8 to 2.3), and that of the infants with underlying disease was 3.0±2.6 months (range, 0.5 to 8.0). Eighteen infants were boys, and 10 were girls. The mean duration of symptoms compatible with respiratory syncytial virus infection before admission to the hospital was 3.4±2.3 days (range, 1 to 12).
Entry Criteria
Ten infants were eligible for study enrollment because they had hypercapnia, seven because they had hypoxemia, and three because they had both hypercapnia and hypoxemia. Six infants entered the study because they had respiratory arrest, and two (one normal without underlying disease and one with bronchopulmonary dysplasia) because they had clinical respiratory failure, and arterial blood gas analysis was not performed. Statistical evaluation of the results did not differ when data on these two infants were excluded. Among the infants enrolled because they had hypercapnia, the mean PaCO2 was 9.5±1.7 kPa (range, 8.1 to 14.1); the mean PaCO2 in the placebo recipients was 10.1 ±2.0 kPa (range, 8.1 to 14.1), which was not significantly different from the mean PaCO2 of 8.4±0.3 kPa in those who received ribavirin (range, 8.1 to 8.9). Among the infants enrolled because they had hypoxemia, the mean ratio of oxygen tension to inspired oxygen was 7.2±2.4 (range, 4.0 to 11.3). In the ribavirin recipients the mean ratio was 5.9±1.2 (range, 4.0 to 6.7), which was not significantly different from the mean ratio in the placebo recipients (7.6±3.5; range, 4.7 to 11.3). When we considered only the infants with underlying disease, the mean PaCO2 was not significantly different in the two groups, being 8.7±0.3 kPa for the two infants who received ribavirin and 11.7±2.1 kPa for the three who received placebo.
Interval from Enrollment to the Start of Aerosol Treatment
The mean length of time between admission to the hospital and the initiation of aerosol treatment was 25±19 hours (range, 5 to 96). The mean duration of mechanical ventilation before aerosol treatment began was 26±16 hours (range, 5 to 72). The characteristics of the infants, according to their treatment groups, are shown in Tables 1Table 1
Characteristics of the Study Groups.* and 2Table 2
Ventilatory and Blood Gas Variables in the Study Groups after the Initiation of Mechanical Ventilation but before Aerosol Treatment.*. As shown in Table 1, there were no significant differences between the ribavirin and placebo recipients in age, duration of symptoms before admission, entry criteria, and time from admission or the start of ventilation to the initiation of aerosol therapy. As outlined in Table 2, there were no significant differences between the two groups in any of the ventilatory or blood gas variables assessed before aerosol therapy began. Furthermore, when they were analyzed as groups of infants with and groups without underlying disease, there remained no significant differences between those given ribavirin and those given placebo in any of the variables assessed before the beginning of aerosol therapy.Aerosol Administration
Placebo was administered for an average of 19.9± 1.0 hours per 24-hour interval (range, 18.6 to 20.5). This was significantly longer than the average daily duration of administration of ribavirin, which was 18.0±1.2 hours (range, 16.7 to 19.7; P<0.05). Six infants in each treatment group received volume-limited ventilation, and eight infants in each group received pressure-limited ventilation. No technical difficulties were encountered during the course of the study. There were no incidents of ventilator malfunction, and no inadvertent expiratory pressure due to block-age of the exhalation limb of the ventilatory circuit was ever measured.
Hospital Course
The hospital course after entry into the study is summarized in Figures 1Figure 1
Percentage of Infants in the Ribavirin (□) and Control (■) Groups Requiring Mechanical Ventilation after Aerosol Therapy Began. , 2Figure 2Percentage of Infants in the Ribavirin (□) and Control (■) Groups Requiring Supplemental Oxygen after Aerosol Therapy Began. , and 3Figure 3
Percentage of Infants in the Ribavirin (□) and Control (■) Groups Remaining in the Hospital after Aerosol Therapy Began.. Figure 1 shows the percentage of infants requiring ventilation, according to the number of days after the initiation of aerosol therapy. The recipients of ribavirin required significantly less mechanical ventilation than the placebo recipients (P = 0.01 by the Mann—Whitney rank-sum test). The mean duration of ventilation was 4.9±3.7 days (range, 0.8 to 10.6) for the recipients of ribavirin and 9.9±5.6 days (range, 4.6 to 24.5) for those who received placebo. For the 21 previously normal infants, the mean duration of ventilation was 4.4±3.7 days (range, 0.8 to 10.6) for the ribavirin recipients and 10.1±5.6 days (range, 4.6 to 24.5) for the placebo recipients (P = 0.01). Five infants who received ribavirin and 10 who received placebo required further ventilatory support after the seven days of their assigned therapy.Figure 2 shows the percentage of infants requiring supplemental oxygen, according to the number of days after the initiation of aerosol therapy. The mean duration of oxygen administration was calculated for the 26 infants weaned from supplemental oxygen before discharge; it was 8.7±6.0days (range, 2.4 to 22.1) for the infants who received ribavirin and 13.5±5.0 days (range, 6.6 to 24.5) for those who received placebo (P = 0.01). For the previously normal infants the mean duration of supplemental oxygen administration was 7.7±5.2 days (range, 2.4 to 19.6) in the ribavirin group and 14.1±5.1 days (range, 6.6 to 24.5) in the placebo group (P = 0.002). Infants were discharged from the hospital a mean of 35±22 hours after being weaned from supplemental oxygen; the ribavirin recipients were discharged within 38±22 hours (range, 15 to 89), and the placebo recipients within 31±21 hours (range, 3.2 to 79.2), which was not significantly different.
Figure 3 shows the percentage of infants hospitalized, according to the number of days after the initiation of aerosol therapy. The mean duration of the hospital stay was 13.3±13.3 days (range, 3.6 to 53.7) for the ribavirin recipients and 15.0±5.4 days (range, 7.7 to 24.5) for the placebo recipients (P = 0.04). For the previously normal infants, the mean duration of the hospital stay was 9.0±5.3 days (range, 3.6 to 19.7) for the ribavirin recipients and 15.3±5.3 days (range, 7.7 to 24.5) for the placebo recipients (P = 0.005).
Two previously normal infants given placebo met preestablished exit criteria on their fifth day of ventilation. One of these infants subsequently died despite support with extracorporeal membrane oxygenation.
Ventilatory and Blood Gas Variables
The mean rates of change (slope of the regression analysis) in the ventilatory and blood gas variables for the two groups over the study period are summarized in Table 3Table 3
Daily Rates of Change in Ventilatory and Blood Gas Variables in the Study Groups.*. Although the rate of improvement in all the variables was greater in the infants who received ribavirin, only the rate of decrease in the ventilatory rate among the ribavirin recipients without underlying disease was statistically significant. There were no significant differences between the two groups in the intercepts of the regression analysis.Cost of Hospitalization
The mean hospital bill for the infants given ribavirin was $68,067±54,280, not significantly different from the mean of $77,666±26,615 for the placebo recipients. However, when only the 21 previously normal infants were considered, the mean hospital bill was $50,738±21,083 for the ribavirin recipients, significantly less than the mean of $77,693±25,180 for the placebo recipients (P<0.05). The average cost per day was $5,231±1,237 for the ribavirin recipients, not significantly different from the average of $5,329±1,217 for the placebo recipients. This financial analysis excluded the infant given placebo who met the preestablished exit criteria and who received extracorporeal membrane oxygenation.
Discussion
In this randomized, double-blind trial the use of aerosolized ribavirin reduced by approximately five days the duration of mechanical ventilation required by infants who were critically ill as a result of lower respiratory tract infections caused by respiratory syncytial virus. We also found an almost seven-day reduction in the length of the hospital stay, with attendant substantial savings in hospital costs, among the recipients of ribavirin who had no underlying disease at the onset of their infection. These findings were not what we had expected, considering the limited efficacy of ribavirin therapy in infants who are not on mechanical ventilation.4 5 6 Furthermore, in our original report describing the administration of ribavirin to infants on mechanical ventilation, we compared the outcome of 15 ribavirin recipients with that of 14 untreated historical controls. No difference in the duration of mechanical ventilation was found.9
All previously published placebo-controlled evaluations of ribavirin have been conducted among spontaneously breathing infants hospitalized because of lower respiratory tract infections caused by respiratory syncytial virus. These studies have consistently demonstrated greater or more rapid improvement in the severity of illness.4 5 6 The scoring systems used in these studies have been criticized as lacking objectivity and assessments of intraobserver and interobserver reliability and reproducibility.7 An additional limitation of the scoring systems is that the clinical and biologic relevance of the absolute and relative scores has never been specified.7 Although one of the studies reported a significantly greater improvement in arterial oxygen saturation in infants who received ribavirin,4 none demonstrated significant reductions in the requirement for oxygen or mechanical ventilation, duration of hospitalization, or mortality.4 5 6 A number of subsequent studies have confirmed the efficacy of ribavirin in infants with respiratory syncytial virus infection who are not on mechanical ventilation.14 15 16 17 One of these studies reported a faster rate of improvement in oxyhemoglobin saturation among infants treated with ribavirin,15 and another demonstrated a significant decrease in the duration of supplementary oxygen use in infants treated with the drug.17
Previous data concerning the safety and efficacy of ribavirin in infants with respiratory syncytial virus infections who are receiving mechanical ventilation have been anecdotal, uncontrolled, or historically controlled.4 , 5 , 9 , 14 Although we failed to demonstrate a clinical benefit in our historically controlled evaluation of ribavirin, another historically controlled study attributed substantial benefit to ribavirin therapy.4
Because the number of infants enrolled in the present study was small, recommendations must be developed cautiously. Furthermore, no definitive conclusions can be drawn regarding the efficacy of ribavirin in infants with underlying disease, since only 7 of our 28 subjects were so compromised. Our study did not address the issue of whether ribavirin affects long-term respiratory morbidity after respiratory syncytial virus infection, since there was no long-term follow-up of pulmonary function.
This study demonstrates clinically significant effects of ribavirin in the group of very young infants without underlying disease who present with severe respiratory syncytial virus infection. Young infants have been recognized as being susceptible to severe disease.18 This increased susceptibility may be due to aspects of developmental respiratory physiology.19 No side effects were associated with ribavirin therapy in our study. We encountered no technical problems related to the crystallization of ribavirin in the ventilatory circuit, and no infant had a pneumothorax or other pulmonary barotrauma because of aerosol therapy.
In summary, this study demonstrates that ribavirin aerosol is associated with significant clinical benefits in previously normal infants who require mechanical ventilation for severe respiratory syncytial virus infection. Safe administration is possible, provided that careful attention is given to the design and maintenance of the circuit. On the basis of these findings, we recommend that infants with severe respiratory syncytial virus infection who require mechanical ventilatory support be treated with ribavirin. Such treatment should be administered in facilities whose personnel are trained and experienced in the use of the drug in critically ill infants. Further study of ribavirin should involve larger numbers of infants, including those with underlying cardiopulmonary, neuromuscular, and immunologic diseases.
Supported in part by a grant from the Stanford University Medical Center Technology Transfer Program, and in part by a National Institutes of Health General Clinical Research Center grant (RR-00081). Dr. Prober is the recipient of a National Institutes of Health Academic Award (AI 008844).
We are indebted to the study children for their participation and to their parents for their consent and patience; to the respiratory therapy and nursing staffs and the pediatric house officers at Stanford University Medical Center, without whose cooperation this study would not have been possible; to Drs. William Benitz and William Rhine for assistance with computing; and to Dr. Byron Brown for assistance with statistical analysis.
Source Information
From the Divisions of Intensive Care (D.W.S., L.R.F., L.H.M., A.T.S.T.), Infectious Diseases (C.G.P.), and Neonatology (R.L.A.), Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif. Address reprint requests to Dr. Smith at the Department of Pediatrics, Stanford University Hospital, Stanford, CA 94305.
- References
References
1
Huffman
Web of Science | Medline2
Sidwell
CrossRef | Web of Science | Medline3
Witkowski
CrossRef | Web of Science | Medline4
Hall
Full Text | Web of Science | Medline5
Hall
CrossRef | Web of Science | Medline6
Taber
Web of Science | Medline7
Wald
CrossRef | Web of Science | Medline8
Virazole. Costa Mesa, Calif.: ICN Pharmaceuticals, 1986 (package insert).
9
Frankel
CrossRef | Web of Science | Medline10
Rosenfeld W. Ventilatory management: strategies in weaning. In: Bancalari E, Stocker JT, eds. Bronchopulmonary dysplasia. Washington, D.C.: Hemisphere Publishing, 1988:366–9.
11
American Academy of Pediatrics Committee on Infectious Diseases
Web of Science | Medline12
Frankel
CrossRef | Web of Science | Medline13
Kwong
Web of Science | Medline14
Conrad
CrossRef | Web of Science | Medline15
Rodriguez
CrossRef | Web of Science | Medline16
Barry
CrossRef | Web of Science | Medline17
Edelson
CrossRef | Web of Science | Medline18
Green
CrossRef | Web of Science | Medline19
Mansell
Web of Science | Medline
- Citing Articles (64)
Citing Articles
1
Kathryn A. Radigan, Richard G. Wunderink. (2011) Epidemic Viral Pneumonia and Other Emerging Pathogens. Clinics in Chest Medicine 32:3, 451-467
CrossRef2
Lynn Rasmussen, Clinton Maddox, Blake P. Moore, William Severson, E. Lucile White. (2011) A High-Throughput Screening Strategy to Overcome Virus Instability. ASSAY and Drug Development Technologies 9:2, 184-190
CrossRef3
Melvin Wright, Giovanni Piedimonte. (2011) Respiratory syncytial virus prevention and therapy: Past, present, and future. Pediatric Pulmonology 46:4, 324-347
CrossRef4
Myrna B Dolovich, Rajiv Dhand. (2011) Aerosol drug delivery: developments in device design and clinical use. The Lancet 377:9770, 1032-1045
CrossRef5
Kathleen Ventre, Adrienne Randolph, Kathleen Ventre. 2010. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children. .
CrossRef6
Avigdor Mandelberg, Israel Amirav. (2010) Hypertonic saline or high volume normal saline for viral bronchiolitis: Mechanisms and rationale. Pediatric Pulmonology 45:1, 36-40
CrossRef7
Archanna Priyadarshi, Adam Jaffe, Tony Walls, Ju Lee Oei. (2009) Strategies for reducing the burden of respiratory syncytial virus in high-risk infants. Pediatric Health 3:4, 391-406
CrossRef8
Rajiv Dhand. (2007) Inhalation therapy in invasive and noninvasive mechanical ventilation. Current Opinion in Critical Care 13:1, 27-38
CrossRef9
Kathleen Ventre, Adrienne Randolph, Kathleen Ventre. 2007. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children. .
CrossRef10
Rajiv Dhand, Emmanuelle Mercier. (2007) Effective inhaled drug administration to mechanically ventilated patients. Expert Opinion on Drug Delivery 4:1, 47-61
CrossRef11
F. Freymuth. (2007) Virus respiratorio sincitial, metapneumovirus y virus parainfluenza humanos. IV. Tratamiento y prevenci??n. EMC - Pediatr??a 42:3, 1-5
CrossRef12
J. Chaves, A. Huen, C. Bueso-Ramos, A. Safdar, S. Vadhan-Raj. (2006) Aerosolized Ribavirin--Induced Reversible Hepatotoxicity in a Hematopoietic Stem Cell Transplant Recipient with Hodgkin Lymphoma. Clinical Infectious Diseases 42:8, e72-e75
CrossRef13
2006. Ribavirin. , 3036-3039.
CrossRef14
Azzeddine Dakhama, Young Mok Lee, Erwin W. Gelfand. (2005) Virus-Induced Airway Dysfunction. The Pediatric Infectious Disease Journal 24:Supplement, S159-S169
CrossRef15
Sharon M. Chidgey, Kenneth J. Broadley. (2005) Respiratory syncytial virus infections: characteristics and treatment. Journal of Pharmacy and Pharmacology 57:11, 1371-1381
CrossRef16
Mark H. Yudin, Donna M. Steele, Michael D. Sgro, Stanley E. Read, Peter Kopplin, Kevin A. Gough. (2005) Severe Acute Respiratory Syndrome in Pregnancy. Obstetrics & Gynecology 105:1, 124-127
CrossRef17
K Ventre, AG Randolph, Kathleen Ventre. 2004. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children. .
CrossRef18
Caroline Davison, Kathleen M. Ventre, Marco Luchetti, Adrienne G. Randolph. (2004) Efficacy of interventions for bronchiolitis in critically ill infants: A systematic review and meta-analysis*. Pediatric Critical Care Medicine 5:5, 482-489
CrossRef19
G. R. Sethi, Gaurav Nagar. (2004) Evidence based treatment of bronchiolitis. The Indian Journal of Pediatrics 71:8, 733-737
CrossRef20
Robert C. Welliver. (2004) Respiratory syncytial virus infection: therapy and prevention. Paediatric Respiratory Reviews 5, S127-S133
CrossRef21
Poutanen, Susan M., Low, Donald E., Henry, Bonnie, Finkelstein, Sandy, Rose, David, Green, Karen, Tellier, Raymond, Draker, Ryan, Adachi, Dena, Ayers, Melissa, Chan, Adrienne K., Skowronski, Danuta M., Salit, Irving, Simor, Andrew E., Slutsky, Arthur S., Doyle, Patrick W., Krajden, Mel, Petric, Martin, Brunham, Robert C., McGeer, Allison J., . (2003) Identification of Severe Acute Respiratory Syndrome in Canada. New England Journal of Medicine 348:20, 1995-2005
Full Text22
Krystal L. Hicks, Roy F. Chemaly, Dimitrios P. Kontoyiannis. (2003) Common community respiratory viruses in patients with cancer. Cancer 97:10, 2576-2587
CrossRef23
KLE Hon, CW Leung, WTF Cheng, PKS Chan, WCW Chu, YW Kwan, AM Li, NC Fong, PC Ng, MC Chiu, CK Li, JS Tam, TF Fok. (2003) Clinical presentations and outcome of severe acute respiratory syndrome in children. The Lancet 361:9370, 1701-1703
CrossRef24
Howard B. Panitch. (2003) Treatment of Bronchiolitis in Infants. Pediatric Case Reviews 3:1, 3-19
CrossRef25
Peter Barry. (2002) Aerosols in Bronchiolitis. Journal of Aerosol Medicine 15:2, 109-116
CrossRef26
LEONARD R. KRILOV. (2002) Safety issues related to the administration of ribavirin. The Pediatric Infectious Disease Journal 21:5, 479-481
CrossRef27
Shuang-Cheng Ma, Jiang Du, Paul Pui-Hay But, Xue-Long Deng, Yong-Wen Zhang, Vincent Eng-Choon Ooi, Hong-Xi Xu, Spencer Hon-Sun Lee, Song Fong Lee. (2002) Antiviral Chinese medicinal herbs against respiratory syncytial virus. Journal of Ethnopharmacology 79:2, 205-211
CrossRef28
Jan L.L. Kimpen. (2001) Management of respiratory syncytial virus infection. Current Opinion in Infectious Diseases 14:3, 323-328
CrossRef29
A Greenough. (2001) Recent advances in the management and prophylaxis of respiratory syncytial virus infection. Acta Paediatrica 90, 11-14
CrossRef30
JOHN P. DEVINCENZO. (2000) Therapy of respiratory syncytial virus infection. The Pediatric Infectious Disease Journal 19:8, 786-790
CrossRef31
RC Tasker, I Gordon, K Kiff. (2000) Time course of severe respiratory syncytial virus infection in mechanically ventilated infants. Acta Paediatrica 89:8, 938-941
CrossRef32
M R Keating. (1999) Antiviral agents for non-human immunodeficiency virus infections.. Mayo Clinic Proceedings 74:12, 1266-1283
CrossRef33
Eric AF Simoes. (1999) Respiratory syncytial virus infection. The Lancet 354:9181, 847
CrossRef34
Larry S. Jefferson, Jorge A. Coss-Bu, Janet A. Englund, David Walding, Fernando Stein. (1999) Respiratory system mechanics in patients receiving aerosolized ribavirin during mechanical ventilation for suspected respiratory syncytial viral infection. Pediatric Pulmonology 28:2, 117-124
CrossRef35
L. Williams, G. C. Fletcher, M. Daniel, J. Kinsella. (1999) A simple in vitro method for the evaluation of an ultrasonic nebulizer for drug delivery to intubated, ventilated patients and the effect of nebulizer and ventilator settings on the uptake of fluid from the nebulizer chamber. European Journal of Anaesthesiology 16:7, 479-484
CrossRef36
Wataru Watanabe, Kenji Sudo, Ryu Sato, Tsuyoshi Kajiyashiki, Kenji Konno, Shiro Shigeta, Tomoyuki Yokota. (1998) Novel Anti-respiratory Syncytial(RS) Viral Compounds: Benzodithiin Derivatives. Biochemical and Biophysical Research Communications 249:3, 922-926
CrossRef37
Rahul Aggarwal. (1998) Lower airway disease caused by respiratory syncytial virus. The Indian Journal of Pediatrics 65:3, 355-362
CrossRef38
Dean Edell, Erik Bruce, Kathe Hale, Debra Edell, Vikram Khoshoo. (1998) Reduced long-term respiratory morbidity after treatment of respiratory syncytial virus bronchiolitis with ribavirin in previously healthy infants: A preliminary report. Pediatric Pulmonology 25:3, 154-158
CrossRef39
Robert C. Welliver. (1998) Respiratory syncytial virus immunoglobulin and monoclonal antibodies in the prevention and treatment of respiratory syncytial virus infection. Seminars in Perinatology 22:1, 87-95
CrossRef40
CHRISTINE E. LONG, KAREN Z. VOTER, WILLIAM H. BARKER, CAROLINE B. HALL. (1997) Long term follow-up of children hospitalized with respiratory syncytial virus lower respiratory tract infection and randomly treated with ribavirin or placebo. The Pediatric Infectious Disease Journal 16:11, 1023-1028
CrossRef41
G. Mlinaric-Galinovic, A. R. Falsey, E. E. Walsh. (1996) Respiratory syncytial virus infection in the elderly. European Journal of Clinical Microbiology & Infectious Diseases 15:10, 777-781
CrossRef42
SCOTT F. DOWELL, ZDENKA PAPIC, JOSEPH S. BRESEE, CARMEN LARRAÑAGA, MIGUEL MENDEZ, ANNE L. SOWELL, HOWARD E. GARY, LARRY J. ANDERSON, LUIS F. AVENDAÑO. (1996) Treatment of respiratory syncytial virus infection with vitamin A: a randomized, placebo-controlled trial in Santiago, Chile. The Pediatric Infectious Disease Journal 15:9, 782-786
CrossRef43
D. E. Fixler. (1996) Respiratory syncytial virus infection in children with congenital heart disease: A review. Pediatric Cardiology 17:3, 163-168
CrossRef44
Suzanne E. Ohmit, Frank W. Moler, Arnold S. Monto, Ali S. Khan. (1996) Ribavirin utilization and clinical effectiveness in children hospitalized with respiratory syncytial virus infection. Journal of Clinical Epidemiology 49:9, 963-967
CrossRef45
A. J. A. M. Ven, R. Crevel, G. P. Bootsma, P. P. Koopmans, C. M. A. Swanink, J. M. D. Galama. (1996) Respiratory syncytial virus pneumonia in an AIDS patient. Infection 24:5, 375-377
CrossRef46
B. WÅhlin, B. Malmström, M. Soop, L.-G. Hellströ;m. (1996) A paediatric canopy system for aerosol administration and minimized environmental pollution. Acta Anaesthesiologica Scandinavica 40:8, 932-939
CrossRef47
Erik De Clercq. (1996) Perspectives for the chemotherapy of respiratory syncytial virus (RSV) infections. International Journal of Antimicrobial Agents 7:3, 193-202
CrossRef48
PETER C. RIMENSBERGER, ANNA BUREK-KOZLOWSKA, ANDREAS MORELL, DANIEL GERMANN, ANNE K. EIGENMANN, FELICITAS STEINER, RENÉ BURGER, MARKUS KUENZLI, URS B. SCHAAD. (1996) Aerosolized immunoglobulin treatment of respiratory syncytial virus infection in infants. The Pediatric Infectious Disease Journal 15:3, 209-216
CrossRef49
Aaron R. Zucker, William L. Meadow. (1995) Pediatric critical care physicians' attitudes about guidelines for the use of ribavirin in critically ill children with respiratory syncytial virus pneumonia. Critical Care Medicine 23:4, 767-772
CrossRef50
F FREYMUTH, G EUGENE, J BROUARD, A VABRET, J PETITJEAN, F BONNIN. (1995) Le virus respiratoire syncytial: importance en pathologie, méthodes diagnostiques, traitement et prévention. Annales de l'Institut Pasteur/Actualités 6:1, 23-29
CrossRef51
F. Leclerc, Y. Riou, A. Martinot, L. Storme, V. Hue, V. Flurin, A. Deschildre, A. Sadik. (1994) Inhaled nitric oxide for a severe respiratory syncytial virus infection in an infant with bronchopulmonary dysplasia. Intensive Care Medicine 20:7, 511-512
CrossRef52
William J. Rodriguez, Caroline B. Hall, Robert Welliver, Eric A.F. Simoes, Michael E. Ryan, Harris Stutman, George Johnson, Russell Van Dyke, Jessie R. Groothuis, Julita Arrobio, Kenneth Schnabel. (1994) Efficacy and safety of aerosolized ribavirin in young children hospitalized with influenza: A double-blind, multicenter, placebo-controlled trial. The Journal of Pediatrics 125:1, 129-135
CrossRef53
John J. Treanor. (1994) Viral infections of the respiratory tract: prevention and treatment. International Journal of Antimicrobial Agents 4:1, 1-22
CrossRef54
J. CLIFFORD WALDREP, PETER W. SCHERER, G. DALE HESS, MELANIE BLACK, VERNON KNIGHT. (1994) Nebulized Glucocorticoids in Liposomes: Aerosol Characteristics and Human Dose Estimates. Journal of Aerosol Medicine 7:2, 135-145
CrossRef55
Ronald C. McGlennen, George L. Adams, Cynthia M. Lewis, Anthony J. Faras, Ronald S. Ostrow. (1993) Pilot trial of ribavirin for the treatment of laryngeal papillomatosis. Head & Neck 15:6, 504-512
CrossRef56
Eve Roberts, E.L. Ford-Jones, M. James Phillips. (1993) Ribavirin for syncytial giant cell hepatitis. The Lancet 341:8845, 640-641
CrossRef57
Olli Ruuskanen, Pearay L. Ogra. (1993) Respiratory syncytial virus. Current Problems in Pediatrics 23:2, 50-79
CrossRef58
W. J. E. Tissing, H. A. Steensel-Moll, M. Offringa. (1993) Risk factors for mechanical ventilation in respiratory syncytial virus infection. European Journal of Pediatrics 152:2, 125-127
CrossRef59
Matti Waris, Olli Meurman, Maurice A. Mufson, Olli Ruuskanen, Pekka Halonen. (1992) Shedding of infectious virus and virus antigen during acute infection with respiratory syncytial virus. Journal of Medical Virology 38:2, 111-116
CrossRef60
S.P. Fisher-Hoch, S. Gborie, L. Parker, J. Huggins. (1992) Unexpected adverse reactions during a clinical trial in rural West Africa. Antiviral Research 19:2, 139-147
CrossRef61
Mark Stretton, Samuel J. Ajizian, Ian Mitchell, Christopher J. L. Newth. (1992) Intensive care course and outcome of patients infected with respiratory syncytial virus. Pediatric Pulmonology 13:3, 143-150
CrossRef62
Craig Sherman, Humberto Fernandez. (1992) Ribavirin aerosols and respiratory syncytial virus infection. The Lancet 339:8786, 190-191
CrossRef63
(1991) Ribavirin for Severe RSV Infection. New England Journal of Medicine 325:26, 1884-1886
Full Text64
Hall, Caroline Breese, McBride, John T., . (1991) Respiratory Syncytial Virus — From Chimps with Colds to Conundrums and Cures. New England Journal of Medicine 325:1, 57-58
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