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Beclomethasone for treating premature infants with bronchopulmonary dysplasia
490
Editorial correspondence
Reply
The Journal of Pediatrics September 1993
REFERENCES
To the Editor: The issues raised by Drs. Baskin, Fleisher, and O'Rourke allow us to clarify key points about our overview on the use of diagnostic tests for febrile infants less than 3 months of age. 1 The reason for basing our likelihood ratio calculations on just two studies is that these were the only studies that combined clinical and laboratory criteria validated in a prospective manner. 2, 3 The studies had high methodologic validity, used the most comprehensive definition for serious bacterial infection (i.e., a positive result on bacterial culture of the cerebrospinal fluid, blood, urine, and stool), and performed consistently in different geographical locales--Rochester, N.Y., and Beer-Sheva, Israel. Because we were interested in a diagnostic test that could be applied to all febrile infants less than 3 months of age, we excluded any study that did not enroll infants less than 1 month of age. The study by Baskin et al. was one of these. 4, 5 The study by Baskin et al. did not strictly examine the performance characteristics of the Rochester criteria. Its primary purpose was to describe the outcomes of a cohort of febrile infants 28 to 89 days of age who bad received an intramuscular injection of ceftriazone. 5 In the process, the investigators did not microscopically examine the urine of all patients, excluded some febrile infants within the 28- to 89-day age range, and excluded the youngest infants. As Powell and Dagan 6 stated in earlier correspondence, if the Rochester criteria are to be validated by others, it is imperative that the actual Rochester criteria be applied in an unbiased sample of previously healthy infants with fever, and in a prospective manner to ensure that all important data are collected. Without the minimal requirement that the diagnostic _test and the population under study be the same in each study, discussions of spectrum bias miss the mark. In the final analysis, empiric testing is the best form of validation for any diagnostic protocol, as Dr. Baskin et al. have indicated. The Rochester criteria have been tested on about 1000 infants in hospitals across the United States and Canada. 6, 7 The likelihood ratio has not changed significantly despite use in a variety of centers. Indeed, the negative likelihood ratio has become more precise as the 95% confidence interval has narrowed. The choice for clinicians is clear. Do they feel more confident utilizing a diagnostic protocol that has undergone extensive validation in a variety of centers? Or do they opt to base their management on a single-center study?
Terry P. Klassen, MD Associate Chief, Division of Emergency Medicine Children's Hospital of Eastern Ontario Assistant Professor of Pediatrics University of Ottawa Ottawa, Ontario K1H 8L1, Canada Peter C. Rowe, MD Associate Director for Medical Education Department of Pediatrics Assistant Professor of Pediatrics Johns Hopkins University Baltimore, MD 21205 9/35/48136
1. Klassen TP, Rowe PC. Selecting diagnostic tests to identify febrile infants less than 3 months of age as being at low risk for serious bacterial infection: a scientific overview. J PEDIATR 1992;121:671-6. 2. Dagan R, Sofer S, Phillip M, Shachak E. Ambulatory care of febrile infants younger than 2 months of age classified as being at low risk for having serious bacterial infections. J PEDIATR 1988;112:355-60. 3. Dagan R, Powell KR, Hall GB, Menegus MA. Identification of infants unlikely to have serious bacterial infection although hospitalized for suspected sepsis. J PEDIATR 1985;107:85560. 4. Baker MD, Avner JR, Bell LM. Failure of infant observation scales in detecting serious illness in febrile, 4 to 8 week old infants. Pediatrics 1990;85:1040-3. 5. Baskin MN, O'Rourke E J, Fleisher GR. Outpatient treatment of febrile infants 28 to 89 days of age with intramuscular administration of ceftriaxone. J PEDIATR 1992;120:483-5. 6. Powell KR, Dagan R. Criteria for exclusion of serious bacterial infections in young children [Letter]. J PEDIATR 1992; 121:831-2. 7. Jaskiewicz JA, McCarthy CA, Richardson AC, Powell KR. Reevaluation of criteria to identify infants evaluated for possible sepsis at low risk for serious bacterial infection [Abstract]. Am J Dis Child 1992;146:483.
Beclomethasone for treating premature infants with
bronchopulmonary dysplasia To the Editor: We read with interest the article by Laforce and Brudno ~ regarding the use of nebulized beclomethasone in neonates with bronchopulmonary dysplasia (BPD). We have used a beclomethasone metered-dose inhaler (MDI) in very low birth weight ventilator-dependent infants and have found this treatment to be virtually free of side effects and effective in a majority of our patients. 2 We initiated treatment in very low birth weight ventilator-dependent infants whose chest radiographs were compatible with early-stage BPD at 2 to 5 weeks of age. An MDI adapter (Medicomp Metered Dose Straight Swivel) was placed in line at the level of the proximal endotracheal tube, and beclomethasone was administered at a dose of two puffs (84 #g) every 4 to 6 hours. Of the 32 patients studied, 25 (78%) were considered to have responded, on the basis of the reduction in oxygen requirement and subsequent extubation. The endotracheal tube was removed from infants who responded within an average period of 10.5 days of treatment, versus 40.8 days in nonresponders. Patients who responded to inhalation therapy were those who received ~0.50 fractional inspired oxygen at the time of initiation of therapy; patients with peak inspiratory pressure _< 18 cm H20 also seemed to respond favorably to beclomethasone. There was a tendency for infants with a gestational age of >26 weeks to respond better to therapy; We noted no untoward effects. W e recognize the possibility that some patients' condition would have improved without administration of inhaled corticosteroids, but the condition of the patients involved in the study had remained
The Journal of Pediatrics Volume 123, Number 3
Editorial correspondence
static with ventilator use for a week before treatment. We agree that using inhaled corticosteroids may provide a safe alternative in attempting to discontinue use of the endotracheal tube in these ventilator-dependentinfants, and that large prospective studies are needed to confirm these results.
Peter Gal, PharmD Philip R. Diaz, PharmD Pharmacy Research and Education Greensboro Area Health Education Center Moses H. Cdne Memorial Hospital School of Pharmacy School of Medicine University Of North Carolina at Chapel Hill , Neonatal Medicine, Women's Hospital of Greensboro Greensboro, NC 27401-1020 J. Laurence Ransom, MD Rita Q. Carlos, MD School of Medicine University of North Carofina at Chapel Hill Neonatal Medicine, Women's Hospital of Greensboro Greensboro, NC 27401-1020 Dean W. Thorson School of Pharmacy University of North Carolina Chapel Hill, N C 27599 9/35/48446
quire a higher dose of nebulized medication per kilogram of body weight than do older children and adults because infants have lower inspiratory flow rates, so less of the aerosol is entrained into the lungs. Furthermore, it is difficult to administer the aerosol to infants in a closed system, so much of the drug is lost to the atmosphere. Larger doses of salbutamol have been safely used in infants. Sly et al. 2 administered 5 mg of salbutamol by nebulizer (approximately 0.2 ml/kg, or about 6.5 times the dose used in the study by Sanchez et al.) to infants with bronchiolitis with a tight face-mask system, and at Madigan Army Medical Center we routinely use 2.5 to 5 mg of nebulized albuterol per treatment for infants with bronchiolitis and have yet to observe any clinically relevant adverse effects. Sly et al. found no significant effect with salbutamol either, but the patient population (infants recovering from an episode of bronchiolitis) and the outcome measure (maximal flow at functional residual capacity) were different from those in the study by Sanchez et al. Although the dose of salbutamol used by Sanchez et al. was probably not maximal, the dose of racemic epinephrine was relatively high. In The Harriet Lane Handbook, 3 the recommended dose of racemic epinephrine is 0.05 ml of the 2.25% solution per kilogram up to a maximum of 0.5 ml; Sanchez et al. used 0.1 ml/kg (average dose, 0.67 ml). Maximal bronchodilation may have been achieved with this large dose, which could explain the significant improvement observed after epinephrine. Until the study is repeated with higher doses of salbutamol, the statement that salbutamol is less beneficial than racemic epinephrine in the treatment of acute bronchiolitis may not be true.
Edward R. Carter, MAJ, MC Donald R. Moffitt, COL, MC Division of Pediatric Pulmonology Madigan Army Medical Center Tacoma, WA 98431-5000
REFERENCES
1. LaForce WR, Brudno DS. Controlled trial of beclomethasone dipropionate by nebulization in oxygen- and ventilator-dependent infants. J PEDIATR 1993;122:285-8. 2. Thorson DW, Gal P, Diaz PR, Ransom JL, Weaver RL, Carlos RQ. Beclomethasone MDI for treating bronehopulmonary dysplasia in premature infants: a preliminary report. Pharmacotherapy 1992;12:261.'
Nebulized salbutamol versus racemic epinephrine in the treatment of infants with bronchiolitis To the Editor." We commend Sanchez et alJ for their well-designed study, which attempted to answer important questions about the efficacy of nebulized/32-adrenergic agonists in the treatment of infants with bronchiolitis. However, we find it difficult to accept their conclusion that racemic epinephrine is superior to nebulized salbutamol (albuterol) in the treatment of infants with bronchiolitis because they did not demonstrate that the dose of salbutamol used resulted in maximal bronchodilation; the dose of salbutamol may have been too low. Salbutamol has a dose-responsecurve, and unless the dose delivered is sufficient to cause maximal bronchodilation, a larger dose would prove more efficacious. The amount of salbutamol required to produce maximal bronchodilation in infants with bronchiolitis has not been established, but it is probably higher than the 0.03 ml/kg (0.15 mg/kg) dose used by Sanchez et al. Infants may re-
491
9/3s/486ol REFERENCES
1. Sanchez I, De Koster J, Powell RE, Wolstein R, Chernick V. Effect of racemic epinephrine and salbutamol on clinical score and pulmonary mechanics in infants with bronchiolitis. J PEDIATR 1993;122:145-51. 2. Sly PD, Lanteri C J, Raven JM. Do wheezy infants recovering from bronchiolitis respond to salbutamol? Pediatr Pulmonol 1991:10:36-9. 3. Greene MG, ed. Harriet Lane handbook. 12th ed, St. Louis: Mosby-Year Book, 1990:182.
Reply To the Editor: Drs. Carter and Moffitt raise some important issues, not only for our study, but in relation to aerosol administration to infants and children in general. We did not attempt to study increased doses of salbutamol because this would have made an already complex study of sick infants even more complicated. Doses of epinephrine and salbutamol were used that were in common use in our hospital, and we take some solace in the fact that Sly et al.l did not find a response in infants with bronchiolitis using 6.5 times the dose of salbutamol that we used. Nevertheless, the points raised by Carter and Moffitt are valid, and a study of the clinical response (or lack thereof) to varying doses of salbutamol by infants with bronchiolitis is needed.
Editorial correspondence
Reply
The Journal of Pediatrics September 1993
REFERENCES
To the Editor: The issues raised by Drs. Baskin, Fleisher, and O'Rourke allow us to clarify key points about our overview on the use of diagnostic tests for febrile infants less than 3 months of age. 1 The reason for basing our likelihood ratio calculations on just two studies is that these were the only studies that combined clinical and laboratory criteria validated in a prospective manner. 2, 3 The studies had high methodologic validity, used the most comprehensive definition for serious bacterial infection (i.e., a positive result on bacterial culture of the cerebrospinal fluid, blood, urine, and stool), and performed consistently in different geographical locales--Rochester, N.Y., and Beer-Sheva, Israel. Because we were interested in a diagnostic test that could be applied to all febrile infants less than 3 months of age, we excluded any study that did not enroll infants less than 1 month of age. The study by Baskin et al. was one of these. 4, 5 The study by Baskin et al. did not strictly examine the performance characteristics of the Rochester criteria. Its primary purpose was to describe the outcomes of a cohort of febrile infants 28 to 89 days of age who bad received an intramuscular injection of ceftriazone. 5 In the process, the investigators did not microscopically examine the urine of all patients, excluded some febrile infants within the 28- to 89-day age range, and excluded the youngest infants. As Powell and Dagan 6 stated in earlier correspondence, if the Rochester criteria are to be validated by others, it is imperative that the actual Rochester criteria be applied in an unbiased sample of previously healthy infants with fever, and in a prospective manner to ensure that all important data are collected. Without the minimal requirement that the diagnostic _test and the population under study be the same in each study, discussions of spectrum bias miss the mark. In the final analysis, empiric testing is the best form of validation for any diagnostic protocol, as Dr. Baskin et al. have indicated. The Rochester criteria have been tested on about 1000 infants in hospitals across the United States and Canada. 6, 7 The likelihood ratio has not changed significantly despite use in a variety of centers. Indeed, the negative likelihood ratio has become more precise as the 95% confidence interval has narrowed. The choice for clinicians is clear. Do they feel more confident utilizing a diagnostic protocol that has undergone extensive validation in a variety of centers? Or do they opt to base their management on a single-center study?
Terry P. Klassen, MD Associate Chief, Division of Emergency Medicine Children's Hospital of Eastern Ontario Assistant Professor of Pediatrics University of Ottawa Ottawa, Ontario K1H 8L1, Canada Peter C. Rowe, MD Associate Director for Medical Education Department of Pediatrics Assistant Professor of Pediatrics Johns Hopkins University Baltimore, MD 21205 9/35/48136
1. Klassen TP, Rowe PC. Selecting diagnostic tests to identify febrile infants less than 3 months of age as being at low risk for serious bacterial infection: a scientific overview. J PEDIATR 1992;121:671-6. 2. Dagan R, Sofer S, Phillip M, Shachak E. Ambulatory care of febrile infants younger than 2 months of age classified as being at low risk for having serious bacterial infections. J PEDIATR 1988;112:355-60. 3. Dagan R, Powell KR, Hall GB, Menegus MA. Identification of infants unlikely to have serious bacterial infection although hospitalized for suspected sepsis. J PEDIATR 1985;107:85560. 4. Baker MD, Avner JR, Bell LM. Failure of infant observation scales in detecting serious illness in febrile, 4 to 8 week old infants. Pediatrics 1990;85:1040-3. 5. Baskin MN, O'Rourke E J, Fleisher GR. Outpatient treatment of febrile infants 28 to 89 days of age with intramuscular administration of ceftriaxone. J PEDIATR 1992;120:483-5. 6. Powell KR, Dagan R. Criteria for exclusion of serious bacterial infections in young children [Letter]. J PEDIATR 1992; 121:831-2. 7. Jaskiewicz JA, McCarthy CA, Richardson AC, Powell KR. Reevaluation of criteria to identify infants evaluated for possible sepsis at low risk for serious bacterial infection [Abstract]. Am J Dis Child 1992;146:483.
Beclomethasone for treating premature infants with
bronchopulmonary dysplasia To the Editor: We read with interest the article by Laforce and Brudno ~ regarding the use of nebulized beclomethasone in neonates with bronchopulmonary dysplasia (BPD). We have used a beclomethasone metered-dose inhaler (MDI) in very low birth weight ventilator-dependent infants and have found this treatment to be virtually free of side effects and effective in a majority of our patients. 2 We initiated treatment in very low birth weight ventilator-dependent infants whose chest radiographs were compatible with early-stage BPD at 2 to 5 weeks of age. An MDI adapter (Medicomp Metered Dose Straight Swivel) was placed in line at the level of the proximal endotracheal tube, and beclomethasone was administered at a dose of two puffs (84 #g) every 4 to 6 hours. Of the 32 patients studied, 25 (78%) were considered to have responded, on the basis of the reduction in oxygen requirement and subsequent extubation. The endotracheal tube was removed from infants who responded within an average period of 10.5 days of treatment, versus 40.8 days in nonresponders. Patients who responded to inhalation therapy were those who received ~0.50 fractional inspired oxygen at the time of initiation of therapy; patients with peak inspiratory pressure _< 18 cm H20 also seemed to respond favorably to beclomethasone. There was a tendency for infants with a gestational age of >26 weeks to respond better to therapy; We noted no untoward effects. W e recognize the possibility that some patients' condition would have improved without administration of inhaled corticosteroids, but the condition of the patients involved in the study had remained
The Journal of Pediatrics Volume 123, Number 3
Editorial correspondence
static with ventilator use for a week before treatment. We agree that using inhaled corticosteroids may provide a safe alternative in attempting to discontinue use of the endotracheal tube in these ventilator-dependentinfants, and that large prospective studies are needed to confirm these results.
Peter Gal, PharmD Philip R. Diaz, PharmD Pharmacy Research and Education Greensboro Area Health Education Center Moses H. Cdne Memorial Hospital School of Pharmacy School of Medicine University Of North Carolina at Chapel Hill , Neonatal Medicine, Women's Hospital of Greensboro Greensboro, NC 27401-1020 J. Laurence Ransom, MD Rita Q. Carlos, MD School of Medicine University of North Carofina at Chapel Hill Neonatal Medicine, Women's Hospital of Greensboro Greensboro, NC 27401-1020 Dean W. Thorson School of Pharmacy University of North Carolina Chapel Hill, N C 27599 9/35/48446
quire a higher dose of nebulized medication per kilogram of body weight than do older children and adults because infants have lower inspiratory flow rates, so less of the aerosol is entrained into the lungs. Furthermore, it is difficult to administer the aerosol to infants in a closed system, so much of the drug is lost to the atmosphere. Larger doses of salbutamol have been safely used in infants. Sly et al. 2 administered 5 mg of salbutamol by nebulizer (approximately 0.2 ml/kg, or about 6.5 times the dose used in the study by Sanchez et al.) to infants with bronchiolitis with a tight face-mask system, and at Madigan Army Medical Center we routinely use 2.5 to 5 mg of nebulized albuterol per treatment for infants with bronchiolitis and have yet to observe any clinically relevant adverse effects. Sly et al. found no significant effect with salbutamol either, but the patient population (infants recovering from an episode of bronchiolitis) and the outcome measure (maximal flow at functional residual capacity) were different from those in the study by Sanchez et al. Although the dose of salbutamol used by Sanchez et al. was probably not maximal, the dose of racemic epinephrine was relatively high. In The Harriet Lane Handbook, 3 the recommended dose of racemic epinephrine is 0.05 ml of the 2.25% solution per kilogram up to a maximum of 0.5 ml; Sanchez et al. used 0.1 ml/kg (average dose, 0.67 ml). Maximal bronchodilation may have been achieved with this large dose, which could explain the significant improvement observed after epinephrine. Until the study is repeated with higher doses of salbutamol, the statement that salbutamol is less beneficial than racemic epinephrine in the treatment of acute bronchiolitis may not be true.
Edward R. Carter, MAJ, MC Donald R. Moffitt, COL, MC Division of Pediatric Pulmonology Madigan Army Medical Center Tacoma, WA 98431-5000
REFERENCES
1. LaForce WR, Brudno DS. Controlled trial of beclomethasone dipropionate by nebulization in oxygen- and ventilator-dependent infants. J PEDIATR 1993;122:285-8. 2. Thorson DW, Gal P, Diaz PR, Ransom JL, Weaver RL, Carlos RQ. Beclomethasone MDI for treating bronehopulmonary dysplasia in premature infants: a preliminary report. Pharmacotherapy 1992;12:261.'
Nebulized salbutamol versus racemic epinephrine in the treatment of infants with bronchiolitis To the Editor." We commend Sanchez et alJ for their well-designed study, which attempted to answer important questions about the efficacy of nebulized/32-adrenergic agonists in the treatment of infants with bronchiolitis. However, we find it difficult to accept their conclusion that racemic epinephrine is superior to nebulized salbutamol (albuterol) in the treatment of infants with bronchiolitis because they did not demonstrate that the dose of salbutamol used resulted in maximal bronchodilation; the dose of salbutamol may have been too low. Salbutamol has a dose-responsecurve, and unless the dose delivered is sufficient to cause maximal bronchodilation, a larger dose would prove more efficacious. The amount of salbutamol required to produce maximal bronchodilation in infants with bronchiolitis has not been established, but it is probably higher than the 0.03 ml/kg (0.15 mg/kg) dose used by Sanchez et al. Infants may re-
491
9/3s/486ol REFERENCES
1. Sanchez I, De Koster J, Powell RE, Wolstein R, Chernick V. Effect of racemic epinephrine and salbutamol on clinical score and pulmonary mechanics in infants with bronchiolitis. J PEDIATR 1993;122:145-51. 2. Sly PD, Lanteri C J, Raven JM. Do wheezy infants recovering from bronchiolitis respond to salbutamol? Pediatr Pulmonol 1991:10:36-9. 3. Greene MG, ed. Harriet Lane handbook. 12th ed, St. Louis: Mosby-Year Book, 1990:182.
Reply To the Editor: Drs. Carter and Moffitt raise some important issues, not only for our study, but in relation to aerosol administration to infants and children in general. We did not attempt to study increased doses of salbutamol because this would have made an already complex study of sick infants even more complicated. Doses of epinephrine and salbutamol were used that were in common use in our hospital, and we take some solace in the fact that Sly et al.l did not find a response in infants with bronchiolitis using 6.5 times the dose of salbutamol that we used. Nevertheless, the points raised by Carter and Moffitt are valid, and a study of the clinical response (or lack thereof) to varying doses of salbutamol by infants with bronchiolitis is needed.