Oral versus intravenous corticosteroids in children hospitalized with asthma

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1 Oral versus intravenous corticosteroids in children hospitalized with asthma Jack M. Becker, MD, a Anjali Arora, MD, b Richard J. Scarfone, MD, d Nancy D. Spector, MD, a Mary Elizabeth Fontana-Penn, MD, c Edward Gracely, PhD, a Mark D. Joffe, MD, d Donald P. Goldsmith, MD, a and J. Jeffrey Malatack, MD a Philadelphia, Pa, and Baltimore, Md Background: Previous studies have demonstrated that in the emergency treatment of an asthma exacerbation, corticosteroids used in conjunction with β-agonists result in lower hospitalization rates for children and adults. Furthermore, orally administered corticosteroids have been found to be effective in the treatment of outpatients with asthma. However, similar data in inpatients is lacking. Objective: The purpose of this study was to determine the efficacy of oral prednisone versus intravenous methylprednisolone in equivalent doses for the treatment of an acute asthma exacerbation in hospitalized children. Methods: We conducted a randomized, double-blind, doubleplacebo study comparing oral prednisone at 2 mg/kg/dose (maximum 120 mg/dose) twice daily versus intravenous methylprednisolone at 1 mg/kg/dose (maximum 60 mg/dose) four times daily in a group of patients 2 through 18 years of age hospitalized for an acute asthma exacerbation. All patients were assessed by a clinical asthma score 3 times a day. The main study outcome was length of hospitalization; total length of stay and time elapsed before β-agonists could be administered at 6-hour intervals. Duration of supplemental oxygen administration and peak flow measurements were secondary outcome measures. Results: Sixty-six patients were evaluated. Children in the prednisone group had a mean length of stay of 70 hours compared with 78 hours for the methylprednisolone group (P =.52). Children in the prednisone group were successfully weaned to β-agonists in 6-hour intervals after 59 hours compared with 68 hours for the methylprednisolone group (P =.47). Patients receiving prednisone required supplemental oxygen for 30 hours compared with 52 hours for the methylprednisolone group (P =.04). Conclusion: There was no difference in length of hospital stay between asthmatic patients receiving oral prednisone and those receiving intravenous methylprednisolone. Because hospitalization charges are approximately 10 times greater for intravenous methylprednisolone compared with oral prednisone, the use of oral prednisone to treat inpatients with acute asthma would result in substantial savings. (J Allergy Clin Immunol 1999;103: ) From a the Department of Pediatrics, MCP Hahnemann School of Medicine; b Private Practice, Baltimore; c the Department of Pediatrics, Thomas Jefferson University; and d the Department of Pediatrics, the University of Pennsylvania, Philadelphia. Supported by grant # SCHC from Allegheny-Singer Research Institute. Received for publication Apr 23, 1998; revised Oct 1, 1998; accepted for publication Oct 5, Reprint requests: Jack M. Becker, MD, St Christopher s Hospital for Children, Section of Allergy, Front at Erie St, Philadelphia, PA Copyright 1999 by Mosby, Inc /99 $ /1/ Key words: Children, prednisone, methylprednisolone, asthma, hospitalized, status asthmaticus, length of stay Asthma is the most prevalent chronic disease of childhood. 1 Standard therapy for an acute asthma exacerbation includes inhaled β-agonists, which relieve bronchospasm, and corticosteroids, which decrease airway inflammation. Previous studies have demonstrated that the use of oral corticosteroids in the outpatient setting results in fewer hospitalizations in pediatric and adult patients treated for an acute asthma exacerbation. 2-7 Other studies have shown that corticosteroids can halt the progression of an asthma exacerbation and reduce the rate of early relapse Parenterally administered corticosteroids have been found to be efficacious for pediatric patients hospitalized with acute asthma, 13,14 but corresponding data supporting the use of orally administered corticosteroids is lacking. This study sought to determine whether 4 mg/kg/day of oral prednisone is equally as effective as 4 mg/kg/day intravenous methylprednisolone in the treatment of pediatric patients with asthma hospitalized on the general ward. METHODS Patients Patients included in this study were children between 2 and 18 years of age with an acute asthma exacerbation treated in the emergency department (ED) of St Christopher s Hospital for Children between November 1995 and March Patients with the diagnosis of an acute exacerbation of reactive airways disease were initially evaluated by the ED staff who assessed their degree of illness and need for hospitalization. All study children were treated in the ED with frequent β-agonists delivered by nebulization and oral prednisone; none received intravenous methylprednisolone as part of their ED management. Indications for admission included the need for frequent β-agonist nebulization treatments as judged by the attending ED physician and the need for supplemental oxygen. Patients requiring hospitalization were eligible for the study. Patient s were excluded from the study if they had pneumonia or chronic lung disease, had received oral corticosteroids within 5 days before admission, had a recent varicella exposure, or had been previously enrolled in the study. Also excluded were patients requiring intensive care management, continuously nebulized β-agonists, intravenous β-agonists, or mechanical ventilation or patients who had repeatedly vomited oral medication in the ED. The protocol was reviewed and approved by the institutional review board of St Christopher s Hospital for Children. Protocol Once the decision was made to hospitalize the patient, a study investigator was contacted. After informed consent, a study investi-

2 J ALLERGY CLIN IMMUNOL VOLUME 103, NUMBER 4 Becker et al 587 TABLE I. Asthma scoring index Score Respiratory rate <6 years 0-30 BPM BPM BPM >60 BPM >6 years 0-20 BPM BPM BPM >50 BPM O 2 requirement RA 1-2 L 3-4 L >50% Wheezing None Expiratory Inspiratory and expiratory Audible Retractions None Mild Moderate Severe Color Pink Oral cyanosis Perioral cyanosis Cyanotic The index was used to score patients at admission and during the hospital stay. BPM, Breaths per minute; RA, room air. Abbreviations used ED: Emergency department PEFR: Peak expiratory flow rate gator assigned the patient an asthma score to assess the patient s degree of illness (Table I). 15,16 Patients were then randomly assigned to receive either oral prednisone or intravenous methylprednisolone in a double-blinded, double-placebo fashion. Assignment to either study group was based on a computer-generated randomization list. Once a patient was enrolled in the study, an intravenous catheter was placed, and assignment to the general pediatric ward was made. The patient s therapy was directed by the ward team in consultation with the attending physician, who was one of the study team members (JB, NS, MFP). All study patients received either oral prednisone (2 mg/kg/dose rounded to the nearest 5 mg, with a maximum of 120 mg) or placebo (sucrose pill) at 8 AM and 8 PM. The oral prednisone was mixed with chocolate syrup or applesauce if necessary. All patients also received either methylprednisolone (1 mg/kg rounded to the nearest 5 mg, up to a maximum of 60 mg) or saline placebo every 6 hours on an 8 AM, 2 PM, 8 PM, and 2 AM schedule. The medications were administered by nurses in the absence of study investigators. The first dose of study medication was administered 6 to 12 hours after the initial dose of prednisone given in the ED. If the patient received oral prednisone, he or she was given intravenous saline placebo. If the patient received oral placebo, he or she was given intravenous methylprednisolone. If there was a long delay before the patient was transferred from the ED to the hospital room, the protocol was begun in the ED. Any patient who vomited the oral medication twice, complained of nausea or abdominal pain, or had an aversion to the taste of the oral medication was removed from the study. The study investigators, as the attending physicians, managed all aspects of the study patients care with the help of the pediatric residents. Supplemental oxygen was given to patients, with pulse oximetry values consistently less than 95% and was discontinued when the patient s pulse oximetry readings were 95% or above while the patient was breathing room air. 15 Nebulized ipratropium bromide was given to patients who had received 6 or more albuterol treatments in the 12 hours before being seen in the ED and still had significant distress. Theophylline was given only if the patients did not appear to be improving or if they were already receiving an oral theophylline preparation on admission. When chronic asthma therapy was indicated, an inhaled anti-inflammatory medication (cromolyn sodium or corticosteroids) was started once patients were able to tolerate nebulized β-agonists delivered every 3 to 4 hours. Patients were evaluated by a member of the study team and given an asthma score at 8 AM,4 PM, and midnight (Table I). On a random basis, the principal investigator (JB) performed a second evaluation to validate scoring consistency. The frequency with which β-agonist nebulization treatments were delivered was decreased if a patient s asthma score was 4 or less. Time zero was set as the time a patient was evaluated by a triage nurse in the ED. Length of hospital stay was defined in the following 2 ways: (1) as the time elapsed between time zero and the time the discharge order was written; and second, as the time elapsed between time zero and the time when nebulized β-agonists were changed from every 4 to every 6 hours. At the time of the study, a patient needed to be able to tolerate every 6-hour nebulization treatment before being discharged. The latter definition of length of stay was used because in some cases it may have more accurately reflected a patient s readiness for discharge. For example, a child may have been well enough to tolerate β-agonists given at 6-hour intervals beginning at midnight but could not be discharged until the morning pending the arrival of a parent. Complications of corticosteroids were evaluated by routine blood pressure monitoring, screening for the presence of abdominal pain, polyuria, and polydipsia. If indicated, urine and serum glucose were measured, and stool was tested for occult blood. Statistical analysis We assumed that there could be as great as a 2-day difference in length of hospitalization in patients receiving intravenous methylprednisolone versus oral prednisone. Therefore we designed a study with adequate power for a conservative 1-day difference in length of hospital stay to increase sensitivity and allow for a potential overestimation of the difference. The 2 groups were compared by unpaired t tests for symmetrically distributed variables (age), Mann-Whitney U tests for skewed variables (including the major study outcomes), and chi-square tests for nonnumeric variables (gender and initial nebulization schedule). The power analysis, based on an estimated 1-day standard deviation of time until discharge, required a minimum of 22 patients per group to provide at least 90% power. A 95% confidence interval was constructed for the mean differences in length of stay and time to 6-hour nebulizer treatments. Because the data were skewed, a 95% confidence interval for the difference in median length of stay was also determined. RESULTS Seventy patients were initially enrolled in the study. Subsequently, 4 patients were removed from the study, 3

3 588 Becker et al J ALLERGY CLIN IMMUNOL APRIL 1999 TABLE II. Patient characteristics and time spent in the ED Prednisone Methylprednisolone P value Boys/girls 19/14 22/11.45 Average age 8.1 (2-17) 6.7 (2-17).23 in years (range) Patients <6 years 42% 54%.32 old Time in ED in 5.4 (2.5-14) 5.6 (2-15).11 hours (range) FIG 1. PEFRs for patients greater than 6 years old (18 in the prednisone group and 13 in the methylprednisolone group). Initial is at time of enrollment, midpoint is a time point during hospitalization, and final is before discharge. Difference between last available and initial PEFR was determined for each subject and compared between groups. An effect of treatment over time was significant (P <.001), but the effect between the groups was not (P =.2). TABLE III. Number of patients receiving concomitant medication during the study Prednisone Methylprednisolone P value Ipratropium bromide Inhaled anti inflammatory Aminophylline as a result of medication errors and one who required transfer to the intensive care unit for more aggressive management. Sixty-six patients completed the study, 33 in each group. There was no difference between the prednisone and methylprednisolone groups for patient gender, age, or time spent in the ED (Table II). At the time of admission in the oral prednisone treated group, 12 (36%) patients were treated with β-agonists every 2 hours, 20 (61%) patients were treated every 3 hours, and 1 (3%) patient was treated every 4 hours. In the methylprednisolone group, 12 (36%) patients were treated with β-agonists every 2 hours and 21 (64%) patients were treated every 3 hours (P = not significant). Twenty (61%) patients in the prednisone-treated group required supplemental oxygen compared with 19 (58%) patients in the methylprednisolone group (P =.80). The use of additional medications during hospitalization did not differ between the 2 groups (Table III). Children in the prednisone group had a mean length of stay of 70 hours compared with 78 hours for the methylprednisolone group (P =.52). A 95% confidence interval was constructed for total mean length of stay. This demonstrated a difference of means, which ranged from 23 hours shorter for the subjects receiving prednisone to 4 hours longer. The median confidence interval is similar. Children in the prednisone group were successfully weaned to β-agonists in 6-hour intervals after 59 hours compared with 68 hours for the methylprednisolone group (P =.47). For patients requiring supplemental oxygen, the mean duration of oxygen administration (30 hours) was significantly less for children in the prednisone-treated group compared with the children in the methylprednisolonetreated group (52 hours, P =.04). Peak expiratory flow rates (PEFRs) were recorded for 18 prednisone-treated patients and 13 methylprednisolone-treated patients over the age of 6 years (Fig 1). Although each group showed significant improvement in PEFR over time (P <.001), there was no significant difference between groups (P =.2). No patients were removed from the study because of intolerance to either drug or placebo. One patient randomized to the prednisone group had one episode of emesis. One patient randomized to the methylprednisolone group was readmitted to the hospital within 2 weeks of discharge because of noncompliance with outpatient medications. Cost data were obtained by surveying the pharmacies of 4 community hospitals and 3 university-based health care networks. The community hospital charges for prednisone ranged from $2 to $4 for a 120-mg dose compared with $8 to $22 for the university-based networks. The community hospital charges for 60 mg of methylprednisolone ranged from $14 to $180 in contrast to $63 to $252 dollars for the university-based network hospitals. DISCUSSION These data show that equipotent daily doses of oral prednisone and intravenous methylprednisolone were equally efficacious in the treatment of pediatric patients hospitalized with acute asthma. The 1997 National Institutes of Health guidelines 15 recommend oral prednisone for hospitalized patients, even though there has not been a well-designed randomized controlled trial done to support this. In a 1993 review article, McFadden 17 concluded that oral and intravenous corticosteroids were probably equivalent, but he could not make a definitive statement about corticosteroid use in children. Ratto et al 18 found no difference between adult patients with acute asthma exacerbations who were treated with intravenous corticosteroids and those treated with oral corticosteroids, but this study was not blinded and included patients who received cortico-

4 J ALLERGY CLIN IMMUNOL VOLUME 103, NUMBER 4 Becker et al 589 steroids before admission. Also, patients in this study received doses of oral corticosteroids well in excess of current standards. Harrison et al 19 found that adult patients who received one dose of intravenous hydrocortisone in addition to oral prednisone in the initial management of an acute asthma exacerbation had no additional benefit. Several aspects of our study merit further discussion. Because methylprednisolone is administered in its active form, whereas prednisone needs to be metabolized by the liver to its active compound prednisolone, intravenous methylprednisolone has long been considered the corticosteroid of choice for hospitalized patients with asthma. Vichyanond et al 20 examined the penetration of methylprednisolone in the rabbit lung, and their data supported the advantage of methylprednisolone. Most probably, if methylprednisolone has any advantage at all, it would be within the first few hours of administration, and this benefit would be negated over the course of a hospitalization. Our study had 80% power to detect a difference in hospitalization duration as small as 19 to 20 hours. In addition, the confidence interval sets a likely upper boundary on the extent to which methylprednisolone may be superior. This value shows that it is unlikely that the use of methylprednisolone would result in more than 4 fewer hours of hospitalization as compared with the use of prednisone. Corticosteroids administered in different forms at equipotent doses have similar side-effect profiles A 4 mg/kg/day dose of intravenous methylprednisolone is routinely administered. In this study 4 mg/kg/day of oral prednisone was well tolerated. There were no significant side effects in either group, as one would expect with a short course of corticosteroids. At the time of inclusion in the study, the number of patients receiving oxygen supplementation was approximately the same in each group, but the prednisone group had a significantly shorter time on supplemental oxygen. The reason for this difference is unclear. A subanalysis revealed that there were 3 patients in the methylprednisolone group who received more than 100 hours of supplemental oxygen, whereas no one in the prednisone group received more than 56 hours. Oral therapy would seem to have several advantages over intravenous therapy. Placement of an intravenous catheter in a child is often difficult and labor intensive, and it is associated with the risk of infection. In addition, the cost of administering intravenous methylprednisolone is much greater than the cost of administering oral prednisone. There are limitations of the study that should be noted. The standard recommended dose of oral prednisone is 1 mg/kg/dose every 12 hours. In this study a prednisone schedule of 2 mg/kg/dose every 12 hours was used. This allowed for comparison of nearly equipotent oral and intravenous doses of corticosteroids. Four milligrams of methylprednisolone has anti-inflammatory activity equal to 5 mg of prednisone. 24 Patients tolerated the higher dose of oral corticosteroid without significant side effects. Another potential limitation was variability in ED management, but initial time zero was the time that the patient arrived for care in the ED, allowing for assessment of the total length of time in the hospital. Importantly, the mean time in the ED did not differ between the 2 groups, and there were no significant delays in the administration of the initial dose of corticosteroids. The protocol allowed for patients to receive their initial corticosteroid dose in the ED if they had a prolonged stay in the ED. Evidence that the degree of illness between the 2 groups was comparable includes that all patients were judged by attending ED physicians to require hospitalization, there was no difference in the mean time spent in the ED, and there were no differences in the frequency of β-agonist treatments required or in the proportion of patients requiring supplemental oxygen at admission. Attempts to increase intraobserver reliability on the decision to wean β-agonist therapy and the decision to discharge patients included using the same scoring system for each patient and the fact that 1 of 3 attending investigators (JB, NS, MFP) was the attending physician for study patients while they were hospitalized. These attending physicians evaluated and scored patients once or twice daily in addition to the study investigators and made management decisions in conjunction with the house staff. Interobserver reliability was also increased by validation of scoring of investigators by a second study investigator several times. Prednisone, 2 mg/kg orally every 12 hours, is as effective as intravenous methylprednisolone, 1 mg/kg every 6 hours, in the treatment of pediatric patients hospitalized with an acute asthma exacerbation in a nonintensive care setting. Prednisone is easier to administer and more cost effective than intravenous methylprednisolone. Further studies will be needed to determine the optimal dose and frequency of administration of oral prednisone in this setting. REFERENCES 1. Ellis ET. Asthma in infancy and childhood. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, Yunginger JW, editors. Allergy: principles and practice. 3rd ed. St. Louis: Mosby, p Larsen GL. Asthma in children. N Engl J Med 1992;326: Henry RL, Robertson CF, Asher I, Cooper DM, Cooper P, Dawson KP, et al. Consensus view: management of asthma. 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5 590 Becker et al J ALLERGY CLIN IMMUNOL APRIL Harris JB, Weinberger MM, Nassif E, Smith G, Milavetz G, Stillerman A. Early intervention with short courses of prednisone to prevent progression of asthma in ambulatory patients incompletely responsive to bronchodilators. J Pediatr 1987;110: Shapiro GG, Furukawa CT, Pierson WE, Gardinier R, Bierman W. Double blind evaluation of methylprednisolone versus placebo for acute asthma episodes. Pediatrics 1983;71: Pierson WE, Bierman CW, Kelley VC. A double blind trial of corticosteroid therapy in status asthmaticus. Pediatrics 1974;54: Younger RE, Gerber PS, Herrod HG, Cohen RM, Crawford LV. Intravenous methylprednisolone efficacy in status asthmaticus of childhood. Pediatrics 1987;80: Expert Panel Report 2: Guidelines for the diagnosis and management of asthma. Clinical practice guidelines. Bethesda (MD): National Institutes of Health; April 1997; NIH Publication Wood DW, Downes JJ, Lecks HI. A clinical scoring system for the diagnosis of respiratory failure. Am J Dis Child 1972;123: McFadden ER Jr. Dosages of corticosteroids in asthma. Am Rev Respir Dis 1993;147: Ratto DR, Alfaro C, Sipsey J, Glovsky MM, Sharma OP. Are intravenous corticosteroids required in status asthmaticus? JAMA 1988;260: Harrison BDW, Stokes TC, Hart GJ, Vaughan DA, Ali NJ, Rovinson AA. Need for intravenous hydrocortisone in addition to oral prednisolone in patients admitted to hospital with severe asthma without ventilatory failure. Lancet 1986;2: Vichyanond P, Irvin CG, Larsen GL, Szefler SJ, Hill MR. Penetration of corticosteroids into the lung: evidence for a difference between methylprednisolone and prednisone. J Allergy Clin Immunol 1989;84: Nall M, Corbett M, McLoughlin J, Petrosko J, Garcia D, Karibo J. Impact of short-term oral steroid use upon children s school achievement and behavior. Ann Allergy 1992;69: Grant CC, Duggan AK, Santosham M, DeAngelis C. Oral prednisone as a risk factor for infections in children with asthma. Arch Pediatr Adolesc Med 1996;150: Spahn JD, Kamada AK. Special considerations in the use of glucocorticoids in children. Pediatr Rev 1995;16: Schimmer BP, Parker KL. ACTH; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In: Hardman JG, Limbird LE, editors-in-chief. Goodman and Gillman s the pharmacologic basis of therapeutics. 9th ed. St. Louis: McGraw-Hill; p Bound volumes available to subscribers Bound volumes of The Journal of Allergy and Clinical Immunology are available to subscribers (only) for the 1999 issues from the Publisher, at a cost of $ for domestic, $ for Canadian, and $ for international subscribers for Vol. 103 (January-June) and Vol. 104 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby, Inc., Subscription Services, Westline Industrial Dr., St. Louis, MO ; phone 1 (800) or (314) Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.