A Randomized Comparison of Helium– Mixture () and Racemic Epinephrine for the Treatment of Moderate to Severe Croup

Jim Edward Weber, DO*‡; Carl R. Chudnofsky, MD*‡; John G. Younger, MD‡; G. Luke Larkin, MDʈ; Michael Boczar, DO*‡; Mark D. Wilkerson, MD*‡; George Y. Zuriekat, MD‡§; Brian Nolan, MD‡§; and David M. Eicke, BS, RRT‡

ABSTRACT. Objective. To compare the additive ef- to severe cases, aggressive may be necessary fect of a helium–oxygen mixture (Heliox) or racemic epi- to avoid exhaustion and subsequent respiratory fail- nephrine (RE) on croup scores (CSs) in children with ure. Although steroids have gained widespread ac- moderate to severe croup treated with humidified oxygen ceptance as a means of attenuating subglottic edema, and steroids. racemic epinephrine (RE) has long been considered Design. A prospective, randomized, double-blind the mainstay of acute therapy for moderate to severe trial. 1 Setting. and pediatric inten- croup. sive care unit of an urban level I trauma center. Helium is a biologically inert gas that possesses a Participants. Randomly assigned, consecutive chil- very low specific gravity (density) and is one third dren ages 6 months to 3 years presenting with moderate the viscosity of air.2 These properties result in a to severe croup (CS: >5). decreased resistance to airflow (lower Reynolds Interventions. After cool humidified oxygen and 0.6 number), and suggest that a helium–oxygen mixture mg/kg of intramuscular , patients were may be a useful adjunct to improve ventilation via randomized to receive either Heliox or RE. Vital signs, enhanced laminar airflow in the face of moderate to , and CSs were recorded at regular in- severe croup. Recently, mixtures of helium and oxy- tervals. gen have been used successfully in the pediatric Outcome/Analysis. Reductions in CSs were com- pared using repeated-measures analysis of variance. intensive care unit setting for treatment of both re- 3–5 Results. Thirty-three patients were enrolled. Three fractory viral and postextubation croup. were excluded because of protocol violations, and 1 was Although both Heliox (AGA Gas, Flint, MI) and excluded because of lack of documentation, leaving 29 RE have been independently shown to decrease the patients for final analysis. The average age was 24.2 work of and lower croup scores (CSs),3,4,6 months, 20 were male (68.8%). Both Heliox and RE were no study to date has compared these modalities in associated with improvement in CSs over time. There the management of moderate to severe croup. There- were no significant differences in mean CS, oxygen sat- fore, the purpose of this study was to compare the uration, respiratory rate, or heart rate between groups at relative effect of Heliox and RE on CSs in pediatric baseline or at the end of the treatment period. patients with moderate to severe croup. Conclusion. In patients with moderate to severe croup, the administration of Heliox resulted in similar improvements in CS compared with patients given RE. METHODS Pediatrics 2001;107(6). URL: http://www.pediatrics.org/ This was a prospective, randomized, double-blind study con- cgi/content/full/107/6/e96; helium–oxygen mixture, croup. ducted at an urban level I trauma center that serves as a primary teaching site for an residency. The study was initiated by emergency department (ED) attending physicians and ABBREVIATIONS. RE, racemic epinephrine; CS, croup score; ED, continued by pediatric intensive care unit staff for children requir- emergency department. ing admission. This study was approved by the institutional re- view board of the hospital; written informed consent was obtained from the parents of all participants. aryngotracheobronchitis, or croup, is a com- Children between the ages of 6 months and 3 years with an ED mon respiratory illness in children. Most cases diagnosis of moderate to severe croup were eligible for the study. of croup are mild and require only supportive Moderate to severe croup was defined as the presence of hoarse- L ness, barking cough, and stridor in a patient with a preceding (Յ1 care with humidified oxygen. However, in moderate week) upper respiratory infection, and a corresponding Modified Taussig CS of 5 or greater (Table 1). Children with a Modified Taussig CS of Յ5 were also eligible for enrollment if they scored From the *Hurley Medical Center, Flint, Michigan; ‡University of Michigan a 3 in any 1 of the 5 individual categories. Exclusion criteria Medical School, Ann Arbor, Michigan; §Michigan State University College included a history of congenital cardiac disease, tracheal stenosis, of Human Medicine, East Lansing, Michigan; and the ʈUniversity of Pitts- or bronchopulmonary dysplasia; signs or symptoms suggesting burgh School of Medicine, Pittsburgh, Pennsylvania. other causes of stridor, such as epiglottitis, bacterial tracheitis, This work was presented at the Annual Meeting of the Society for Academic retropharyngeal or peritonsillar abscess, reactive airway disease, Emergency Medicine; May 17, 1998; Chicago, IL. tumor, or supraglottic foreign body. Received for publication Feb 2, 2001; accepted Feb 2, 2001. Patients were randomized via a computer-generated random- Reprint requests to (J.E.W.) Department of Emergency Medicine, Hurley ization scheme to receive RE or a blend of 70% helium:30% oxygen Medical Center, Flint, MI 48503. E-mail: [email protected] mixture administered via facemask or tent house at a flow rate of PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad- 10 to 12 L/minute. Oxygen flowmeters (Chemtron Allied Health emy of Pediatrics. Care, St Louis, MO) were calibrated at 345 kPa (50 lb/in2-gauge) in http://www.pediatrics.org/cgi/content/full/107/6/Downloaded from www.aappublications.org/newse96 by guestPEDIATRICS on September 25, Vol. 2021 107 No. 6 June 2001 1of4 TABLE 1. Modified Taussig CS 01 2 3 Color Norm Dusky Cyanotic in RA Cyanotic on 30% oxygen Air entry Norm Mildly decreased Moderately decreased Substantially decreased Retractions None Mild Moderate Severe Consciousness Norm Restless Lethargy (depressed) Obtunded Stridor None Mild Moderate Severe or absent in the presence of severe obstruction Modified from: Taussig LM, Castro O, Beaudry PH, et al. Treatment of laryngotracheobronchitis (croup). Am J Dis Child. 1975;129:790–793. advance to correct for the differences in physical properties of the either RE or placebo, if they could not tolerate the facemask or tent 2 gases. Children randomized into the Heliox arm received 3 house, or if their clinical condition deteriorated at any time during hours of continuous gas therapy, with nebulized saline adminis- the study. tered as a placebo. Children randomized into the RE arm received All results were reported as mean Ϯ standard deviation. Inde- 0.5 mL of RE in 2.5 mL of normal saline, with 100% oxygen for a pendent samples t tests were used to compare continuous vari- total of 3 hours; therefore, both arms required 3 hours of therapy. ables between groups. Similarly, ␹2 analysis was used to compare Nebulized RE and saline (placebo) were powered using 100% frequency data. To compare changes in CS, heart rate and respi- oxygen and 70%/30% helium–oxygen mixture, respectively. ratory rate, and arterial oxygen saturation over the course of the Therefore, gas therapy was not interrupted at any time during the study, repeated-measures analysis of variance was used. Physio- study. RE treatment was considered finished once the logic measurements were examined first for change over time, cup was empty and mist was no longer visualized. If no significant then for differences in change over time between the 2 treatment improvement in symptoms was observed after 15 minutes, a sec- arms. Statistical significance was set at .05, although exact P values ond dose of either RE or an equal volume of placebo was given. were reported when significant. All statistical analysis was per- Data were collected for a total of 4 hours. Enrolling physicians formed using SAS, Version 6.12 (SAS Institute, Cary, NC). reserved the right to exclude patients and administer rescue med- ications (RE) at any time during the study. Gas delivery was provided by size H and E cylinder tanks RESULTS (AGA Gas, Flint, MI). The helium and air tanks were blinded with Between September 1, 1997, and March 1, 1998, 58 double cloth covers with identical standard compensated patients met inclusion criteria. The parents of 14 flow meters exposed. Venturi ports on all were closed, thus, ensuring no difference in sound or appearance of the setup. patients declined participation. Of the remaining RE or placebo was given with small volume nebulizers (Vixone, participants, 11 patients were not prospectively iden- Westmed Inc, Tuscon, AZ) and similar medication volumes. Only tified, and 4 patients were later excluded because of a knew which treatment the patient was protocol violations (2 patients unable to tolerate face- receiving. This individual was not involved in patient recruitment or data collection. mask, 1 patient with reactive airway disease and Our minimum sample size of 14 patients in each group yielded , and 1 patient with incomplete data). an ϳ80% power to detect a difference of change in CSs of 2 Two other patients who were excluded required res- between groups and Ͼ90% power to detect a change in CSs of 3 cue doses of RE (1 in the Heliox group and 1 in the between groups. The principal outcome measure was the change RE group). No patients required intubation. Com- in CS. Secondary outcome measures included changes in oxygen saturation, respiratory rate, and heart rate. All baseline parameters parison of these individuals with the 29 patients were measured on room air. CSs were recorded at baseline and at successfully studied demonstrated no apparent en- 30, 60, 90, 120, 150, 180, and 240 minutes. All children received rollment bias (Table 2). In the Heliox arm, 11 patients continuous cool mist and 0.6 mg/kg of intramuscular dexameth- were treated using a facemask apparatus and 3 via asone. A 3-hour treatment and 1-hour observation period was considered optimal to avoid compromising patient safety. This tent house. No differences were noted between observation period is consistent with previously published data groups when considering change in CSs, vital signs, by Ledwith et al7 regarding safe discharge of patients after the or oxygen saturation. Four patients in the RE arm administration of RE. Standardized CS training was conducted by and 3 in the Heliox arm received a second dose of RE the principal investigator before the beginning of the study and and saline placebo, respectively; outcomes for both quarterly throughout the study; all enrolling investigators partic- ipated. Logistic constraints prohibited comparisons of CS between groups were similar. enrolling physicians during the study. However, interobserver Among the patients included in the randomiza- agreement was assessed for 5 patients with moderate to severe tion, there were no significant differences at baseline croup before the study, with good agreement (␬ ϭ 0.76). Although between patients treated with Heliox and those a CS of 5 or greater was necessary for enrollment into this study, CSs were not used as a basis for providing or withholding treat- treated with RE (Table 2). Initial CSs ranged from 5 to ment in enrolled patients. Patients were withdrawn from the 9. Two children with an initial CS of 5 were classified study if their oxygen saturation was Ͻ90% after a second dose of as severe based on a stridor score of 3.

TABLE 2. Baseline Characteristics of Enrolled Versus Nonenrolled Patients and Heliox- Versus Re-treated Patients Parameter Enrolled Nonenrolled Heliox RE P (n ϭ 29) *(n ϭ 15) (n ϭ 14) (n ϭ 15) Value Age (mo) 24 Ϯ 623Ϯ 7 24.4 Ϯ 9 24.0 Ϯ 6.7 NS Male gender 68.8% 76.8% 64.3% 73.3% NS Initial severity CS 6.7 Ϯ 0.6 6.5 Ϯ 1.1 6.8 Ϯ 0.9 6.7 Ϯ 0.9 NS Heart rate (minϪ1) 162 Ϯ 13 154 Ϯ 24 159 Ϯ 15 164 Ϯ 11 NS Respiratory rate (minϪ1)44Ϯ 940Ϯ 744Ϯ 10 45 Ϯ 8NS Arterial oxygen saturation (%) 95 Ϯ 596Ϯ 395Ϯ 596Ϯ 2NS NS indicates not significant. Results reported as mean Ϯ standard deviation. Ninety-five percent confidence intervals calculated with independent samples t test or ␹2 distribution where appropriate. * Nonenrolled patients were reported as the 11 patients not prospectively identified plus the 4 patients excluded from the study (n ϭ 15).

2of4 COMPARISONDownloaded OF HELIOX from ANDwww.aappublications.org/news RACEMIC EPINEPHRINE by guest on FOR September THE TREATMENT25, 2021 OF CROUP Improvements in all measured parameters were these patients is based only on the opinion of the seen in both treatment arms over time (P Ͻ .01 in author. each case). Although significant differences in CSs In a recent prospective, double-blind study com- were noted between Heliox-treated and RE-treated paring Heliox with humidified oxygen in children participants at all time intervals after 90 minutes (P Ͻ with acute viral croup, Terregino et al8 found no .05), the overall results using repeat-measures anal- statistically significant difference in CSs between the ysis of variance revealed no significant differences in 2 groups. However, in this study, patients ill enough CSs at the end of the observation period (P ϭ .13; Fig to require RE were excluded. Because most cases of 1). In addition, there were no statistically significant mild croup will respond to humidified oxygen alone, differences between treatment groups in other mea- this study population was less likely to benefit from sured severity parameters (heart rate, P ϭ .29; respi- Heliox. ratory rate, P ϭ .94; arterial oxygen saturation, P ϭ Several study limitations merit discussion. Be- .28). cause of the relatively small numbers of participants, the study was not powered to detect small differ- DISCUSSION ences between groups. Although we did not include We believe that this is the first report of a double- a control arm of patients who received only cool mist blind, randomized study comparing the effects of RE and steroids, all enrolled children were sufficiently and Heliox in children with acute viral croup. We ill to require aggressive treatment. Thus, it was most have shown that compared with RE, Heliox results in appropriate that all patients received either RE or a similar reduction in CS in pediatric ED patients Heliox. This study was sufficiently large to detect with moderate to severe croup. Our results are con- differential improvements in the CS over time. How- sistent with other studies evaluating the clinical effi- ever, because a control arm was not studied, we cacy of Heliox in the treatment of acute croup. In cannot exclude the possibility that the incremental 1979, Duncan3 treated 7 patients refractory to RE improvement noted in the Heliox arm after 90 min- with a 70% helium–oxygen mixture and noted a utes was not attributable, at least in part, to cool mist significant decrease in their CSs. Duncan concluded and oxygen. Furthermore, the relevance of this im- that Heliox was efficacious for the treatment of croup provement is unknown, because outcomes such as and that intubation was avoided in each of the 7 admission rates and hospital length of stay were not patients. In 1982, Nelson and McClellan4 reproduced specifically measured. these results in 14 children with croup not respond- CSs are a helpful research tool used to standardize ing to RE, concluding that Heliox was useful as disease severity at an arbitrary point, and a decreas- adjunctive therapy. Unfortunately, both studies were ing score provides an objective measure of clinical small, nonblinded, and uncontrolled. In addition, improvement. However, CSs are poor predictors of Duncan enrolled patients with other underlying and none have been universally medical problems (teratoma, tetralogy of Fallot, accepted as the gold standard. We chose the Modi- pneumonia), making the cause of airway obstruction fied Taussig CS because it weighs patient color, anx- less clear. Finally, the need for intubation was not iety, retractions, stridor, and level of consciousness defined or intended as an outcome measure in either equally, yet classifies disease as severe if a maximal study. Therefore, the suggestion that the administra- score is present in any 1 category (Table 1). This is tion of Heliox obviated the need for intubation in particularly important when grading stridor and re-

Fig 1. Comparison of change in croup score over time (RE vs Heliox)

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/107/6/ by guest on September 25, 2021 e96 3of4 tractions, because both have been fluroscopically consider the usefulness of Heliox alone or as an shown to inversely correlate with the diameter of the adjunct to RE, when evaluating outcomes, such as .9 hospital admission rates and length of stay. Twenty-five patients who were eligible for the study were not enrolled, and it is possible that this ACKNOWLEDGMENTS group may have responded differently to treatment. This study was funded, in part, by the Hurley Respiratory However, initial CSs of study patients were similar Therapy Department, Hurley Medical Center. to those children who were not enrolled because of parental refusal. REFERENCES Although helium–oxygen mixtures are considered 1. Bank DE, Krug SE. New approaches to upper airway disease. Emerg safe, has been previously reported with use Med Clin North Am. 1995;13:473–487 in preterm infants with a history of bronchopulmo- 2. McGee DL, Wald DA, Hinchliffe S. Helium-oxygen therapy in the 10 emergency department. J Emerg Med. 1997;15:291–296 nary dysplasia and subglottic stenosis. In our 3. Duncan PG. Efficacy of helium-oxygen mixtures in the management of study, 3 patients with an initial oxygen saturation of severe viral and post-extubation croup. Can Anaesth Soc J. 1979;26: Յ90% received Heliox. All 3 responded promptly 206–212 with normal oximetry, and none experienced any 4. Nelson DS, McClellan L. Helium-oxygen mixtures as adjunctive sup- serious sequelae. Oxygen saturation did not differ port for refractory viral croup. Ohio State Med J. 1982;10:729–730 5. Kemper KJ, Ritz RH, Benson MS, et al. Helium-oxygen mixture in the between the study groups, and no patients required treatment of postextubation stridor in pediatric trauma patients. Crit exclusion because of sustained hypoxia. Finally, it is Care Med. 1991;19:356–359 possible that observer bias influenced the reporting 6. Westley CR, Cotton EK, Brooks JG. Nebulized racemic epinephrine by of CSs. However, previously mentioned measures to IPPB for the treatment of croup. Am J Dis Child. 1978;132:484–487 7. Ledwith CA, Shea LM, Mauro RD. Safety and efficacy of nebulized ensure blinding were adhered to meticulously. racemic epinephrine in conjunction with oral dexamethasone and mist in the outpatient treatment of croup. Ann Emerg Med. 1995;25:331–337 CONCLUSION 8. Terregino CA, Nairn SJ, Chanski ME, Kass JE. Effect of Heliox in croup: Our data suggest that the administration of Heliox a pilot study. Acad Emerg Med. 1998;5:1130–1133 results in a similar reduction in CSs compared with 9. Corkey CWB, Barker GA, Edmonds JF, et al. Radiographic tracheal diameter measurements in acute infectious croup: an objective scoring RE in children with moderate to severe croup. Larger system. Crit Care Med. 1981;9:587–590 studies examining the utility and cost-effectiveness 10. Butt WW, Koren G, England S, et al. Hypoxia associated with helium- of Heliox seem warranted. Future studies should oxygen therapy in neonates. J Pediatr. 1985;106:474–476

4of4 COMPARISONDownloaded OF HELIOX from ANDwww.aappublications.org/news RACEMIC EPINEPHRINE by guest on FOR September THE TREATMENT25, 2021 OF CROUP A Randomized Comparison of Helium−Oxygen Mixture (Heliox) and Racemic Epinephrine for the Treatment of Moderate to Severe Croup Jim Edward Weber, Carl R. Chudnofsky, John G. Younger, G. Luke Larkin, Michael Boczar, Mark D. Wilkerson, George Y. Zuriekat, Brian Nolan and David M. Eicke Pediatrics 2001;107;e96 DOI: 10.1542/peds.107.6.e96

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Downloaded from www.aappublications.org/news by guest on September 25, 2021 A Randomized Comparison of Helium−Oxygen Mixture (Heliox) and Racemic Epinephrine for the Treatment of Moderate to Severe Croup Jim Edward Weber, Carl R. Chudnofsky, John G. Younger, G. Luke Larkin, Michael Boczar, Mark D. Wilkerson, George Y. Zuriekat, Brian Nolan and David M. Eicke Pediatrics 2001;107;e96 DOI: 10.1542/peds.107.6.e96

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2001 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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