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Croup: Common Syndromes and Therapy

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EDUCATIONAL OBJECTIVES

1. Delineate the differential diagnosis of croup in children. 2. Review the clinical evidence supporting the use of nebulized epinephrine for croup in the emergency department, as well as the criteria for discharge home after treatment. 3. Discuss the clinical evidence supporting the use of systemic or nebulized steroids in the treatment of viral laryngotracheobronchitis. Eric L. Wald, MD, is with the Division of Critical Care Medicine, Northwestern University, Chicago. Address correspondence to: Eric L. Wald, MD, 2300 Childrens Plaza, Box 73, Chicago, IL 60614; fax: 773-880-6300; e-mail EWald@ childrensmemorial.org. Dr. Wald has disclosed no relevant nancial relationships. doi: 10.3928/00904481-20091210-04

iseases resulting in airway compromise are the leading cause of cardiac arrest in children.1 The narrowest portion of the pediatric airway (in those younger than 10 years) is at the level of the cricoid cartilage, termed the subglottis, just below the vocal cords. This anatomic feature makes children more susceptible to airway obstruction from infectious diseases than adults.

Eric L. Wald, MD
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SIDEBAR.

Differential Diagnosis of Acute Laryngeal Obstruction

Acute laryngotracheitis Spasmodic croup Epiglottitis Bacterial tracheitis Foreign body aspiration (tracheal and esophageal) Laryngeal inammation caused by thermal injury Angioneurotic edema Allergic reaction Retropharyngeal abscess Peritonsillar abscess Neoplasm/hemangioma Vocal cord paresis/paralysis Laryngeal diphtheria

ammation of structures superior to the cords, such as the epiglottis, arytenoids, and aryepiglottic folds, is termed supraglottitis. All of these processes are similar enough to consider them within the spectrum of a single disease. The discussion here focuses on the history, epidemiology, pathogenesis, clinical presentation, and management of croup illnesses: epiglottitis, laryngotracheitis [including laryngotracheobronchitis (LTB) and laryngotracheobronchopneumonitis], and bacterial tracheitis. Classication and clinical characteristics are shown in Table 1 (see page 17). EPIDEMIOLOGY Croup occurs in children younger than 6 years, with a peak incidence from 7 to 36 months.2 Approximately 5% of children have croup during the second year of life. The incidence in boys is 1.4 to 2 times higher than in girls.2 Longitudinal croup studies have described a biennial mid-autumn peak in North America, occurring in odd years, which correlates with the prevalence of parainuenza virus infection, as well as an annual summer trough.3,4 The most frequent etiologic agents include parainuenza viruses (types 1-3), respiratory syncytial virus, inuenza viruses A and B, and adenovirus, while Mycoplasma pneumoniae, herpes simplex type I, measles, and varicella have also been reported. Human metapneumovirus and human coronavirus HL-63 are two newly described pathogens that are strongly associated with croup in children.5 CLINICAL PRESENTATION Patients with laryngotracheitis commonly present with 1 to 3 days of nonspecic upper respiratory tract symptoms, with progression to the characteristic barking cough, stridor, and respiratory distress. Symptom onset is abrupt and typically occurs during nighttime hours. Several hypotheses exist to explain the nighttime onset, including nocturnal

airway cooling, gastroesophageal reux and concomitant inammation, and the effect of nadir levels of cycling endogenous substances, such as cortisol and epinephrine.6,7 Inspiratory stridor is most common, with biphasic stridor suggesting a more severe or xed obstruction. Low-grade fever is often present. Tachypnea, retractions, hypoxia, or desaturation are often ominous signs of worsening obstruction and impending respiratory failure. DIFFERENTIAL DIAGNOSIS Children with classic croup symptoms are readily diagnosed, but clinicians must be cognizant that there may be progression of infection into the trachea and lower airways. Furthermore, there are several other acute obstructive disease processes that occur in the larynx and are also present with stridor and respiratory distress (see Sidebar). First described in 1878 by Michel as angina epiglottidea anterior, epiglottitis in children has become a rarity since the introduction of Hemophilus inuenzae type b (Hib) conjugate vaccines in 1991.8 It represents a bacterial infection of the supraglottic structures in which worsening edema forces the epiglottis posteriorly, causing airway obstruction. Epiglottitis usually occurs in patients 2 to 8 years, although the average age is increasing as is the ratio of adult to pediatric cases since the introduction of the Hib vaccine.9 Despite a sharp drop in incidence, H. inuenzae is still seen secondary to vaccine failure and in unimmunized children. Group A beta hemolytic Streptococcus is now the leading cause of epiglottitis, although its absolute frequency has not increased. Staphylococci, pneumococci, moraxella, and candida species, as well as many other bacteria and viruses, have been isolated from surface cultures of the epiglottis. Children usually have rapid onset of symptoms and present with throat pain, a mufed, hot potato voice, fever, irri-

Because airway resistance is inversely proportional to the fourth power of the radius, minimal reductions in cross-sectional area of the airway secondary to inammation or edema can exponentially increase airway resistance, as well as work of breathing. The term croup describes a constellation of mainly acute and infectious illnesses characterized by varying degrees of barking cough, hoarseness, inspiratory stridor, and respiratory distress. Most clinicians use the term laryngotracheitis or laryngotracheobronchitis for the most common form of croup in which involvement of the larynx is enough to produce typical symptoms, and they reserve the term laryngotracheobronchopneumonitis for more severe disease that extends into the lower airways. A distinction is made between spasmodic croup, an entity thought to have an allergic component that rarely requires treatment, and laryngotracheitis, which is thought always to have an infectious etiology. All these terms describe inammation of the vocal cords and structures inferior to the cords. In-

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TABLE 1.

Classication, Denition, and Clinical Features of Croup Illnesses

Denition and Characteristic Spasmodic Croup
Acute nighttime onset of inspiratory stridor; sometimes associated with mild URI or allergic component

Epiglottitis
Inammation of the supraglottic structures, bacterial cellulitis of the epiglottis, and aryepiglottic folds

Acute Laryngotracheitis

Bacterial Tracheitis
Inammation of the larynx, trachea and bronchi, or lung; represents extension of laryngotracheitis but more severe illness pattern

Denition

Inammation of the larynx and trachea

Typical age at occurrence Individual and family history

3 months to 3 years

2 to 8 years

3 months to 3 years

3 months to 3 years

Possible family history of croup; allergic history

No family history

Possible family history of croup

Possible family history of croup

Prodrome

Minimal coryza

Minimal coryza

Usually coryza

Usually coryza

Onset

Sudden, always at night; typically a well child or with mild URI symptoms who awakens with barking cough and/or stridor

Rapid progression within hours

Variable, similar to common cold presentation; fever in rst 24 hours and within 24 to 48 hours, stridor, or signs of obstructed airway

Gradually progressive over 2 to 5 days; originally may present like laryngotracheitis but refractory to typical therapy

Symptoms on presentation

Hoarseness, barking cough, minimal to moderate inspiratory stridor, no dysphagia, nontoxic

Fever, dysphagia, odynophagia, drooling, irritability; stridor is a late nding, toxic appearance

Hoarseness, barking cough, minimal to severe inspiratory stridor; no dysphagia, usually nontoxic

Hoarseness, barking cough, usually severe inspiratory stridor; typically toxic presentation

Signs on presentation

No fever; no pharyngitis; normal epiglottis

Fever, generally 37.8 to 40.5 C; pharyngitis; abnormal epiglottis Thickening, rounding of epiglottis (thumbprint sign); loss of vallecular air space; normal subglottis Elevated with > 70% neutrophils

Fever, generally 37.8 to 40.5 C; minimal pharyngitis; normal epiglottis

Fever, generally 37.8 to 40.5 C; minimal pharyngitis; normal epiglottis

Radiographic ndings

Subglottic narrowing on posterior-anterior view

Subglottic narrowing on posterior-anterior view

Subglottic narrowing on posterior-anterior view; irregular soft tissue densities on lateral view, bilateral pneumonia

White cell count

Normal

Mildly elevated, with > 70% neutrophils Parainuenza viruses (type 1 responsible for fall outbreaks, type 3 for severe disease), inuenza viruses, respiratory syncytial virus, adenoviruses, measles virus, rhinoviruses, metapneumoviruses, and coronaviruses

Elevated or abnormally low, with > 70% neutrophils/bandemia

Microbiologic ndings

Etiologic agents similar to those in laryngotracheitis

Haemophilus inuenzae type B (with vaccine failure and unimmunized), group A beta-hemolytic Streptococcus, Staphylococci, Pneumococci, Candida

Initial infection likely caused by viruses (parainuenza or inuenza), but evolution usually due to bacterial superinfection, particularly from Staphylococcus aureus, group A Streptococci, and Haemophilus inuenzae

LTB = laryngotracheobronchitis; LTBP = laryngotracheobronchopneumonia; adapted from Cherry JD

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TABLE 2.

Assessment of the Severity of Croup*

Level of Severity
Mild Moderate Severe Impending respiratory failure

Characteristics
Occasional barking cough, no audible stridor at rest, no chest wall retractions Frequent barking cough, audible stridor at rest, mild chest wall retractions at rest but no agitation Frequent barking cough, prominent stridor, tachypnea, and marked chest wall retractions; agitation and/or distress Frequent barking cough, stridor at rest, chest wall retractions (cough, stridor, retractions may not be prominent due to increasing fatigue/airway compromise), lethargy or decreased level of consciousness, cyanosis

*Adapted from the Alberta Medical Association16

tability and respiratory distress. Drooling is common secondary to airway obstruction and odynophagia. Patients are usually toxic appearing, often assuming a snifng position with the chin thrust forward to open their airway, or a tripod position, leaning forward on both arms to allow maximal use of accessory respiratory muscles. Notably, a croupy cough is absent, and stridor is a late clinical nding. Secondary sites of infection, such as meningitis, otitis media, and cellulitis, are present 50% of the time, and pneumonia is reported in up to 25% of cases.1,10 If the diagnosis is uncertain after performance of the history and physical examination, a lateral radiograph of the neck can aid in conrmation. In epiglottitis, the lateral neck radiograph often reveals a swollen and edematous epiglottis (thumbprint sign), with loss of the vallecular air space. Once epiglottitis is suspected, a multidisciplinary team should be assembled, including pediatric intensive care physicians, anesthesiologists, and otolaryngologists. To conrm the diagnosis, the child should proceed to the operating room for anesthesia, to obtain intravenous access, and to perform laryngoscopy with direct visualization and airway placement. It is recommended that personnel be available to perform an emergency tracheostomy if an airway cannot be secured with an endotracheal tube. Once the airway is secure, some prefer

changing the oral endotracheal tube to a nasotracheal tube for easier positioning, to minimize secretions and to prevent unnecessary trauma. Cultures of the blood and surface of the epiglottis should be obtained for precise microbiologic diagnosis. Antibiotics active against H. inuenzae type b and group A Streptococcus should be started; children usually require intubation for 24 to 72 hours, until reduction in airway edema occurs. Another potentially life-threatening infection that often represents the evolution of common croup to a more acute disease is bacterial tracheitis. First described in the American literature in 1912, it was re-described in 1979.11,12 Jones et al reported eight cases of a disease that shared features of croup and epiglottitis. They called it bacterial tracheitis.12 It occurs predominantly in the fall and winter months in children 6 months to 6 years but has been reported in older children. The most common etiologic agent isolated is S. aureus, but other pathogens, such as H. inuenzae, alpha-hemolytic Streptococcus, group A Streptococcus, moraxella species, and pneumococci, have also been reported. Most view the disease as a complication of viral laryngotracheitis in which injury to respiratory epithelium predisposes to bacterial superinfection. The clinical presentation of bacterial tracheitis is not as rapid as epiglottitis; children usually have a mild to moderate illness (typical of classic viral croup)

for several days before an acute change or decompensation is noted. High fever, productive cough, and a toxic appearance is common, without odynophagia or drooling. These last two features are useful in differentiating bacterial tracheitis from epiglottitis. These patients often have an increased oxygen requirement but respond poorly to therapies, such as racemic epinephrine and steroids that are aimed at reducing airway edema. About 60% to 80% of these children will require endotracheal intubation and respiratory support due to thick tracheal secretions that are the cause of the obstruction.13,14 At the time of endoscopy for intubation, subglottic edema, thick inammatory exudates, mucosal ulceration, and sloughed mucosa are observed. A bacterial culture of tracheal secretions and a viral culture of the pharynx should be obtained at the time of intubation to help guide therapy. Concurrent sites of infection are seen often with up to 60% of patients also having pneumonia.1 Lateral neck x-rays can aid in diagnosis, revealing a hazy tracheal air column and soft densities representing purulent material or pseudomembranes. Treatment consists of close airway monitoring and intravenous antibiotics active against the common pathogens for 10 to 14 days. A recent study found that bacterial tracheitis was three times more likely to cause respiratory failure than croup and epiglottitis combined.14

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Other rare causes of stridor in children presenting with croup-like symptoms include foreign body aspiration, peritonsillar or retropharyngeal abscess, angioneurotic edema, and laryngeal diphtheria. In foreign body aspiration, there is usually a history of aspiration, and symptoms are acute in onset, without signs of prodrome or local or systemic infection. Deep neck space infections tend to be preceded by viral upper respiratory tract infections and a high index of clinical suspicion is necessary to diagnose them. Clinical ndings, such as fever, neck pain and swelling, and torticollis, are common, whereas signs of airway obstruction, such as wheezing and stridor, are relatively rare initially. Drooling, limitation in neck movement, and cervical lymphadenopathy are other presenting signs that may prompt medical attention. Angioedema or allergic reactions are often associated with an offending allergen, have an acute onset, and may be accompanied by other ndings, such as swollen lips and facial tissue or urticarial rash. Finally, in the unimmunized pediatric population, laryngeal diphtheria must always be considered. Although there have been no cases in the United States since 2003, diphtheria still occurs in Asia, Africa, and the former Soviet Union. It presents with all of the hallmarks of laryngotracheitis, but a membranous pharyngitis is notable on physical examination. ASSESSMENT OF SEVERITY The diagnosis of croup usually relies solely on astute clinical assessment. The best known croup severity score, the Westley score, evaluates ve components in the child with respiratory distress: air entry, stridor, cyanosis, retractions, and level of consciousness.15 In recent years, a more clinically useful severity scale and clinical practice guidelines were developed by the Alberta Clinical Practice Guideline Working Group.16 Based on this scale, less than 1% of children seen in 21 emergency departments in Alberta, Canada, had severe croup, while 85% of children had mild croup17 (see Table 2, page 18). TREATMENT Despite the large body of anecdotal testimonials supporting humidied air for croup syndromes, there is no evidencebased medicine to support its use. Several randomized, controlled trials showed mild to moderate croup and moderate to severe croup. There was a vefold decrease in the rate of intubation in children with severe croup (or impending respiratory failure) among those who received steroids.21 In children already intubated, one-third less time was spent on the ventilator, and there was a sevenfold decrease in frequency of reintubation.22 Corticosteroid trials in croup have investigated an assortment of drugs, dosages, and routes of administration. Single dose dexamethasone [0.6 mg/kg given orally or intramuscularly (IM)] has been studied and compared most frequently. Oral dexamethasone, when compared with other steroid preparations, such as oral prednisone, has been found equivalent or superior in reducing croup scores and in the rate of return to medical care.23 Oral and IM administration of dexamethasone have been compared, and no differences were seen in reduction of croup scores, escalation of medical care, return to medical care, or hospital admission rates.24,25 Oral and IM routes of administration have also been compared with inhalational routes (chiey comparing inhaled budenoside with oral dexamethasone) and they were found to be equivalent. In some cases, oral and IM routes were found to be superior to inhalation.26,27 At the bedside, the route of administration of steroid may vary according to the tolerance of the child and the associated symptoms and severity of illness. Dosing regimens for corticosteroids have also been evaluated in various studies. Randomized trials showed the efcacy of a single-dose administration and multiple-dose administration of steroids in croup. Because the duration of action for a single dose of dexamethasone is 48 to 96 hours, it seems sufcient to treat the most common croup symptoms in children. No studies have performed outcome analyses comparing single dose therapy with multiple dose treatment schedules. Randomized, controlled

Corticosteroid trials in croup have investigated an assortment of drugs, dosages, and routes of administration.
no difference among groups in terms of croup score, need for epinephrine or steroid treatment, or need for additional medical care or hospital admission.18,19 Corticosteroid Therapy Until recently, a controversial issue surrounding the treatment of croup corticosteroid therapy is now uniformly recommended for croup of all levels of severity. Meta-analyses of 37 trials revealed lower croup scores at 6 hours postmedication, a decrease in return visits (in some cases up to 50% reduction) and a decrease in time spent during the emergency room visit or hospitalization.20 These benets occurred in children with

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studies have shown that 0.15 mg/kg of dexamethasone may be adequate in children with croup, although the severity of illness in those studies was variable.28,29 In contrast, a meta-analysis of several studies reported that a higher initial dose of steroids was associated with clinical improvement in a larger proportion of hospitalized croup patients.21 Steroid treatment for croup is generally thought to be safe, especially when limited to a single dose. The American Academy of Pediatrics (AAP) and the U.S. Food and Drug Administration (FDA) recommend caution when using steroids in children exposed to the varicella virus, although there is controversy about whether inhaled steroids or a single systemic dose can be harmful. Epinephrine Nebulized epinephrine has been well studied and is usually reserved for children with moderate to severe croup, serving as a temporary treatment bridge to allow the steroids to take effect. It likely works by stimulating the alpha-adrenergic receptors in airway mucosa, resulting in vasoconstriction of precapillary arterioles. This decreases hydrostatic pressure, allows uid absorption, and decreases airway edema. Racemic epinephrine, a 1:1 mixture of the levo and dextro isomers of epinephrine, has been used in the United States since 1971. Early trials of 2.25% racemic epinephrine (0.5 mL in 2.5 mL normal saline) administered via intermittent positive pressure breathing showed reduction of croup severity scores.15,30 Later trials revealed that nebulized administration of racemic epinephrine was an equally effective route for treating airway obstruction, improving croup scores within 10 to 30 minutes.31 Nebulization of L-epinephrine (1:1000) diluted in 5 mL of saline provides similar efcacy in children with moderate to severe croup, although the racemic form is most commonly used in the United States.32 Clinical effects last up to 1 to 2 hours, and with the development of rebound tracheal edema, patients may return to their baseline level of distress but rarely worsen.15,33 Repeated doses are often necessary and have been reported to reduce the need for intubation in children with severe croup.34 Prospective studies suggest that patients receiving epinephrine and steroids may be discharged home safely treatment for upper airway obstruction, including croup syndromes. Because the density of helium is one-seventh that of air, heliox decreases turbulence and improves gas ow through high-resistance airways. A 70:30 helium:oxygen mixture of heliox was compared with racemic epinephrine in a small prospective, randomized, double-blind trial in hospitalized children with moderate to severe croup who were already receiving steroids.38 There was no difference in the modied croup score between the two treatment groups. A signicant oxygen requirement (greater than 40%) limits the use of heliox, as does its expense and complexity of setup. It also serves more as a therapeutic bridge because it lacks a direct effect on inamed, edematous airways. Heliox can reduce work of breathing enough to prevent intubation and allow other medications to reach therapeutic peak. Heliox has a lower side effect prole than corticosteroids and epinephrine, however, and may be useful in those children in whom those medications are contraindicated. Other Treatments Children experiencing hypoxia with moderate to severe croup should receive oxygen therapy. Antitussive and decongestant agents have no role in the treatment of croup illnesses. Antibiotics are unnecessary in the treatment of laryngotracheitis and spasmodic croup unless clinical symptoms, laboratory data, or microbiology support the presence of secondary bacterial infection. Antiviral therapy can be considered in cases of inuenza virus infection. CONCLUSIONS AND FUTURE CONSIDERATIONS Croup in its most common form (laryngotracheitis) is a pediatric respiratory illness that provokes anxiety in the patient and their parents because of airway obstruction. Despite anecdotal evidence, cool mist or humidied air

Heliox can reduce work of breathing enough to prevent intubation and allow for other medications to reach therapeutic peak.
from the emergency department after an observation period of 2 to 4 hours, as long as their symptoms have not recurred.35,36 If treatment fails to abolish croup symptoms, or multiple epinephrine doses have been used, admission for clinical observation is warranted. Although nebulized epinephrine is generally safe, one case report describes ventricular tachycardia and myocardial infarction in a previously healthy child with severe croup who received three nebulized treatments within 1 hour.37 Helium Helium-oxygen mixtures (heliox) have been demonstrated to be an effective

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has not been proven to be effective in the treatment of croup. Regardless of the level of illness acuity, corticosteroid therapy (0.6 mg/kg dexamethasone either orally or IM) is now the standard of care. In cases of milder disease, reassurance and close outpatient observation is recommended. Patients with moderate symptoms or those who fail to respond to corticosteroids should be evaluated in an emergency department. There is evidence to support the use of epinephrine for short-term relief of symptoms, and it may be a useful therapeutic bridge until the effect of steroids is realized. In children who appear toxic or in severe respiratory distress, endoscopy, blood work, as well as bacterial and viral cultures, may be useful. Repeated epinephrine doses and inhaled helium-oxygen mixture may help avoid intubation in severe cases. Admission to the ICU, intravenous antibiotics, and intubation may be required to support these children through severe illness. REFERENCES
1. Jardine DS, Martin LD. Specic Diseases of the Respiratory System: Upper Airway. In: Fuhrman BP, Zimmerman J. Pediatric Critical Care. 3rd ed. Philadelphia, PA: Mosby Elsevier; 2006:571-587. 2. Denny FW, Murphy TF, Clyde WA, Collier AM, Henderson FW. Croup: an 11-year study in a pediatric practice. Pediatrics. 1983;71(6):871-876. 3. Segal AO, Crighton EJ, Moineddin R, Mamdani M, Upshur RE. Croup hospitalizations in Ontario: a 14-year time-series analysis. Pediatrics. 2005;116(1):51-55. 4. Marx A, Torok T, Holman R, Clarke M, Anderson L. Pediatric hospitalizations for croup (laryngotracheobronchitis): biennial increases associated with human parainuenza virus 1 epidemics. J Infect Dis. 1997;176(6):1423-1427. 5. van der Hoek L, Sure K, Ihorst G, et al. Human coronavirus NL63 infection is associated with croup. Adv Exp Med Biol. 2006;581:485-491. 6. Calhoun W. Nocturnal asthma. Chest. 2003;123(3 Suppl):399-405. 7. Bjornson CL, Johnson DW. Croup. Lancet. 2008;371(9609):329-339. 8. Theisen CF. Angina epiglottidea anterior: 19. 9. report of three cases. Albany Med Ann. 1900;21:395-405. Shah RK, Roberson DW, Jones DT. Epiglottitis in the hemophilus inuenza type B vaccine era: changing trends. Laryngoscope. 2004;114(3):557-560. Stroud RH, Friedman NR. An update on inammatory disorders of the pediatric airway: epiglottitis, croup, and tracheitis. Amer J Otolaryng. 2001;22(4):268-275. Jackson C. Inuenzal tracheitis. Laryngoscope. 1912;22:130. Jones R, Santos JI, Overall JC. Bacterial tracheitis. JAMA. 1979;242(8):721-726. Bernstein T, Brilli R, Jacobs B. Is bacterial tracheitis changing? A 14-month experience in a pediatric intensive care unit. Clin Infect Dis. 1998;27(3):458-462. Hopkins A, Lahiri T, Salerno R, Heath B. Changing epidemiology of life-threatening upper airway infections: the reemergence of bacterial tracheitis. Pediatrics. 2006;118(4):1418-1421. Westley CR, Cotton EK, Brooks JG. Nebulized racemic epinephrine by IPPB for the treatment of croup: a double-blind study. Am J Dis Child. 1978;132(5):484-487. Guideline for the diagnosis and management of croup. Alberta, ON, Canada: Alberta Medical Association; 2007. Bjornson CL, Johnson DW. Croup treatment update. Pediatr Emerg Care. 2005;21(12):863-873. Moore M, Little P. Humidied air inhalation for treating croup. Cochrane Database Syst Rev, 2006;3:CD002870. Scolnik D, Coates AL, Stephens D, Da Silva Z, Lavine E, Schuh S. Controlled delivery of high vs low humidity vs mist therapy for croup in emergency departments: a randomized controlled trial. JAMA. 2006;295(11):1274-1280. Russell K, Wiebe N, Saenz A, et al. Glucocorticoids for croup. Cochrane Database Syst Rev. 2004;1:CD001955. Kairys SW, Olmstead EN, OConnor GT. Steroid treatment of laryngotracheitis: a metaanalysis of the evidence from randomized trials. Pediatrics. 1989;83(5):683-693. Tibballs J, Shann FA, Landau LI. Placebo-controlled trial of prednisolone in children intubated for croup. Lancet. 1992;340(8822):745-748. Sparrow A, Geelhoed G. Prednisolone versus dexamethasone in croup: a randomized equivalence trial. Arch Dis Child. 2006;91(7):580-583. Rittichier K, Ledwith C. Outpatient treatment of moderate croup with dexamethasone: intramuscular versus oral dosing. Pediatrics. 2000;106(6):1344-1348. Donaldson D, Poleski D, Knipple E, et al. Intramuscular versus oral dexamethasone for the treatment of moderate-to-severe croup: a 26. randomized, double-blind trial. Acad Emerg Med. 2003;10(1):16-21. Geelhoed GC. Budesonide offers no advantage when added to oral dexamethasone in the treatment of croup. Pediatr Emerg Care. 2005;21(6):359-362. Klassen T, Craig W, Moher D, et al. Nebulized budesonide and oral dexamethasone for treatment of croup: a randomized controlled trial. JAMA. 1998;279(20):1629-1632. Geelhoed GC, Macdonald W. Oral dexamethasone in the treatment of croup: 0.15 mg/kg versus 0.3 mg/kg versus 0.6 mg/kg. Pediatr Pulmonol. 1995;20(6):362-368. Chub-Uppakarn S, Sangsupawanich P. A randomized comparison of dexamethasone 0.15 mg/kg versus 0.6 mg/kg for the treatment of moderate to severe croup. Internat J Pediatr Otorhinolaryngol. 2007;71(3):473-477. Taussig LM, Castro O, Beaudry PH, Fox WW, Bureau M. Treatment of laryngotracheobronchitis (croup): use of intermittent positivepressure breathing and racemic epinephrine. Am J Dis Child. 1975;129(7):790-793. Fogel JM, Berg IJ, Gerber MA, Sherter CB. Racemic epinephrine in the treatment of croup: nebulization alone versus nebulization with intermittent positive pressure breathing. J Pediatr. 1982;101(6):1028-1031. Waisman Y, Klein BL, Boenning DA, et al. Prospective randomized double-blind study comparing L-epinephrine and racemic epinephrine aerosols in the treatment of laryngotracheitis (croup). Pediatrics. 1992;89(2):302-306. Kristjansson S, Berg-Kelly K, Winso E. Inhalation of racemic adrenaline in the treatment of mild and moderately severe croup: clinical symptom score and oxygen saturation measurements for evaluation of treatment effects. Acta Paediatrica. 1994;83(11):1156-1160. Cherry JD. Croup. New Eng J Med. 2008;358(4):384-391. Johnson DW, Jacobson S, Edney P, et al. A comparison of nebulized budesonide, intramuscular dexamethasone, and placebo for moderately severe croup. N Engl J Med. 1998;339(8):498-503. Rizos J, DiGravio B, Sehl B, et al. The disposition of children with croup treated with racemic epinephrine and dexamethasone in the emergency department. J Emer Med. 1998;16(4):535-539. Butte M, Nguyen B, Hutchison T, et al. Pediatric myocardial infarction after racemic epinephrine administration. Pediatrics. 1999;104(1):e9. Weber JE, Chudnofsky CR, Younger JG, et al. A randomized comparison of helium-oxygen mixture (Heliox) and racemic epinephrine for the treatment of moderate to severe croup. 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Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.