Humidity has been used routinely to treat croup ever since steam produced by hot baths appeared to alleviate symptoms of croup during the 19th century. “Croup kettles” became popular to achieve relief “...by applying hot fomentations to the throat...and by steam inhalations.”36 Umbrellas and bed sheets were tied over a child’s crib in the fashion of a canopy, and boiling water from a kettle was administered through an opening in the sheets. Not unexpectedly, scald burns were a common adverse effect of this therapy.37 Croup kettles were progressively replaced by cool air mist after the observation that cool night air seemed to be more effective at reducing the symptoms of upper airway obstruction.38 Croup tents were a common therapeutic modality in hospitals until the 1990s. They are now rarely used, as they isolate and separate the child from the caregiver, increasing the child’s anxiety, which then potentiates the symptoms of upper airway obstruction. Humidity, if used, is now delivered in the hospital setting by a “blow-by” flexible tubing hose, which is usually held by a caregiver and aimed towards the child’s face. Discharge instructions also routinely recommend that parents run hot water in the shower and sit with the child in the steam-filled bathroom or in front of a freezer or outdoors for a period of time, if living in a cooler climate.6,39 There are no studies, however, evaluating the effectiveness of this practice.
The postulated benefits of mist therapy include the decreased viscosity of tracheal secretions as well as mucosal cooling and a subsequent reduction in edema.40 Nonetheless, known adverse effects include bronchospasm in children who are prone to airway hyperreactivity, hyponatremia secondary to excessive moisture, and secondary infection by pathogens such as Pseudomonas aeruginosa or fungi.38 Randomized controlled trials with small numbers of patients failed to show improvement after the administration of humidified air by croup tents and blow-by technique, respectively.41,42 One hypothesis to explain the failure to show positive results was that the water particles were not of the correct size to reach the larynx. Scolnik et al designed a randomized controlled trial with 140 patients to try to identify the ideal particle size for laryngeal deposition.43 As explained by the investigators, particles larger than 10 micrometers in diameter deposit in the nose and mouth, whereas particles smaller than 5 micrometers reach the lower airway where they may cause bronchospasm. Therefore, particles that are 5 to 10 micrometers in diameter have the greatest probability of reaching the larynx, making this particle size the most appropriate choice for croup therapy. Despite empirically testing this theory, the investigators were unable to demonstrate any improvement in Westley Croup Score with humidity as compared to placebo. A systematic review and meta-analysis by Moore and Little reviewed the aforementioned randomized controlled trials and concluded that there was insufficient evidence of therapeutic benefit to support the routine use of humidified air in the treatment of croup.40 When pooling the results to perform a meta-analysis, their results were not methodologically strong enough to rule in or out any beneficial effect of humidified air.
Nebulized epinephrine has been thoroughly studied for the treatment of croup.31,44,45 Epinephrine induces vasoconstriction in laryngeal mucosa by stimulating alpha-adrenergic receptors, thus decreasing the symptoms of upper airway narrowing. It also promotes bronchial smooth muscle relaxation and thinning of bronchial secretions by stimulation of beta-adrenergic receptors. Epinephrine comes under 2 different forms: racemic, which is composed of equal parts of L- and D-isomers, and L-epinephrine, which is the drug routinely used in acute situations in concentrations of 1:1000 and 1:10,000.
In 1971, Adair et al first reported the benefits of administration of nebulized epinephrine by intermittent positive-pressure breathing (IPPB) by observing a significant reduction in clinical croup score, although the beneficial effect lasted for less than 2 hours.46 Subsequent trials showed that similar benefits were achieved if racemic epinephrine was administered via IPPB or only nebulized without IPPB.47 Racemic epinephrine was initially used in the treatment of croup because it was thought to cause fewer cardiovascular effects than L-epinephrine. In a study of 66 patients, Waisman et al showed no difference in croup score at 30 minutes when comparing administration of 2.25% racemic epinephrine 0.5 mL diluted in 2.5 mL of saline versus L-epinephrine 1:1000 diluted in 5 mL of saline.48 In addition, L-epinephrine showed a statistically significant longer duration of benefit with a better croup score at 120 minutes as opposed to racemic epinephrine.1,48 Nebulized epinephrine has also been shown to decrease the rate of admission to the hospital and the need for intubation or tracheotomy.1 The rarity of adverse effects makes it a safe drug to give for otherwise healthy children with symptoms of croup.49,50 Butte et al reported 1 case of ventricular tachycardia and myocardial infarction in a child with severe croup who received 3 doses of epinephrine within 1 hour.51 Up to 2 doses of nebulized epinephrine administered every 15 to 20 minutes within the same hour is most likely safe in an otherwise healthy child. Consultation with a pediatric critical care unit for cardiac monitoring should be made if more doses are required.6 If a child continues to exhibit symptoms of stridor and altered level of consciousness after repeated doses of epinephrine, urgent consultation with the ICU, an ENT specialist, and an anesthesiologist is mandated to prepare for further airway management, as this clinical situation may quickly lead to respiratory failure.
A systematic review conducted by Bjornson et al looking at 8 studies (with a total of 225 participants) concluded that nebulized epinephrine may be used to alleviate symptoms of croup in patients with moderate-to-severe presentation and that these symptoms do not tend to worsen after the effect of epinephrine dissipates.1 In the early 1990s, standard ED practice was to hospitalize all patients with a presentation severe enough to require the use of nebulized epinephrine. Since then, several trials have demonstrated that patients treated with nebulized epinephrine and therapeutic doses of corticosteroids may be observed for 2 to 4 hours, and, if they remain stable, they may be safely discharged home.49,52,53
The use of corticosteroids has truly revolutionized the management of croup in the last 30 years. The first trials addressing the role of corticosteroids in the 1950s were unable to show any effect on the severity or length of symptoms of acute viral croup.7,8 Further investigations conducted until the late 1980s consistently demonstrated significant improvement in patients treated with corticosteroids compared to placebo.9-12 The meta-analysis published by Kairys et al in 1989 included 10 studies with a total of 1286 patients and provided the most reliable estimate of the impact of steroid therapy on the morbidity associated with croup.13 Their results showed significant clinical improvement 12 hours and 24 hours posttreatment and a significantly reduced incidence of endotracheal intubation. Super at al confirmed these results in a well-designed randomized controlled trial looking at 29 hospitalized patients.54 The Canadian Pediatric Society published a position statement in 1992 recommending the use of steroid therapy as a single dose of dexamethasone (Decadron ®) 0.6 mg/kg IV or intramuscular (IM) in children admitted to hospital with severe croup.5
The recently updated Cochrane review on glucocorticoids looked at 24 studies involving 2878 patients and found that treatment with glucocorticoids is effective in improving symptoms in children as early as 6 hours and up to 12 hours after treatment, and that it significantly reduces hospital admissions and return visits to EDs.2 When compared to children with croup who received placebo, children who received steroid therapy spent significantly less time in the ED or hospital.
The benefits of glucocorticoid therapy are not limited to children with moderate croup. A large multicenter randomized controlled trial involving 720 children demonstrated multiple benefits in treating children with mild symptoms of croup with 0.6 mg/kg of oral dexamethasone as compared to placebo.55 The treated children had half the rate of revisits to a healthcare practitioner and lost less sleep in 48 hours, and their parents experienced less stress in the 24 hours following treatment.
Trials comparing oral, parenteral, and nebulized corticosteroids have demonstrated similar efficacy and superiority of the different treatment groups to placebo.55-60 Oral dexamethasone has become the preferred choice of treatment because it is less expensive than budesonide (Pulmicort®) and is easier to administer to children with croup. The parenteral-injectable preparation (which is more palatable and less diluted than the oral preparation) can be given in a smaller volume mixed with syrup, is rarely vomited, and is recommended for use in children.6,57 Nonetheless, budesonide 2.5 mg by nebulization may be safely substituted for dexamethasone if a child cannot tolerate the oral administration.56,57 Combining inhaled corticosteroids with oral dexamethasone does not confer any added benefit when looking at length of hospital stay, croup score, revisit rate, or admission to the hospital.57,61 To the authors' knowledge, there is no study, to date, looking at the benefit of multiple doses of corticosteroids in children with croup.
While most of the larger studies on glucocorticoids in croup have been done using 0.6 mg/kg of oral dexamethasone, there is ongoing debate about the optimal dosing regimen, particularly in mild croup. A randomized controlled trial by Geelhoed with 120 enrolled patients tried to identify the minimum effective dose of dexamethasone.62 Initially, 60 patients were randomized to receive 0.6 versus 0.3 mg/kg dexamethasone. A second group of 60 patients was randomized to receive 0.3 versus 0.15 mg/kg of dexamethasone. There were no significant differences in outcome detected between the 3 treatment dosages; however, given the small number of subjects in the study (only 30 were treated with 0.15 mg/kg of dexamethasone), the study was underpowered to demonstrate the equivalence of the lower dose of dexamethasone with the more-studied 0.6 mg/kg dose. Another small study of 99 subjects with croup found similar outcomes in patients randomized to 1 of 3 orally administered treatment regimens: 0.15 mg/kg of dexamethasone, 0.6 mg/kg dexamethasone, and 1 mg/kg of prednisolone (a dose of 1 mg/kg of prednisolone is equivalent to 0.15 mg/kg of dexamethasone).58 A retrospective descriptive report by Dobrovoljac and Geelhoed describes the experience at their center in the 11 years since they adopted the 0.15 mg/kg oral dose of dexamethasone.63 While these studies demonstrate that the 0.15 mg/kg dose of dexamethasone is beneficial in reducing the symptoms and the admission rate in children with mild croup, there is not enough evidence to conclude that this dose is equivalent to the more rigorously studied dose of 0.6 mg/kg. A large randomized controlled trial is currently underway to answer the question of the optimal dose of dexamethasone in the treatment of croup.64,65
Heliox, a mixture of helium and oxygen, is a gas with similar viscosity and a sevenfold lower density than air. It was successfully pioneered in the 1930s for the treatment of asthma and upper airway obstruction in adults and children.66 It is thought to reduce flow resistance by creating a less turbulent flow, thus decreasing the work of breathing and improving gas exchange by delivering an increased tidal volume. Several trials have demonstrated beneficial effect in children with croup, but they are mostly anecdotal case reports or small case series.67-69 A systematic review conducted by the Cochrane Collaboration identified 2 small studies that both found a greater improvement in croup score in the helium-oxygen group, but this change did not reach statistical significance.70,71 Thus, they concluded that there is a lack of evidence to determine whether heliox inhalation is beneficial in the treatment of croup. An ongoing randomized controlled trial that aims to enroll 142 participants plans to compare changes in croup score as well as need for additional therapy, admission to hospital, intubation rate, length of stay, and use of subsequent health services between patients treated with heliox and patients breathing room air.72
Analgesics, Antipyretics, Antitussives, And Antibiotics
While the authors were not able to identify any controlled trials that specifically addressed the use of antipyretics or analgesics in children with croup, there are no known contraindications to their use for relief of fever and pain. Anecdotally, reducing pyrexia often has the added benefit of reducing the respiratory rate, and thus the work of breathing. There is, however, no rationale to support the use of antitussives in the treatment of croup. Furthermore, the average age of patients affected with croup is < 2 years, and both the United States Food and Drug Administration and Health Canada have issued strong recommendations stating that use of antitussive medication should be discouraged in children < 6 years of age.73-75
As croup is most likely the result of viral infection, antibiotic therapy is generally not indicated. Antibiotics should be reserved for cases of suspected bacterial tracheitis or laryngotracheobronchopneumonitis. Since the rate of secondary bacterial infection in croup is estimated to be < 1 case in 1000, there is no rationale for using antibiotics for prophylaxis in viral croup.6