Heliox for croup in children
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this review is to examine the effect of heliox on relieving symptoms and distress determined by a croup score or clinical assessment variables through comparisons with placebo or active treatment(s) in children with croup.
Background
Description of the condition
Croup is an acute clinical syndrome, primarily used to describe laryngotracheobronchitis. It is characterised by a barking cough, hoarseness, varying degrees of inspiratory stridor and chest wall retractions, and is usually preceded by a one to three day period of upper respiratory tract infection type symptoms. Croup commonly affects children up to the age of six years, with the highest incidence in the second year of life (Denny 1983; Rittichier 2000). A seasonal variation in the occurrence of croup, with a peak in the autumn and winter, has been reported (Denny 1983; Segal 2005).
Croup is thought to be triggered by a viral infection, most commonly by human parainfluenza virus (HPIV), particularly HPIV type 1, and less so by influenza virus, respiratory syncytial virus, rhinovirus, adenovirus, enteroviruses and Mycoplasma pneumoniae (M. pneumoniae) (Denny 1983; Marx 1997; Segal 2005). Viral invasion of the subglottic mucosa causes inflammation and oedema, leading to narrowing of the upper airway. As this narrowing progresses, the pressure gradient necessary to move air through the upper airway becomes greater, leading to an increased effort in breathing. This may result in fatigue of the respiratory muscles and subsequently to respiratory failure, requiring emergency intubation. Systemic or nebulised corticosteroids are the current treatment , supplemented in more severe cases by nebulised epinephrine and oxygen. Corticosteroids have been shown to improve symptoms of croup but it takes time for their full effect to be achieved (Russell 2005). Nebulised budesonide has been shown to have a beneficial effect as early as two hours after administration (Fitzgerald 1996; Klassen 1998), but in the meantime, the child's condition remains at risk of deterioration and of developing respiratory failure, thereby requiring emergency intubation and ventilation.
Description of the intervention
Helium is a biologically inert, colourless, odourless and non‐combustible gas and was first discovered in 1868 by Jannsen and Lockyer. It has a similar viscosity and a substantial sevenfold lower density than air, and when combined with oxygen results in heliox, a gas mixture with an up to threefold (heliox 80/20) lower density than air (Papamoschou 1995). The density of a gas mixture is proportional to the Reynolds number (Re), a dimensionless ratio of the inertial to the viscous force, and will thus have an effect on the type of gas flow present in the airway. It is known that turbulent flow occurs when Re > 3000 and laminar flow occurs when Re < 2000 (Glauser 1969). Pathological narrowing of the airway, as seen in croup, will lead to increased turbulence and higher gas flow resistance, resulting in an increased breathing effort. In theory, a gas of low density, such as heliox, should create a less turbulent or even laminar flow, by reducing the Reynolds number, leading to a decrease in resistance to gas flow and work of breathing (Houck 1990). Heliox is also believed to improve gas exchange, due to a delivery of increased tidal volume as a result of lowering the resistive forces within the airway (Katz 2001; Katz 2003).
In the early 1930's Barach pioneered the successful use of a helium‐oxygen mixture (heliox) in the treatment of adults and children with asthma and upper airway obstruction (Barach 1935; Barach 1936). However, it was not until the 1980's that helium‐oxygen mixtures regained popularity, possibly due to the rising mortality from asthma (Robin 1988). This led to an increase in clinical trials assessing the effect of heliox in the management of acute upper and lower airway obstructive disorders in children (Cambonie 2006; Grosz 2001; Hollman 1998; Martinon‐Torres 2002). The use of helium‐oxygen mixtures in acute paediatric asthma reached conflicting conclusions (Carter 1996; Kim 2005; Kudukis 1997; Rivera 2006). In children with croup the treatment with heliox had demonstrated a beneficial effect, albeit in small numbers (Beckmann 2000; DiCecco 2004; Duncan 1979; Nelson 1982). It remains unclear whether there is any evidence to support the implementation of heliox for croup in clinical practice.
Objectives
The objective of this review is to examine the effect of heliox on relieving symptoms and distress determined by a croup score or clinical assessment variables through comparisons with placebo or active treatment(s) in children with croup.
Methods
Criteria for considering studies for this review
Types of studies
Randomised and quasi‐randomised controlled trials.
Types of participants
Children with the clinical diagnosis of croup or laryngotracheobronchitis will be included. Other conditions of upper airway obstruction such as epiglottitis, foreign body inhalation or peritonsillar abscess will be excluded.
Types of interventions
Studies will be included where the effect of heliox is compared to placebo or any active treatment and where similar routes of administration are used for both groups.
Types of outcome measures
Primary outcomes
A change in croup score.
Secondary outcomes
Efficacy of heliox on respiratory rate, oxygen requirements, heart rate, hospital admission rates, need for intubation and adverse effects.
Studies that fail to meet all four inclusion criteria will be excluded.
Search methods for identification of studies
Electronic searches
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library latest issue); MEDLINE (1950 to present); EMBASE (1974 to present); and CINAHL (1982 to present).
MEDLINE and CENTRAL will be searched using the following terms. The search terms will be adapted for EMBASE and CINAHL.
MEDLINE
(Croup[MeSH] OR Croup.mp. OR laryngotracheobronchitis.mp. OR laryngo‐tracheo‐bronchitis.mp.)
AND
(Helium[MeSH] OR Helium.mp. OR Helium oxygen.mp. OR Heliox.mp.)
AND
(child[MeSH] OR child$.mp. OR infant[MeSH] OR infant$.mp. OR pediatric$.mp. OR paediatric$.mp.)
There will be no language or publication restrictions. We will search the National Research Register, Clinical Trials.gov and Current Controlled Trials for any ongoing and unpublished trials.
Searching other resources
We will also search the references of review articles and all included studies to find other potentially eligible studies. We will also contact the authors of the included studies and leading medical gas suppliers, such as British Oxygen Company (BOC), Linde Gas and Praxair, to enquire whether they know of any published or unpublished trials.
Data collection and analysis
Selection of studies
Two review authors (CV and TC) will independently assess the titles and abstracts of all studies identified by our search strategy. All potentially relevant papers will be reviewed in full, to determine if they fulfil the inclusion criteria. If no agreement can be reached, a third independent review author will be consulted until at least two review authors have reached a consensus. A pre‐designed data sheet will be used to apply the inclusion criteria.
Data extraction and management
The two review authors (CV and TC) will independently extract data on the number and types of participants, allocation concealment, use of blinding, type of intervention, outcomes, and loss to follow up. Standard data extraction forms will be used. Disagreement will be resolved by discussion or by consultation with an independent review author.
Assessment of risk of bias in included studies
Both review authors will independently assess the quality of trials by using two empirically derived scoring methods. The Schulz scale (Schulz 1995) will be used to describe concealment of allocation as adequate, unclear or inadequate. The validated five‐point Jadad scale (Jadad 1996) will be used to assess randomisation (zero to two points), double blinding (zero to two points) and the handling of withdrawals or dropouts (zero to one point). Disagreement will be resolved by discussion or by consultation with a third independent review author.
Unit of analysis issues
Continuous outcomes, such as change in croup score, will be expressed as mean difference (MD) with 95% confidence intervals (CI) or, if studies used different croup score, as standardised mean differences (SMD) with 95% CI. Dichotomous variables, such as hospital admission or need for intubation, will be presented as odds ratio (OR) with 95% CI.
Assessment of heterogeneity
Heterogeneity amongst the studies will be assessed by calculating the P‐value of the chi‐squared test and the I‐squared (I2) statistic. If the P‐value is greater than 0.1 and I2 less than 50%, a fixed‐effect model will be used. If the P‐value is less than 0.1 and I2 less than 50%, a random‐effects model will be used, to account for unexplained heterogeneity among studies. If I2 is greater than 50% then no meta‐analysis will be conducted, as this indicates significant heterogeneity between the trials. Adverse events will be presented using descriptive statistics and where possible, an OR with 95% CI will be calculated.
Sensitivity analysis
If a sufficient number of trials can be identified, a sensitivity analysis will be performed, using different helium‐oxygen mixtures (80/20 versus 70/30), methods of heliox administration (face mask versus tent house) and methodological quality (Jadad score of 4 or 5 versus 3 or less).
