Metered dose inhalers versus nebulizers for aerosol bronchodilator delivery for adult patients receiving mechanical ventilation in critical care units
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To compare nebulizers to MDIs for bronchodilator delivery for invasively ventilated critically ill adult patients in terms of physiological response and patient outcomes. Subgroup analyses are planned according to other ventilation and bronchodilation strategies, ventilator settings and administration variables.
Background
Description of the condition
Acute respiratory failure is common amongst patients who are hospitalized with an acute exacerbation of their chronic lung disease. Where optimal medical treatment has failed to relieve symptoms, ventilatory support is recommended (Rodriguez‐Roisin 2006). Despite advances in non‐invasive ventilation strategies, a significant proportion of patients still require invasive ventilation to treat their acute exacerbation (Brochard 1995; Plant 2000). In addition to invasive ventilation, inhaled bronchodilators are an essential component of the treatment and management of this patient group (NICE 2004). Short acting beta2‐agonists and ipratropium are widely used to manage symptoms associated with acute exacerbations and are recommended by international guidelines (GOLD 2008).
Description of the intervention
Bronchodilator therapy aims to resolve bronchoconstriction, decrease the work of breathing, potentially relieve dyspnoea (Dhand 2005) and is frequently administered to mechanically ventilated patients (Boucher 1990). Bronchodilators for mechanically ventilated patients may be administered systemically through intravenous infusion,or directly to the lungs through the inhalation of an aerosol (Georgopoulos 2000). There are currently two main methods of delivering aerosol bronchodilation which have been adapted for use in patients receiving mechanical ventilation; nebulizer and metered‐dose inhaler (MDI). Nebulizers deliver bronchodilators to the lower respiratory tract by converting the liquid drug into smaller particle droplets which can then be inhaled. The production of an aerosol may be achieved through the use of compressed gas, ultrasonic sound frequencies or a vibrating mesh or plate (Dhand 2006a). MDIs contain a pressurized mixture of active drug, surfactants, preservatives and propellants. An aerosol is generated through the actuation of the device which results in a high speed release of the suspension from the MDI (Jantz 1999). Aerosol delivery offers several advantages over the systemic route, namely painless delivery of the drug directly to the site of action, rapid onset of drug effect and the resultant reduction in dosage requirements (Dhand 2004; Fink 1999a). As a result, aerosol inhalation is globally recognized as the preferred route of delivery for bronchodilators in chronic lung diseases (GOLD 2008).
Various pharmacological agents with differing modes of action can be deployed for bronchodilation but their overall effect ‐ relaxation of the bronchial smooth muscle ‐ is congruent (Dhand 2006a). Currently, beta2‐agonists, anticholinergics and methylxanthines make up the three main pharmacologic classes of agents used for bronchodilation. Methylxanthines can only be administered via enteral or parenteral routes, whereas beta2‐agonists and anticholinergics are most frequently utilized through inhalation (BNF 2009) and will therefore be the focus of this review.
Several narrative reviews have attempted to address the issue of which is the most appropriate and effective route of administration of bronchodilator therapy to adult patients receiving mechanical ventilation. Current guidelines endorse either mode of delivery.The suggested advantages of MDIs have been identified as ease of administration, increased reliability in dosing, cost effectiveness including personnel time to administer the drug and freedom from contamination risk (Dhand 2006a; Dhand 2007a; Dhand 1996; Fink 1999a; Hess 1991; Hess 2002). Several reviews have concluded that no apparent advantage exists for either MDI or nebulizer if appropriate administration techniques and dose are utilized (Coleman 1996; Dhand 2004; Dhand 2007b; Dhand 2008; Guerin 2008; Jantz 1999; O'Doherty 1997), although the high dose of bronchodilators needed for nebulizer delivery may be associated with a higher degree of cardiovascular instability (Dolovich 2005).
How the intervention might work
The success of any aerosol bronchodilation therapy is dependant on satisfactory amounts of active drug reaching the bronchial tree (Dolovich 2005). Aerosol deposition is known to be affected by a number of factors, with specific considerations associated with patients receiving mechanical ventilation that are not present in the ambulatory demographic. These include ventilator, circuit, drug and patient related factors (Dhand 2004). Device related factors are also present, with choice of equipment, position in the ventilator circuit and timing of drug delivery affecting both nebulizers and MDIs (Fink 1999a).
The efficacy of aerosol drug delivery from nebulizers and MDIs has been shown to be variable in patients receiving mechanical ventilation. Evidence suggests that performance variability is present both in different models of nebulizer (Loffert 1994) and between individual units of the same model (Alvine 1992). The efficacy of bronchodilator delivery from an MDI is also variable, dependent on timing actuation with inspiration (Crogan 1989; Dhand 2003) and rates of inspiratory flow (Fink 1999b). The use of nebulizers for bronchodilator delivery may lead to hypoventilation in mechanically ventilated patients using older ventilator models (Beaty 1989).
Multi‐center survey data on bronchodilator administration practices in mechanically ventilated neonates highlights variations in practice, with 19% of respondent institutions using MDIs at all times,and 43% using nebulizers exclusively (Ballard 2002). Such figures for the adult patient demographic are not available.
Why it is important to do this review
To date, there has not been an international systematic review to determine which method of aerosol bronchodilator delivery system, nebulizer or MDI, is more effective in mechanically ventilated adult patients. This review therefore will attempt to determine which is the most effective delivery system in terms of physiological response and patient outcomes.
Objectives
To compare nebulizers to MDIs for bronchodilator delivery for invasively ventilated critically ill adult patients in terms of physiological response and patient outcomes. Subgroup analyses are planned according to other ventilation and bronchodilation strategies, ventilator settings and administration variables.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomized controlled trials (RCTs), including randomized cross‐over trials where the order of the intervention is randomized, comparing nebulizer and MDI for aerosol bronchodilation in mechanically ventilated adult patients.
Types of participants
We will include adult patients (as defined by the trialists) receiving invasive mechanical ventilation in critical care units. If no definition is available, we will assume the participants as being adult unless identified as paediatric in the studies.
Types of interventions
We will exclude studies in which aerosol bronchodilation agents are delivered via the same MDI or nebulizer device simultaneously with another drug group. Combination administration of bronchodilators of differing drug groups (for example beta2‐agonists and anticholinergics) will be allowed. We will exclude any studies in which bronchodilator agents are administered by any route other than aerosol. Other ventilation and bronchodilation strategies such as heated humidification, use of spacer devices, helium oxygen and nitric oxide mixtures will be allowed if equally distributed between the intervention and control groups. We will also exclude studies where different bronchodilation agents are used between the intervention and control groups.
Types of outcome measures
Primary outcomes
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Reduction in airway resistance ‐ measured as a reduction in additional effective resistance (ΔRrs)
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Patient outcome ‐ mortality during critical care unit admission
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Patient outcome ‐ duration of mechanical ventilation
Secondary outcomes
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Adverse changes to haemodynamic observations
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Reduction in wheezing
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Freedom from contamination
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Quality of life
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Practitioner satisfaction including ease of use and convenience
Search methods for identification of studies
Electronic searches
We will search the current issue of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library) (Appendix 2); OVID MEDLINE (1950 to date) (Appendix 3);OVID EMBASE (1980 to present) (Appendix 4); and CINAHL via EBSCOhost (1982 to date) (Appendix 5).
Searching other resources
We will not limit the search by language or publication status.
We will contact manufacturers of MDIs and nebulizers that have been adapted for use within a ventilator circuit (for example Philips Respironics, Cardinal Health and Trudell Medical) to identify any published, unpublished or ongoing studies which meet the inclusion criteria.
We will review conference proceedings available online for relevant trials (American Thoracic Society International Conference (2006 to present); European Society of Intensive Care Medicine (2003 to present); and the Respiratory Drug Delivery Conference (2000 to present)).
We will screen reference lists within relevant trials to identify any further potential papers worthy of review.
Data collection and analysis
Selection of studies
We will undertake the systematic review using the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).
Two authors (AH and LV) will independently examine the titles and abstracts identified by the search strategy to remove any duplicate records and obviously irrelevant reports. We will retrieve and evaluate the full text versions of potentially relevant studies identified by at least one author. Two authors (AH and LV) will independently assess each study to determine if they meet the eligibility criteria outlined above in the section Criteria for considering studies for this review. We will resolve any disagreements by discussion between the authors (AH and LV), with a further author (FS) acting as arbiter. We will provide details of both included and excluded studies in the respective tables of the review.
Data extraction and management
AH and FS will extract data independently utilising a standardized data extraction form based on Cochrane Anaesthesia Review Group recommendations (see Appendix 1). We will resolve any disagreements by discussion between the authors (AH and FS), with a further author (LV) acting as arbiter. The data extraction form will include the following:
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general information: author(s), title, source, contact address, year of study, country of study, language of publication, year of publication;
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trial characteristics: design (RCT) and risk of bias assessment criteria as outlined below in the section Assessment of risk of bias in included studies;
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participants: baseline characteristics (including other ventilation and bronchodilation strategies outlined above in the section Types of interventions), inclusion and exclusion criteria, sample size and number of patients allocated to each intervention group, co morbidity;
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interventions: detailed description of the comparison devices and administration methods, bronchodilator administered;
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outcomes: primary outcomes ‐ reduction in airway resistance, measured as a reduction in additional effective resistance (ΔRrs); patient outcome including mortality during critical care unit admission and duration of mechanical ventilation. Secondary outcomes ‐ adverse changes to haemodynamic observations; reduction in wheezing; freedom from contamination; quality of life and practitioner satisfaction including ease of use and convenience;
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other: sources of funding, conflicts of interest, unexpected findings.
We will use the statistical package Review Manager software RevMan 5.0, utilizing double data entry with two authors (AH and FS) to control and correct data entry errors.
Assessment of risk of bias in included studies
We will assess the risk of bias of included studies using The Cochrane Collaboration's tool for assessing risk of bias as outlined by Higgins 2008. The standard components in this tool include adequacy of allocation generation, allocation concealment, blinding, completeness of outcome data, possible selective outcome reporting and any other potential sources of bias. Each component will be judged 'Yes' for low risk of bias, 'No' for high risk of bias or 'Unclear'. We will include a 'Risk of bias' table as part of the 'Table of characteristics of included studies' and a 'Risk of bias summary' figure which will detail all of the judgements made for all included studies in the review.
Assessment of risk of bias will be carried out by two authors independently (AH and FS). We will resolve any disagreements by discussion between the authors, with a further author (LV) acting as arbiter.
Measures of treatment effect
We will use the statistical package Review Manager software RevMan 5.0. For dichotomous outcomes, we will calculate the risk ratio (RR). For continuous outcomes, we will calculate a mean difference (MD) or the standardized mean difference (SMD) with a 95% confidence interval (CI) as appropriate.
Unit of analysis issues
Cross‐over trials
Where suitable data are available from cross‐over trials, we will adopt the approach recommended by Elbourne 2002. We will include data using results from paired analyses, where estimates of within patient differences, means and standard errors are either available, can be obtained from the trialists or can be calculated.
Dealing with missing data
Where data are missing, we will contact the original investigators to request the missing data. We intend to perform intention‐to‐treat (ITT) analysis for dichotomous data. For continuous data we will perform ITT analyses if sufficient results are available from included studies. If data are insufficient, we will undertake an available case analysis and consider the potential impact of the missing data in the interpretation of the results of the review (Higgins 2008).
Assessment of heterogeneity
We will assess clinical heterogeneity using a three step approach. We will initially assess graphical depictions of confidence intervals generated by Review Manager software RevMan 5.0 for the amount of overlap present. Statistical heterogeneity is indicated if there is poor overlap of confidence intervals (Higgins 2008). We will explore the presence of heterogeneity formally using the Chi2 statistic and quantify it using the I2 statistic (Higgins 2008). We will consider meta‐analysis if studies are suitably homogenous, in terms of clinical diversity, to provide a meaningful summary.
Assessment of reporting biases
We will generate funnel plots using the mean differences and standard errors for each primary outcome to visually assess the impact of study size on treatment estimates. If more than 10 studies are to be included in a meta‐analysis, we will also use the regression asymmetry test to test for funnel plot asymmetry as described by Egger 1997. Where the intervention effect is measured in terms of odds ratios for binary data, we will test funnel plot asymmetry using the arcsine test proposed by Rücker 2008.
Data synthesis
We will combine data from parallel group and cross‐over trials for meta‐analysis. In case of bias due to carry‐over effect in cross‐over trials, we will incorporate data from the first time period only if the necessary information is available. For cross‐over trials when both time periods are used and no standard deviation of the mean difference is available, we will impute this using the correlation coefficient from other studies. We will calculate this from as many other studies as possible. We will analyse the results using inverse variance meta‐analysis.
We will also meta‐analyse data from parallel group and cross‐over trials separately. If there is a discrepancy between the two we will report the results separately, otherwise the results of the meta‐analyses will be reported together.
We will employ both a fixed‐effect model and a random‐effects model to combine data. If there is discrepancy between the two, we will report results from both models. If there is no discrepancy, we will report the results from the fixed‐effect model if the I2 is less than 50%, and from the random‐effects model if the I2 is equal to or greater than 50%.
Subgroup analysis and investigation of heterogeneity
If adequate data are available relating to other ventilation and bronchodilation strategies such as heated humidification, use of spacer devices, helium oxygen mixtures and nitric oxide mixtures for ventilation, we will conduct subgroup analyses on these groups. We will also conduct subgroup analyses on groups in which similar ventilation settings were used, in which an inhalation chamber was utilized in the administration process or not, and in which it is possible to group these according to their location in the ventilator circuit.
To estimate the impact of differing doses of bronchodilator agents, we will perform a subgroup analysis comparing the intervention effect in trials in which higher doses of bronchodilator were used to trials in which lower doses were administered, if the data available enable such groupings to be made.
Sensitivity analysis
We will perform a sensitivity analysis comparing the intervention effect in trials judged to have a low risk of bias (that is, trials in which all components of The Cochrane Collaboration's tool for assessing risk of bias have been judged as "Yes") to trials which have been judged as having a moderate to high risk of bias (that is, trials in which one or more of the components of The Cochrane Collaboration's tool for assessing risk of bias have been judged as "Unclear" or "No").
We will perform a sensitivity analysis comparing the intervention effect in trials that based the decision to discontinue mechanical ventilation upon pre‐specified standardized criteria within the study compared to studies that based this decision on clinicians' judgements alone. This will be done to estimate the potential for a biased effect when the duration of mechanical ventilation is determined by a subjective judgement.
We will perform a sensitivity analysis comparing the intervention effect in trials that used combination administration of bronchodilators of differing drug groups to studies that administered a single bronchodilator agent. This will provide an estimate of the potential for a biased treatment effect when combination bronchodilator therapy is utilized.
