Inhaled bronchodilators for acute chest syndrome in people with sickle cell disease

Abstract

Background

Bronchodilators are used to treat bronchial hyper‐responsiveness in asthma. Bronchial hyper‐responsiveness may be a component of acute chest syndrome in people with sickle cell disease. Therefore, bronchodilators may be useful in the treatment of acute chest syndrome. This is an update of a previously published Cochrane Review.

Objectives

The aim of the review is to determine whether the use of inhaled, short‐acting bronchodilators for acute chest syndrome reduces morbidity and mortality in people with sickle cell disease and to assess whether this treatment causes adverse effects.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional searches were carried out on MEDLINE (1966 to 2004) and Embase (1981 to 2004) and ongoing trial registries (28 September 2022).

Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 25 July 2022.

Selection criteria

Randomised or quasi‐randomised controlled trials. Trials using quasi‐randomisation methods will be included in future updates of this review if there is sufficient evidence that the treatment and control groups are similar at baseline.

Data collection and analysis

We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease.

Main results

We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease.

Authors' conclusions

If bronchial hyper‐responsiveness is an important component of some episodes of acute chest syndrome in people with sickle cell disease, the use of inhaled bronchodilators may be indicated. There is need for a well‐designed, adequately‐powered randomised controlled trial to assess the benefits and risks of the addition of inhaled bronchodilators to established therapies for acute chest syndrome in people with sickle cell disease.

Plain language summary

Inhaled drugs for opening up the airways in cases of acute chest syndrome in people with sickle cell disease

Review question

Can inhaled, short‐acting bronchodilators for acute chest syndrome reduce illness and mortality in people with sickle cell disease and does this treatment cause adverse effects? 

Background

Sickle cell disease is an inherited blood disorder. People with sickle cell disease often suffer from acute chest syndrome. Acute chest syndrome can cause fever, coughing, chest pain and shortness of breath and can be life‐threatening. Often, people with sickle cell disease and acute chest syndrome also wheeze. Wheezing suggests that airways are narrowed, as with asthma. Bronchodilators are drugs which relax the muscles in the airways, so they open up to make breathing easier. They are used in this way for asthma, so may be of similar use in acute chest syndrome. This is an update of a previously published Cochrane Review.

Search date

The evidence is current to: 25 July 2022.

Study characteristics

We found no trials to show the effects of these drugs for this condition.

Key results

Research needs to assess the benefits and risks of using inhaled bronchodilators for acute chest syndrome in people with sickle cell disease.

Background

Description of the condition

Sickle cell disease (SCD) is a group of genetic haemoglobin disorders with multicentric origins in sub‐Saharan Africa and the Indian subcontinent. Population mobility has spread the disorders through Europe, Asia and the Americas. Homozygous sickle cell (SS) disease is the most common of all haemoglobin disorders, with 230,000 new cases per year in sub‐Saharan Africa, a region that accounts for 70% of the worldwide prevalence (Weatherall 2001; WHO 1993). Significant morbidity and premature death may result from SS disease with average life expectancy estimated at between 42 and 53 years for men and between 48 and 58 years for women (Platt 1994; Wierenga 2001).

Acute chest syndrome is defined as the onset of pulmonary symptoms accompanied by a new infiltrate on chest radiograph in a person with SCD. Fever is the most frequent symptom, with cough, chest pain, shortness of breath and pain also being common. In the North American National Acute Chest Syndrome Study, wheezing was documented in a quarter of all episodes, and pulmonary function testing during some episodes suggested airways narrowing (Vichinsky 2000).

Acute chest syndrome is one of the most common causes of illness and death in people with SCD. North American data suggest that 50% of children with SS disease have at least one episode of acute chest syndrome (ACS) by 10 years of age (Gill 1995). As a cause of hospital admission in people with SCD, ACS is second only to painful crisis and is the most common cause of premature death (Castro 1994; Gray 1991; Thomas 1982). The aetiology of ACS is diverse including infection, pulmonary fat embolism, infarction, sequestration and pulmonary embolism (Vichinsky 2000). Although asthma has been shown to be associated with recurrent ACS, the role played by bronchial hyper‐responsiveness (BHR) is currently unclear (Knight‐Madden 2005).

Description of the intervention

Bronchial hyper‐responsiveness may be more common in people with SCD than in the general population. In one study, cold air or bronchodilator challenge showed a positive response in 83% of people with SS disease known to have asthma and 64% of those with no history of asthma (Leong 1997). However, other studies suggest that asthma prevalence may be unaffected by coincidental SCD (Bayoumi 1997; Savoy 1988; Sofowora 1970). A case report suggests that ACS may be more difficult to manage in those with severe asthma (Perin 1983) and a clinical response to albuterol inhalations may assist in the treatment of ACS (Handelsman 1991).

Short‐acting inhaled bronchodilators are used to bring prompt symptomatic relief in the treatment of BHR (Barnes 2000). This class of drugs includes beta‐adrenergic receptor agonists such as albuterol and terbutaline and anti‐cholinergic agents such as ipratropium bromide. Albuterol acts within minutes and its effect lasts a maximum of six to eight hours. The most commonly used anti‐cholinergic agent, ipratropium bromide, acts within 15 minutes and its effect lasts from four to six hours. These drugs are effectively administered by metered dose inhaler or nebuliser. The usefulness of bronchodilators in ACS in SCD has not been reviewed before.

While nitric oxide may cause bronchodilation, this is not the primary effect that is sought when it is used, which are the intravascular effects. Therefore, this intervention is not eligible for this review and is considered in another Cochrane Review (Al Hajeri 2008).

Current treatment modalities

It is often impossible to rule out infection thus making antibiotic use important. Due to the frequent involvement of atypical bacteria, appropriate coverage is suggested, but studies have not been conducted to determine the relative efficacies of different antibiotic regimens (Knight 1999; Vichinsky 2000).

How the intervention might work

In the North American Acute Chest Syndrome Study, bronchodilators were used in 61% of the participants, and in 20% of these participants, bronchodilators had a positive effect (defined as an increase of 15% in forced expiratory volume in one second) (Vichinsky 2000). During episodes of ACS characterised by wheezing or chest tightness, or both, and with evidence of BHR, bronchodilators may improve pulmonary function and bring symptomatic relief.

Why it is important to do this review

The routine use of bronchodilators in ACS will add to the cost of care. Also, commonly used bronchodilators can have side effects such as tachycardia, nervousness and hyperactivity and, in one reported case, myocardial infarction (Corso 2005). For these reasons, it is important to have evidence of the beneficial effects of bronchodilators in ACS before recommendations for use are applied uniformly.

Methylxanthines, for example theophylline, are not used primarily as bronchodilators. Long‐acting beta‐agonists are used as prophylaxis rather than in acute management and have long half‐lives. These are beyond the scope of this review. In this review we will examine the usefulness of inhaled bronchodilators in ACS.

This review is an update of a previously published Cochrane Review (Knight‐Madden 2003; Knight‐Madden 2012; Knight‐Madden 2014; Knight‐Madden 2016).

Objectives

The aim of the review is to determine whether the use of inhaled, short‐acting bronchodilators for acute chest syndrome reduces morbidity and mortality in people with sickle cell disease, and to assess whether this treatment causes adverse effects.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised or quasi‐randomised controlled trials. We will include trials, which use quasi‐randomised methods such as alternation, if there is sufficient evidence that the treatment and control groups were similar at baseline.

Types of participants

Eligible participants are people with one of four sickle cell disease (SCD) genotypes (SS, SC, S‐β+‐thalassaemia and S‐β0‐thalassaemia) of all ages and both sexes, who have had an episode of acute chest syndrome (ACS) (defined as the onset of pulmonary signs or symptoms accompanied by a new infiltrate on chest radiograph). The diagnosis of SCD must be proven by electrophoresis and sickle solubility test, with family studies or DNA (deoxyribonucleic acid) tests as appropriate.

Types of interventions

We will compare the acute use of inhaled short‐acting inhaled bronchodilators during an episode of ACS compared to an alternative treatment or no treatment.

Types of outcome measures

We planned to group outcome data into those measured during an episode of ACS, within one month, between one and six months, and between six months and one year. If trials reported outcome data at other time periods, we would have considered examining these as well.

Primary outcomes

1. Mortality.

   1. All causes of mortality.

   2. Mortality with confirmed ACS.

2. Pulmonary function as measured by peak flow, forced vital capacity and forced expiratory flow in one minute.

3. Adverse events.

Secondary outcomes

1. Need for blood transfusion.

2. Duration of oxygen supplementation.

3. Duration of hospital admission.

4. Dyspnoea scores.

5. High dependency and intensive care unit admissions.

6. Occurrence of stroke.

7. Changes in measures of oxygenation (saturation, blood gases).

Search methods for identification of studies

We searched for all relevant published and unpublished trials without restrictions on language, year or publication status.

Electronic searches

We identified relevant trials from the Group's Haemoglobinopathies Trials Register using the terms: (sickle cell OR (haemoglobinopathies AND general)):kw AND acute chest syndrome:kw.

The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library) and weekly searches of MEDLINE. Unpublished work is identified by searching the abstract books of five major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Public Health Agency Annual Scientific Meeting (formerly the Caribbean Health Research Council Meeting); and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group's website.

Date of the most recent search of the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 25 July 2022.

We performed an additional search using MEDLINE (1966 to February 2004) and Embase (1981 to February 2004). For the full search strategy, please see the appendix attached to this review (Appendix 1).

We also searched the following clinical trials registries: 

1. US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov; and 

2. the WHO International Clinical Trials Registry Platform (ICTRP). 

For the full search strategies, please refer to the relevant appendix (Appendix 2). Date of the most recent search: 28 September 2022.

Searching other resources

The electronic searches found no eligible trials, but we had planned to search the bibliographic references of all retrieved literature for additional reports of trials. We would then contact lead authors of published work for their knowledge of other trials. We also planned to obtain full reports from authors where trials have been published in abstract form or presented at meetings.

Data collection and analysis

We planned to undertake the following methods, but we did not identify any potentially eligible trials. If we find trials for future updates of this review, we will conduct the review according to the following methods.

Selection of studies

We will screen the trials found by the initial search of all the databases and reference lists to identify papers with potential relevance to the review. We will seek the full text of selected articles (translated into English where required), and select trials for inclusion using our defined eligibility criteria. We will not be blinded to authors and journal. We plan to resolve disagreements, should they occur, by discussion and if necessary the involvement of a third party. We will assess our level of agreement on inclusion of selected articles using the kappa measure of agreement (Armitage 1994).

Data extraction and management

We plan to independently extract the data from the selected trials using a standard form, to verify numeric calculations when possible, and confirm data when necessary.

Assessment of risk of bias in included studies

We will independently assess the risk of bias of the trials and resolve any disagreements by discussion. For each included trial we will assess six specific features: sequence generation; allocation concealment; blinding; incomplete outcome data; selective outcome reporting; and 'other issues'. We will use the Cochrane risk of bias assessment tool to summarise and judge each feature as low risk, high risk, or unclear risk of bias (Higgins 2017).

For each included trial, we will report the numbers of participants with missing data and any reasons given for these missing data. We will also report on whether the investigators performed and adequately reported a sample‐size calculation, and whether they used and fully described an intention‐to‐treat (ITT) analysis.

Measures of treatment effect

For the dichotomous outcome variables of each individual trial (mortality, adverse events, need for blood transfusion, high dependency and intensive care unit admissions and occurrence of stroke), we will calculate the summary weighted odds ratios and 95% confidence intervals (CIs) (fixed‐effect model). For continuous outcome variables (pulmonary function, duration of oxygen supplementation, duration of hospital admission, dyspnoea scores and changes in measures of oxygenation), we will calculate the mean difference when outcomes are measured in a standard way across trials, or standardised mean difference when outcomes are conceptually the same but measured in different ways, along with corresponding 95% CIs. We will assess the potential impact of missing outcome data as we interpret our results. For all analyses we will use Cochrane's statistical package (Review Manager 2020).

Unit of analysis issues

For cross‐over trials, we will calculate the mean treatment differences where possible and enter these using the fixed‐effect generic inverse variance (GIV) analysis in Review Manager (RevMan), to provide summary weighted differences and 95% CIs (Review Manager 2020). In cross‐over trials, if we believe there is a carryover effect which will outlast any washout period included in the trial, we will include only data from the first arm in the meta‐analysis (Elbourne 2002).

Dealing with missing data

Our primary endpoints are dichotomous (mortality, adverse events) and continuous (pulmonary function). For all endpoints with missing data, we will use available‐case analysis. We will assess the effect of this analysis choice by sensitivity analysis, and we will also assess the risk of bias resulting from incomplete outcome data as part of our general assessment of bias. For missing summary measures, we will request further information from the primary investigators where possible.

Assessment of heterogeneity

We will describe any heterogeneity between the trial results and test this to see if it reached statistical significance using the Chi² test. We will consider heterogeneity to be significant when the P value is less than 0.10 (Higgins 2021). We also plan to use the I² statistic and to categorise heterogeneity using the levels suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2021):

1. 0% to 40%: might not be important;

2. 30% to 60%: may represent moderate heterogeneity;

3. 50% to 90%: may represent substantial heterogeneity;

4. 75% to 100%: considerable heterogeneity.

We will also consider the magnitude and direction of the effects contributing to any heterogeneity found (Deeks 2021).

Assessment of reporting biases

We plan to construct a funnel display of effect size to test for the possible presence of publication bias in our population of trials.

Data synthesis

We will analyse data using a fixed‐effect model. However, we will use the random‐effects model if there are concerns about statistical heterogeneity.

Subgroup analysis and investigation of heterogeneity

We plan to conduct limited a priori subgroup analyses for the known baseline heterogeneity between genotypical clinical courses. We will examine outcome measures in two genotype groups: 'severe genotypes' (SS and S‐β0) and 'mild genotypes' (SC and S‐β+). If we find heterogeneity we will use limited post hoc subgroup analyses in an attempt to identify reasons for this variation.

Sensitivity analysis

If we identify heterogeneity between the included trials, we will perform sensitivity analyses based on risk of bias, and publication status of the trials. For our dichotomous endpoints, we will investigate our choice of available‐case analysis by re‐analysing using ITT with a selected number of outcome data imputation methods:

1. assuming that all missing participants experienced the event;

2. assuming that all missing participants did not experience the event;

3. imputing outcome data according to the event rate observed in the control group.

Summary of findings and assessment of the certainty of the evidence

We plan to use the GRADE approach to create summary of findings tables as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2021). We plan to use this approach to rate the certainty of the evidence as 'high', 'moderate', 'low', or 'very low' using the five GRADE considerations.

1. Risk of bias: serious or very serious.

2. Inconsistency: serious or very serious.

3. Indirectness: serious or very serious.

4. Imprecision: serious or very serious.

5. Publication bias: likely or very likely.

We will include the following outcomes in each summary of findings table.

1. All causes of mortality.

2. Mortality with confirmed ACS.

3. Pulmonary function as measured by forced expiratory flow in one minute.

4. Adverse events.

5. Need for blood transfusion.

6. Duration of oxygen supplementation.

7. Duration of hospital admission.

Results

Description of studies

Results of the search

We identified a total of 87 references through the searches of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register and a further seven from searches of online trials registers; however, all were discarded on title alone and none were eligible for inclusion in any section of the review (Figure 1).

1.

Study flow diagram.

Included studies

We identified no trials for inclusion in this review.

Excluded studies

We identified no trials that were eligible for this section of the review.

Risk of bias in included studies

We found no trials that were eligible for inclusion in this review.

Effects of interventions

We found no trials that were eligible for inclusion in this review.

Discussion

Summary of main results

We have found no appropriate trials to clarify the role of bronchoconstriction and bronchial hyper‐responsiveness (BHR) in acute chest syndrome (ACS) in people with sickle cell disease (SCD).

Overall completeness and applicability of evidence

We found no trials eligible for inclusion in this review.

Quality of the evidence

We found no trials eligible for inclusion in this review.

Potential biases in the review process

We are not aware of any potential biases in the review process.

Agreements and disagreements with other studies or reviews

We have found no appropriate trials to clarify the role of bronchoconstriction and BHR in ACS, and there are conflicting observational reports on the possibly increased prevalence of baseline BHR in people with SCD (Koumbourlis 2001; Leong 1997). Some episodes of ACS are characterised by BHR (Vichinsky 2000). Inhaled bronchodilators predominately work by modulating activity of receptors of the autonomic nervous system leading to airway smooth muscle relaxation, which relieves bronchospasm. The need for a therapeutic trial of inhaled bronchodilator use in people with ACS has been suggested (Vichinsky 2000).

Authors' conclusions

Implications for practice.

We did not identify any randomised controlled trials examining the use of inhaled bronchodilators in acute chest syndrome (ACS) in people with sickle cell disease (SCD) for inclusion in this review. The research evidence on which to base clinical decisions is therefore limited to case reports, and other less robust evidence.

Until adequate data become available, clinicians should be guided by the history, clinical examination and investigations. Inhaled bronchodilators have few significant side effects and are useful in asthma and chronic obstructive airways disease because bronchoconstriction and bronchial hyper‐responsiveness (BHR) play an important role in the pathophysiology of these diseases (Barnes 2000). It is likely that bronchodilators will be helpful in those with ACS who have a history of asthma and in those who demonstrate wheezing or reversible obstructive airways disease during the episode of ACS (Vichinsky 2000).

Clinicians in centres which do not have pulmonary function equipment available, will need to balance the undefined possible benefits against the possible risks of treatment and the additional costs incurred. The additional cost of care that will result from routine use of inhaled bronchodilators cannot be ignored in low and lower‐middle income countries, which carry most of the worldwide SCD burden.

Implications for research.

There is need for a well‐designed, adequately‐powered randomised controlled trial to assess the benefits and risks of the addition of inhaled bronchodilators to established therapies for ACS in people with SCD.

What's new

Date	Event	Description
29 September 2022	New citation required but conclusions have not changed	Minor changes have been made throughout the review, but conclusions have not changed.
29 September 2022	New search has been performed	A search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register identified 46 potentially‐eligible references which were assessed and disregarded as not relevant. A search of ClinicalTrials.gov identified seven potentially‐relevant references, which were all disregarded on title alone. A new section on methods for a summary of findings table has been added to the review.

History

Protocol first published: Issue 3, 2002
Review first published: Issue 3, 2003

Date	Event	Description
20 September 2016	New search has been performed	A search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register identified 10 potentially eligible references, none of which were eligible for any section of the review.
20 September 2016	New citation required but conclusions have not changed	The update contains minor changes throughout the text.
1 August 2014	New search has been performed	A search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register identified 18 potentially relevant references, none of which were eligible for inclusion in the review.
1 August 2014	New citation required but conclusions have not changed	Minor changes have been made throughout the review.
25 May 2012	New citation required but conclusions have not changed	Minor changes have been made throughout the review.
25 May 2012	New search has been performed	A search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register identified two potentially eligible trials, neither of which were eligible for inclusion within the review.
20 September 2010	Amended	Contact details updated.
16 April 2010	New search has been performed	A search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register did not identify any trials potentially eligible for inclusion in the review.
31 July 2008	New search has been performed	A search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register did not identify any trials potentially eligible for inclusion in the review.
31 July 2008	Amended	Converted to new review format. A new plain language summary has been written in line with latest guidance from The Cochrane Collaboration. Parts of the methods section has been re‐worded. The methods sections on 'Assessment of risk of bias in included studies', 'Assessment of heterogeneity', and 'Sensitivity analysis' have been updated. The methods sections on 'Unit of analysis issues' and 'Dealing with missing data' have been added. Four additions have been made to 'Other references'.
1 November 2006	New search has been performed	The search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register found no potentially eligible trials for inclusion in the review. The 'Methods of review' section has been updated.
1 April 2005	New search has been performed	The search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register found no potentially eligible trials for inclusion within the review. The 'Background' section was updated with additional references added to the review.
1 April 2004	New search has been performed	The search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register found no potentially eligible trials for inclusion in the review.

Appendices

Appendix 1. Search strategy using OVID interface

1 exp hemoglobinopathies/
2 sickle.tw.
3 (hemoglobin ss or hemoglobin sc or hemoglobin c).ti,ab.
4 (haemoglobin ss or haemoglobin sc or haemoglobin c).ti,ab.
5 meniscocytosis.tw.
6 hemoglobinopath$.tw.
7 haemoglobinopath$.tw.
8 drepanocyt$.tw.
9 thalassemia.tw.
10 thalassaemia.tw.
11 "acute chest".ti,ab.
12 asthma.ti,ab.
13 'chronic obstructive airways disease'.ti,ab.
14 bronchodilator$.ti,ab.
15 ALBUTEROL/
16 salbutamol.mp.
17 TERBUTALINE/
18 Ipratropium/
19 or/ 1‐10
20 or/ 11‐18
21 19 and 20
22 limit 21 to human

Appendix 2. Search strategies ‐ trial registries

Registry	Search terms	Date of latest search
ClinicalTrials.gov	Advanced Search   Condition or Disease: Sickle Cell Disease Other terms:acute chest syndrome Study type: Interventional Studies (Clinical Trials) Study Results: All Studies Intervention/treatment: Bronchodilator agent	28 September 2022
WHO ICTRP	Condition: sickle cell disease Intervention: bronchodilator Recruitment status: ALL	28 September 2022

Differences between protocol and review

A new heading has been added to the methods section ‐ 'Summary of findings and assessment of the certainty of the evidence' as well as information on how we will present these tables in future updates of this review (if trials are included).

Contributions of authors

This review was conceived by Dr Jennifer Knight‐Madden.

Dr Knight‐Madden, Professor Hambleton and the Cochrane Cystic Fibrosis and Genetics Disorders Group conducted searches for relevant trials.

Dr Knight‐Madden and Professor Hambleton planned to screen, appraise and abstract data for the review.

For future updates, Dr Knight‐Madden and Professor Hambleton will perform data entry and data interpretation, with advice from the Cochrane Cystic Fibrosis and Genetics Disorders Group.

Dr Knight‐Madden and Professor Hambleton have jointly contributed to review writing and subsequent updates.

Dr Knight‐Madden acts as the guarantor of the review.

Sources of support

Internal sources

• No sources of support provided

External sources

• National Institute for Health and Care Research (NIHR), UK

  This systematic review was supported by the NIHR, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group.

Declarations of interest

Jennifer Knight‐Madden declares no known potential conflict of interest.

Ian Hambleton declares no known potential conflict of interest.

New search for studies and content updated (no change to conclusions)