An evaluation of physiotherapy-led inhalation testing in chronic respiratory disease at a tertiary centre

Introduction

Inhaled medications are an integral part of the long-term treatment and management for patients with chronic respiratory disease and are associated with improved patient health outcomes through lower respiratory exacerbation rates (Steinfort & Steinfort 2007), improved spirometry and reduced microbial burden (Kellet & Robert 2011). A trial dose is recommended for patients starting a new antibiotic therapy, or mucoactive agent, due to the risk of bronchoconstriction (Wark et al. 2005; Quon et al. 2014), however the evidence is rated poorly in all guidelines with previous study heterogeneity for bronchiectasis (Pasteur et al. 2010). Bronchoconstriction and symptomatic events during treatment with these medications is minimal across different chronic respiratory diseases (Bathoorn et al. 2007; Brodt et al. 2014).

A literature search specifically reviewing the need for an inhaled therapy trial found only one study by Dennis et al. (2018) which demonstrated that for patients with various respiratory conditions including cystic fibrosis (CF), non-CF bronchiectasis and asthma, a pre-trial FEV₁ predicted >55% was associated with passing the trial. The authors showed that by excluding these patients it would reduce the need to test by 83% over the five-year study period. The study was conducted in a single centre and further research is required to understand potential risk factors. Taube et al. (2001) also found that patients with more severe chronic obstructive pulmonary disease (COPD) (FEV₁% pred 42 ± 9.5) had more stark reactions to 3% hypertonic saline compared to 0.9% saline with added histamine release. The low baseline FEV₁% predicted in this study also reflects findings reported by Dennis et al. (2018) in terms of highlighting those patients that may be more at risk of bronchoconstriction. In selecting patients dependent on their risk factors, it has the potential to reduce hospital appointment time and allow early implementation of treatment. Reducing the number of trials required in all settings would also provide more time to manage disease-specific physiotherapy issues.

The aims of the project therefore were to:

1. Identify the failure rate of inhaled therapy trials in the chronic respiratory cohort seen at St. Bartholomew’s Respiratory Medicine and Cystic Fibrosis services.

2. Predict risk factors associated with trial outcome to establish those who could avoid a trial due to low risk stratification

Methods and materials

Project design

A service evaluation was completed that utilised retrospective data collection and analysis of inhaled therapy trial results from September 2017 until September 2019. Data was collected for all adult respiratory patients with chronic respiratory disease at a tertiary hospital by two senior physiotherapists. The justification for employing a retrospective review was due to:

1 Consent had been obtained from patients as part of their assessment as part of their standard care for the completion of the trial and collection of the measures.

2 Data is routinely recorded and available due to the high level of documentation standards around inhaled therapy trials.

The sample included in the evaluation was reflective of the St. Bartholomew’s adult chronic respiratory disease patient cohort which include the conditions of COPD, asthma, bronchiectasis and CF. All patients who undertook a trial during the timescales for the evaluation were analysed. Those patients that were excluded were not eligible to have a trial based on local guidance, that is that the individuals were unable to perform spirometry, and/or had presented in mid-exacerbation of their condition.

In a previously published study, a power calculation had identified a minimum of 194 patients was required (p <0.05) (Dennis et al. 2018); this figure was therefore used as the minimum number of subjects that would be required for adequate power for statistical analysis. No ethics committee approval was required as it was identified as an evaluation of service and it was registered within the trust’s research and development department: Bart’s Health CEU reference ID 9676. The study was not collaborative and did not involve another organisation.

Inhaled therapy trial protocol

Inhaled therapy trials were carried out following the St. Bartholomew’s standard operating procedure (Appendix 1), as part of either an inpatient admission or outpatient appointment, for all new inhaled therapies, or inhaled therapies restarted after more than a twelve-month break. Anthropometric measurements were documented at the time of the trial for all patients, including sex, age, ethnicity. Results were represented using means and standard deviations (SD). Spirometry (FEV₁) was recorded along with monitoring of symptoms including the BORG Scale of Perceived Breathlessness. FEV₁% predicted was calculated using the Global Lung Function Initiative 2012 formula (Quanjer et al. 2012). A bronchodilator was administered pre-trial based on clinical examination. The trial was completed by a competent respiratory physiotherapist requiring >6 months post-qualification experience that included completion of a respiratory rotation. The trial process usually takes up to 2 hours in total. All measures were repeated immediately after the trial, including FEV₁ and the change was calculated using a percentage change equation (Equation 1).

A failure of the inhalation therapy trial was classified as a FEV₁ drop greater than 15% from initial FEV₁ (British Thoracic Society 1997). Patients that failed an inhalation therapy trial were treated with salbutamol and assessed by the physiotherapist, with all measurements repeated; and the protocol was that examination by a medic would be requested if the patient did not return to base line observations and spirometry within 20 minutes of completing the trial.

Statistical analysis

Statistical analysis was performed using SPSS version 25.0 (Chicago, IL, USA); characteristic differences between success and failure groups were identified using independent t tests (p values documented).

Univariate regression analysis was performed for spirometry (FEV₁ and FEV₁% predicted), age, gender, inhaled therapy and disease group as a precursor for multivariate regression models.  FEV₁% predicted was grouped into 5% increments from 40% to 60% to ascertain a risk point for conducting an inhaled therapy trial.

Results

During the two-year review period 204 patients performed an inhalation therapy trial at St. Bartholomew’s Hospital, with 106 as inpatients and 98 as outpatients (Table 1). The sample consisted of 114 females (55.9%). Mean age of 43.4 years (SD 19.4), FEV₁ of 1.65L (litres) (SD 0.86) and a FEV₁% predicted 52.3% (SD 21.9). Inhaled therapy trials were completed for antibiotic therapy (n = 132, 64.7%), then hypertonic saline (n = 64, 31.4%) and rhDNase (n = 8, 3.9%).

The failure rate was calculated as ten patients (4.9%) of the total inhaled therapy trials, with a statistically significant difference identified in age (42.6 years versus 57.8 years p = -0.027), FEV₁ (1.68L versus 1.06L p = 0.026) and FEV₁% predicted (53.18% versus 35.5% p = 0.012) between patients that passed compared to those that failed respectively. The regression analysis showed that those with an FEV₁ predicted <55% were statistically more likely to fail p = 0.005, R² = 0.039 (Table 2). There was no statistically significant difference found between gender, ethnicity, type of nebulised drug and outcome. Patients with CF were more likely to pass the inhaled therapy trial compared to patients without CF (98.0% versus 83.0% respectively) however this was not statistically significant (p = 0.06).

There were six patients who failed the trial due to being unable to tolerate the medication. This was due to medication taste or symptoms of coughing or tight chest. All six had an acceptable change in FEV₁. Two of these patients had an FEV₁ predicted >55% and these were for patients with bronchiectasis trialling hypertonic saline 6% and had a small change in FEV₁ post trial (-2%). There were five trials with a significant drop in FEV₁ with no symptoms experienced by the patient, all had an FEV₁ less than 55% predicted.

Table 1: Summary of outcomes (mean and standard deviation).

SD = standard deviation; CF = cystic fibrosis; HTS = hypertonic saline; FEV₁ = forced expiratory volume in 1 second.

Table 2: Grouped FEV₁% predicted.

FEV₁ = forced expiratory volume in 1 second; R² = R-squared.

Discussion

Overall this evaluation of service shows that the failure rate for inhaled medication trials was very low in a well powered cohort of patients. The regression analysis demonstrated that FEV₁ predicted <55% is the best point of statistical fit at which risk increases for participants undertaking a nebulised therapy trial. This aligns with the limited but available recent literature on the topic (Dennis et al. 2018). This work further increases the overall diversity of the current published dataset and includes participants from a further specialist tertiary centre.

A proposed new cut-off of FEV₁ predicted <55% would be safe based on the data analysed: patients who were non-symptomatic but had a FEV₁ drop >15% all started with a baseline FEV₁ predicted <55%. If the guidance of a FEV₁ predicted <55% cut off is used, this group of patients would have still been identified for trials. The six patients who were symptomatic did not drop their FEV₁ below 15% after a trial and refused to continue with the nebulised medication based on the symptoms experienced. These patients would have been identified as not tolerating the medication, irrespective as to whether a trial was completed or not.

Reasons why a lower lung function might result in a patient being more likely to fail the trial are that firstly, less of a reduction in millilitres (ml) is required to meet the 15% drop in spirometry cut off for failure, for example for a patient with 1l as a baseline FEV₁ would need to drop 15ml after a trial in contrast with an individual with a 3L baseline FEV₁ would need to drop 45ml. This means a lower ml drop is required for a greater % change. Secondly, doing repeated forced expiratory manoeuvres can cause fatigue (European Lung Foundation 2020). This may be more likely to affect those with a lower baseline FEV₁ due to increased disease severity causing fatigue, potentially predisposing these patients to a significant FEV₁ drop. Patients with a low baseline FEV₁ who during a trial are asymptomatic with no physiological changes but have a signification FEV₁ drop may be denied an inhaled medication that would benefit them long term.

Whilst a medication trial itself is important to ascertain whether an individual can tolerate a new inhaled medication, the spirometry measurements do not always show useful information relating to a person’s tolerability; the test does not replicate a real-life nebuliser routine. Airway clearance techniques are advocated after mucoactive agents and prior to nebulising an antibiotic to ensure maximum deposition. A more useful assessment of tolerability than spirometry could be the reaction of the individual during a realistic, combined physiotherapy and nebuliser session, with symptomatic and physiological measurements such as auscultation, respiratory rate and heart rate being recorded.

The results identify potential patient groups that are ‘low risk’ for inhaled therapy trial failures; if inhalation trials were only carried out on those patients with FEV₁ predicted <55% and not on rhDNase there would have been a 45.6% reduction in the number of trials completed over a two year period. Dennis et al. (2018) also showed no fails for rhDNase trials with patients with an FEV₁ predicted >55%. This suggests this is a very low risk of bronchoconstriction from inhaled therapy that does not require a full inhalation trial. As previously mentioned, a change to clinical practice to exclude rhDNase trials would reduce the burden of hospital appointments and streamline physiotherapy. Outpatient appointments are known to consume time and money for patients, and for those individuals with chronic respiratory disease it has been reported to have reduced adherence and attendance due to treatment burden (Sabaté 2003).

Whilst age initially presented as a statistically significant factor for trial failure, further multi-variate analysis showed non-significance. The positive correlation between the two negated age as a significant factor. There was also no statistical significance between failure rates for the different inhaled medications. Six patients failed due to medication intolerance but had an acceptable change in FEV₁; four of these had an FEV₁ predicted <55% with the other two trials being for bronchiectasis patients for 6% hypertonic saline. From the data from Dennis et al. (2018), inhaled therapy trials for patients with bronchiectasis with hypertonic saline were both associated with a higher risk for failing. This may be because hypertonic saline works through increased sputum mobilisation and ion content of the lung airway surface liquid to replenish the sol layer and accelerate mucus clearance (Robinson et al. 1997). The rate of change of osmolarity is thought to cause airway hyper responsiveness (Taube et al. 2001) and can cause airway narrowing (Elkins & Bye 2011). Hypertonic saline is generally administered prior to or during airway clearance (O’Neill et al. 2017), and so the inhaled test dose is not a veritable representation of physiotherapy treatment. Further work could consider the different groups of non-CF bronchiectasis and effect on nebuliser trial outcomes.

As this evaluation was completed to support service delivery at a local level, the limitation is that these results are also from a single centre. The findings however are supportive and reflective of the current body of evidence reviewing inhaled medication trials. Another limitation of the data is that the antibiotic group was not sub-divided meaning no resolution is available on which antibiotic inhaled therapy medications are better tolerated compared to others.

Conclusions

The findings of the evaluation suggest a low failure rate (4.9%) overall to inhalation therapy trials, with a risk factor for failure being identified as FEV₁ predicted <55%, which correlates with the current evidence base. Appropriate patient selection, using FEV₁ predicted <55% as the risk point, could significantly reduce the number of inhaled therapy trials being performed. The growing evidence base reporting a low failure rate and highlighting lower risk patient groups could help to support a review of national guidelines of inhalation trials.