Inhaler devices and global warming: Flawed arguments

Mark L Levy, Locum general practitioner, Clinical Lead NRAD (2011-2014);Aerosol Drug ManagementImprovement Team (ADMIT), www.inhalers4u.org

Other Contributors:

Darragh Murnane
Peter J Barnes
Mark Sanders
Louise Fleming
Jane Scullion
Chris Corrigan
Omar S Usmani
November 07, 2019

Mark L Levy,1,9 Darragh Murnane2, Peter J Barnes,3,9 Mark Sanders,4 Louise Fleming,5 Jane Scullion,6,9 Chris Corrigan,7,9 Omar S Usmani8,9

1. Locum general practitioner, Clinical Lead NRAD (2011-2014)
2. King’s College London Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences ; School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Hertfordshire
3. National Heart & Lung Institute, Imperial College, London
4. Clement Clarke international Ltd (CCI) and founder of online museum of inhaler devices, www.inhalatorium.com.
5. Imperial College, London and the Royal Brompton and Harefield, NHS Foundation Trust
6. University Hospitals of Leicester
7. King’s College London Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences
8. Imperial College London & Royal Brompton Hospital
9. Aerosol Drug ManagementImprovement Team (ADMIT), www.inhalers4u.org

In an attempt to address issues related to global warming contributed to by the use of pressurised, metered-dose inhalers (pMDIs), Wilkinson et al (1) have succeeded in generating a great deal of negative, potentially harmful media interest for patients who currently rely on these devices. They analysed the potential impact of switching therapy from pMDIs to dry powder inhalers (DPIs) in terms of both changes in greenhouse gas emissions and costs to the UK National Health Service based on prescribing information in England alone. This strategy was apparently devised in a vacuum, without regard to implications for threats to patient wellbeing and safety as a consequence of their being deprived of access to pMDI therapy for obstructive airways disease (asthma and COPD). Physicians are obliged to consider many factors when selecting the most appropriate inhaler device for patients other than the cost to the health care system if they wish the treatment to be effective; (2) these issues were not mentioned in this paper which, in our view, was heavily biased in favour of DPIs, which are seldom appropriate for use in young children, children, the elderly and infirm and those with considerable, irreversible airways obstruction. (3) In addition many patients rely on pMDIs for rapid relief of symptoms.

Their study addressed two possible switching scenarios in the United Kingdom (UK): (i) from pMDIs to currently prescribed DPIs, and (ii) to the cheapest available ‘equivalent’ DPIs based on drug content but not the instrinsic characteristics of the devices. While we agree with one of their conclusions that, with immediate effect, smaller volume HFA134a inhalers (e.g. Salamol) should be prioritised over larger volume or HFA227ea-containing inhalers (e.g. Ventolin) we have major reservations about their remaining assertions, and in particular their conclusion that switching patients’ medication from pMDIs to the cheapest available equivalent DPIs would result in large carbon savings, while ignoring the possible consequences for loss of disease control and consequent morbidity and mortality from obstructive airways diseases such as asthma, which might result in considerable patient harm.

In addition to potential harm from loss of disease control, the burden of suffering and anxiety to patients from this sort of approach to reporting is potentially further amplified by the “guilt factor” already instilled by recent headlines in the media prompted by the report, such as “Asthma inhalers are as bad for the environment as a 180-mile car journey”, “Asthma sufferers should switch to “green” inhalers to help the environment and save millions for the NHS” and “Some asthma inhalers are as bad for the environment as eating meat”. These messages clearly have the potential to stigmatise patients with asthma and COPD for taking their essential medication, and there are anecdotal reports of children, many of whom benefit particularly from pMDI therapy, not wanting to be seen using their inhalers in public. We know of no other situation in the National Health Service where patients are stigmatised for using licensed and approved medications, and the situation will doubtless further impact on the issue of compliance with therapy, which if undermined is another potential threat to their well-being, as well as impacting on morbidity and mortality. (4) Conversely, there was no mention in this commentary, or indeed in the media, that correct delivery of inhaled drugs by an inhaler device which can be used efficiently and reliably by individual patients improves symptoms and quality of life and reduces morbidity, mortality and hospital acute care costs. (5, 6) (3, 7-9)

Further to this last issue, there was correspondingly no mention or consideration of the potential consequences where switching “goes wrong”, resulting in disease destabilisation and the associated “carbon cost” of unnecessary emergency and hospital inpatient management (10); Goulet et al (11) estimated that the carbon footprint of a single bronchodilator dose administered with an electric nebuliser is a considerable 0.0294-0.0477 kg CO¬2-eq. Moorfields Eye Hospital estimate that the carbon footprint of a single patient visit is between 8-10 kg CO2-eq per patient, per visit. It is difficult to assess the current carbon footprint of medical air/oxygen supply, however the European Industry Gas Association lifecycle appraisal framework (document 167/11) identified that the majority of the carbon footprint for liquid gases arises during production and distribution, not during the use of those gases by the end-user. Therefore, unlike the propellant in pMDIs, it is difficult to reduce the carbon footprint of therapeutic gases simply by altering the in-use conditions. (12) One supplier of compressed gases, Linde, in their Corporate Responsibility report of 2017, reported that 5.7 million tonnes of CO2 were produced during liquid gas production, or 52% of their Scope 1 Direct emissions. So the footprint for air therapies is also likely to be significant.

Finally, Wilkinson’s comparison between the UK (70%) and Sweden (10%) pMDI use fails to account for potential differences in disease therapy indications in both countries. For example, both NICE (13) and SIGN/BTS (14) guidelines advocate the use of short-acting, beta-agonist (SABA) use as first line therapy for asthma, which may account for the high levels of prescribing in England. While they acknowledge that they have no idea what disease(s) are being treated in their analysis of prescribing in England, Wilkinson and colleagues have assumed that all patients can be summarily switched from pMDIs to DPIs irrespective of their age, the nature and severity of their disease, their ability to use DPIs efficiently (not all patients can use DPIs efficiently whereas all patients can use pMDIs efficiently if well instructed, with a spacer device), or their satisfaction or preference for the switched device which is a another known factor influencing therapeutic outcome.(15)They have also failed to discuss the fact that not all DPI drugs have clinically equivalent efficacy compared with that of the pMDIs currently in use. It is well known that poor inhaler technique and poor disease outcome are closely related and both NICE (13) and SIGN/BTS (14) guidelines emphasise the necessity of and carefully verifying the ability of individual patients to use inhalers efficiently before prescribing, yet the authors have omitted to address the cost effectiveness and possible carbon footprint of the workload involved in switching and training patients. Furthermore, there was no mention of the chaos familiar to many GPs when patients’ inhalers are switched to “cheaper equivalents” by Clinical Commissioning Group (CCG) employed pharmacists without face to face education and checking technique. Patients become confused when given an unfamiliar device, typically stop using it and in some cases require urgent health care as a consequence. What then often happens is that their GPs will reinstate the original medication. Perhaps the authors could have cited some of the disadvantages arising from switches of medication on non-medical grounds without the patient’s consent, with deterioration of disease control and increased health care utilization. (16) (5) Indeed, data show that stable patients on pMDI maintenance treatment for asthma (17) and COPD (18) achieve better healthcare outcomes than the same drug in a DPI.

While the authors do mention the use of maintenance and reliever regimes (MART and SMART) they do not emphasise the implications, for patient welfare or global warming, of the concerns raised by over usage of short-acting beta-agonists (SABA) as a result of poor education and/or poor overall disease control in patients with asthma. (19, 20) Clearly, simply switching from one SABA to another in this situation will not alter the considerable risk of poor health outcomes, including asthma deaths. (21-23) A strategy is required to eliminate the over usage of SABA by every patient. Combinations of inhaled corticosteroids and long-acting beta-agonists such as formoterol taken “as needed” for the management of mild/moderate asthma are now licensed in five countries based on evidence that they are safer than SABA, (24-27) and it seems very likely that this strategy will be implemented worldwide in the near future, and that it will prove safer and clinically more cost effective. As most of these combination drugs are currently delivered in DPIs this will have an impact on global warming and manufacturers will need to focus on reducing the effect of these on the carbon footprint.

There are considerable shortcomings in carbon footprint modelling in the Wilkinson et al paper. There is relatively scant justification for the carbon footprint of the DPI inhalers included as comparators in this study: in fact, all of the DPIs included in their modelling are assumed to possess the same global warming potential (GWP) as the Ellipta and Diskus devices of ~1kg CO2-eq per device. This is despite the widely different structures and contents of many DPI devices, in terms of parts and plastics involved in their manufacture. In their evidence and subsequent discussion on usage, Wilkinson et al also failed to mention the differential effects on the environment related to the stages of manufacture of pMDIs and DPIs. For example, in the case of GlaxoSmithKline products, the majority of the CO2 emissions from this company’s DPI devices arise from the production of the plastic container and the active pharmaceutical ingredients (APIs) fluticasone propionate (FP) and salmeterol xinafoate (SX), whereas the primary contributors with pMDIs are emissions resulting from actual usage of the devices, and at the end of the life of the device when it is disposed of. (28)
Furthermore it is not apparent that the lactose monohydrate included in DPI formulations is ever included in the Wilkinson or other models of GWP. Lactose monohydrate is a product of the dairy industry contributing considerably to the carbon footprint: for example one study (29) reported that the total carbon required to produce Whey Powder from raw milk is 13.1 kg CO2-eq per kg of Whey Powder product, a value apparently similar to other, international GWP estimates of Whey Powder production (in the USA). Dairy farming is well known to be carbon intensive, not least due to methane production by the herd, but also from the transport and processing of the Whey Powder products
Wilkinson’s approach of simply addressing the GWP of Inhaled Products is misleading; preferably the methodology of Jolliet et al(30) of a holistic Life Cycle Assessment should also be made. This was performed by Jeswani and Azapagic (31)for pMDIs made with HFA134, HFA227, HFA152 and a GSK dry powder inhaler Diskus device. Although the DPI outperformed the HFA134 and HFA227 inhaled devices for Global Warming Potential as expected, however human toxicity, marine eutrophication and fossil depletion are all worse for DPIs than HFA-based pMDIs, when the holistic life-cycle analysis is undertaken. Thus it may be the case that GWP is better for DPIs, but the full long-term environmental effects were actually worse for eight out of fourteen environmental impact metrics for DPIs than pMDIs. It was also noted by the authors (31) that once HFA152a switchover has been made, that pMDIs will have an equivalent carbon footprint to DPIs, but have improved environmental impact profile than DPIs.

While we are concerned about the environment and the effect humans are having on global warming, we are concerned that this article lacks balance in its discussion and conclusions and puts patients with asthma at risk of an attack through inappropriately stopping or switching inhalers. In our view, asthma and COPD management should focus on prescribing appropriate inhaler devices and ancillary equipment such as spacers that individual patients are able to use efficiently after appropriate education and in the context of management plans agreed with appropriately trained health care professionals. These factors should take priority. (32) There may be suitable opportunities to consider the “greenest” alternatives when patients commence therapy or alter it for reasons of poor disease control or inadequate inhaler technique.

Bibliography

1. Wilkinson AJK, Braggins R, Steinbach I, Smith J. Costs of switching to low global warming potential inhalers. An economic and carbon footprint analysis of NHS prescription data in England. BMJ Open. 2019;9.
2. Bjermer L. The Importance of Continuity in Inhaler Device Choice for Asthma and Chronic Obstructive Pulmonary Disease. Respiration. 2014;88(4):346-52.
3. Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. European respiratory Journal. 2002;19(2):246-51.
4. Why asthma still kills: the National Review of Asthma Deaths (NRAD) Confidential Enquiry report: Royal College of Physicians. London; 2014 [Available from: http://www.rcplondon.ac.uk/sites/default/files/why-asthma-still-kills-fu....
5. Melani AS, Paleari D. Maintaining Control of Chronic Obstructive Airway Disease: Adherence to Inhaled Therapy and Risks and Benefits of Switching Devices. COPD: Journal of Chronic Obstructive Pulmonary Disease. 2016;13(2):241-50.
6. Melani AS, Bonavia M, Cilenti V, Cinti C, Lodi M, Martucci P, et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respiratory Medicine. 2011;105(6):930-8.
7. Giraud V, Allaert FA. Improved asthma control with breath-actuated pressurized Metered Dose Inhaler (pMDI): The SYSTER survey. European Review for Medical and Pharmacological Sciences. 2009;13(5):323-30.
8. Molimard M, Gros VL. Impact of patient-related factors on asthma control. Journal of Asthma. 2008;45(2):109-13.
9. Haughney J, Price D, Kaplan A, Chrystyn H, Horne R, May N, et al. Achieving asthma control in practice: Understanding the reasons for poor control. Respiratory Medicine. 2008;102(12):1681-93.
10. Moorfields Hospital Foundation Trust. Sustainable Development Management Plan 2017 [Available from: https://www.moorfields.nhs.uk/sites/default/files/Item%2009%20Sustainabl....
11. Goulet B, Olson L, Mayer BK. A Comparative Life Cycle Assessment between a Metered Dose Inhaler and Electric Nebulizer. Sustainability. 2017;9(10):1725.
12. EUROPEAN INDUSTRIAL GASES ASSOCIATION AISBL. METHODOLOGY TO ESTABLISH A “PRODUCT CARBON FOOTPRINT: IGC Doc 167/11/E 2007 [Available from: https://www.eiga.eu/index.php?eID=dumpFile&t=f&f=2580&token=c87996bc2e26....
13. Commissioned by the National Institute for Health and Care Excellence (NICE). Asthma: diagnosis, monitoring and chronic asthma management. NICE guideline [NG80] 2017 [Available from: https://www.nice.org.uk/guidance/ng80
14. Scottish Intercollegiate Guideline Network (SIGN), the British Thoracic society (BTS). British guideline on the management of asthma 2019 [Available from: https://www.sign.ac.uk/sign-158-british-guideline-on-the-management-of-a....
15. Plaza V, Giner J, Calle M, Rytila P, Campo C, Ribo P, et al. Impact of patient satisfaction with his or her inhaler on adherence and asthma control. Allergy Asthma Proc. 2018;39(6):437-44.
16. Björnsdóttir US, Gizurarson S, Sabale U. Potential negative consequences of non-consented switch of inhaled medications and devices in asthma patients. International Journal of Clinical Practice. 2013;67(9):904-10.
17. Price D, Roche N, Christian Virchow J, Burden A, Ali M, Chisholm A, et al. Device type and real-world effectiveness of asthma combination therapy: An observational study. Respiratory Medicine. 2011;105(10):1457-66.
18. Jones R, Martin J, Thomas V, Skinner D, Marshall J, Stagno d'Alcontres M, et al. The comparative effectiveness of initiating fluticasone/salmeterol combination therapy via pMDI versus DPI in reducing exacerbations and treatment escalation in COPD: a UK database study. Int J Chron Obstruct Pulmon Dis. 2017;12:2445-54.
19. The Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA).2019. Available from: http://www.ginasthma.org.
20. Reddel HK, FitzGerald JM, Bateman ED, Bacharier LB, Becker A, Brusselle G, et al. GINA 2019: a fundamental change in asthma management: Treatment of asthma with short-acting bronchodilators alone is no longer recommended for adults and adolescents 2019 [updated Jun. 2019/06/30:[Available from: https://erj.ersjournals.com/content/53/6/1901046.long.
21. Suissa S, Ernst P, Boivin JF, Horwitz RI, Habbick B, Cockroft D, et al. A cohort analysis of excess mortality in asthma and the use of inhaled beta-agonists. Am J Respir Crit Care Med. 1994;149(3 Pt 1):604-10.
22. Suissa S, Blais L, Ernst P. Patterns of increasing beta-2-agonist use and the risk of fatal or near-fatal asthma. European Respiratory Journal. 1994;7(9):1602-9.
23. Reddel HK, Ampon RD, Sawyer SM, Peters MJ. Risks associated with managing asthma without a preventer: urgent healthcare, poor asthma control and over-the-counter reliever use in a cross-sectional population survey. BMJ Open. 2017;7.
24. Beasley R, Holliday M, Reddel HK, Braithwaite I, Ebmeier S, Hancox RJ, et al. Controlled Trial of Budesonide-Formoterol as Needed for Mild Asthma. N Engl J Med. 2019;380(21):2020-30.
25. Hardy J, Baggott C, Fingleton J, Reddel HK, Hancox RJ, Harwood M, et al. Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial. The Lancet. 2019;394(10202):919-28.
26. O’Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zhong N, Keen C, et al. Inhaled Combined Budesonide–Formoterol as Needed in Mild Asthma. New England Journal of Medicine. 2018;378(20):1865-76.
27. Bateman ED, Reddel HK, O’Byrne PM, Barnes PJ, Zhong N, Keen C, et al. As-Needed Budesonide–Formoterol versus Maintenance Budesonide in Mild Asthma. New England Journal of Medicine. 2018;378(20):1877-87.
28. Carbon Trust. GlaxoSmithKline PLC. Product Carbon Footprint Certification Summary Report 2014 [Available from: https://networks.sustainablehealthcare.org.uk/sites/default/files/media/....
29. Finnegan W, Goggins J, Zhan X. Assessing the environmental impact of the dairy processing industry in the Republic of Ireland. Journal of Dairy Research. 2018;85:1-4.
30. Jolliet O, Margni M, Charles R, Humbert S, Payet J, Rebitzer G, et al. IMPACT 2002+: a new life cycle assessment methodology. Int J Life Cycle Assess 8:324-330. The International Journal of Life Cycle Assessment. 2003;8:324-30.
31. Jeswani HK, Azapagic A. Life cycle environmental impacts of inhalers. Journal of Cleaner Production. 2019;237:117733.
32. Usmani OS, Scullion J, Keeley D. Our planet or our patients-is the sky the limit for inhaler choice? Lancet Respir Med. 2019;7(1):11-3.

Conflict of Interest

MLL Reports : consultancy /advisory board fees from National Services for Health Improvement, Clement Clarke International ,AstraZeneca, Orion,Trudell, Boeringer Ingelheim, Conzorcio Futuro In Ricerca, Novartis Pharmaceuticals, GLaxo Smith Klein , TEVA. Speaker fees from Teva, AstraZeneca, Chiesi, Orion, Menarini, Travel reimbursement for attending meetings from GINA, outside the submitted work. DM reports: Director of Fluid Pharmaceuticals, Deputy Director of EPSRC Centre for Doctoral Training in Aerosol Science, has received research funding or support from Astra Zeneca, Bespak, Cheisi, Clement Clarke International, GlaxoSmithKline, HarroHoffliger, Intertek Melbourn, Teva, Team Consulting, Malvern Panalytical, Zeiss, 3M Ltd., has received consultancy fees, speaker’s fees or hospitality from Adare Pharmaceuticals, DDL/Aerosol Society, Inhalation Asia, MedPharm Ltd. Talipharma Ltd., AstraZeneca, RDD. PB reports: Research funding from AstraZeneca and Boehringer-Ingelheim; scientific advisory boards/consultancies from AstraZeneca, Boehringer-Ingelheim, Novartis, Pieris, speaker fees from AstraZeneca Boehringer-Ingelheim, Chiesi, Menarini, Novartis, Teva. MS reports: CCI has received funding payments in respect of inhaler training development from an Innovate UK grant awarded to Clin-e-cal. CCI has supplied inhaler training tools to GSK, Astra Zeneca, Boehringer Ingelheim, Teva, Menarini, Mundipharma, Napp, Chiesi, Novartis, Orion and Mylan. LF is an Asthma UK Senior Clinical Fellow. She reports fees for expert consultation and speakers fees from Astra Zeneca, GSK, Novartis, Teva, Boehringer Ingelheim, Respiri and Sanofi paid direct to her institution and outside of the submitted work JS: Director of Education for UKIG, ADMIT member I have received support or honoraria from Association of Respiratory Nurse Specialists, AstraZeneca, Boehringer Ingelheim, Chiesi, MIMS, Napp Pharmaceuticals, Mundipharma, Pfizer, Novartis, Primary Care Respiratory Society, NIP, & Haymarket Medical CC reports no conflicts. OSU has received industry to academic funding from Boehringer Ingelheim, Chiesi, Edmond Pharma, GlaxoSmithKline, and Mundipharma International, and has received consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Edmond Pharma, GlaxoSmithKline, NAPP, Novartis, Mundipharma International, Pearl Therapeutics, Roche, Sandoz, Takeda, Trudell Medical, UCB, and Vectura.