Is oxygen an effective treatment option to alleviate the symptoms of breathlessness for patients dying with COVID-19 and what are the potential harms?

May 7, 2020

Matthew Allsop, Lucy Ziegler, Yu Fu, Sarah Rudd*, Michael I Bennett

On behalf of the Oxford COVID-19 Evidence Service Team
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences
University of Oxford

Academic Unit of Palliative Care, Leeds Institute of Health Sciences
University of Leeds

*North Bristol NHS Trust

Correspondence to m.j.allsop@leeds.ac.uk


VERDICT

  • There is no existing research evidence involving patients with COVID-19 to directly inform the use of oxygen therapy in the management of breathlessness for dying patients.
  • For patients with COVID-19, there is no evidence of benefit of oxygen therapy in the absence of hypoxemia. There may be a role for its use to wean patients with COVID-19 from ventilator support.
  • If oxygen therapy is used, existing guidelines contain recommendations for the management of oronasal face masks, the potential adverse effects of oxygen therapy in the palliative care setting (e.g. impaired communication between patient and family) and the need to balance patient factors with cost effectiveness, resources and safety.

 

BACKGROUND
Breathlessness in advanced disease is a common symptom that can be highly distressing, with the majority of people experiencing breathlessness in the weeks before death.[1] An increasingly common approach to managing breathlessness at the end of life is non-invasive respiratory support, despite limited evidence regarding its effectiveness.[2] Non-invasive ventilation has a well-established evidence-based role in the management of respiratory failure due to exacerbations of COPD and cardiogenic pulmonary oedema. However, its role during palliative care is unclear, and evidence of support is limited. Guidance from the British Thoracic Society and American Thoracic Society for oxygen in adults is that oxygen therapy for home use is most useful in chronic hypoxaemia[3] and that little controlled evidence supports its utility for dyspnea in the absence of hypoxemia.[4] Unless the patient is hypoxemic, the benefit of oxygen in improving feelings of breathlessness has not been clearly demonstrated.[5]

This review evaluates the evidence for oxygen as a treatment option to alleviate the symptoms of breathlessness for patients dying with COVID-19 and to identify potential harms. This review focuses on the use of low-flow and non-invasive ventilation in the delivery of oxygen and considers contexts outside intensive care settings (e.g. general medical wards, the hospice setting, and the home environment). Currently, three existing reviews are underway or have recently been completed exploring the effectiveness of invasive ventilation to support critically ill patients and those dying with COVID-19:

  1. Effectiveness of high flow nasal oxygen being conducted by Per Olav Vandvikat the Norwegian Knowledge Centre for the Health Services
  2. Holger Schunemann and a team at McMaster are addressing all modes of invasive and non-invasive ventilation
  3. Oxygen supplementation at higher levels for critically ill patients: Uncertain effects, but may increase mortality and adverse effects

CURRENT EVIDENCE
A rapid search of the Trip Medical Database, PubMed and Google Scholar without date restrictions was undertaken to identify any relevant randomised trials, meta-analyses, or reviews. The following keywords were used: “Coronavirus”, “COVID-19”, “Severe Acute Respiratory Syndrome”, “SARS”, “MERS”, “bronchitis”, “common cold”, “influenza”, “pneumonia”, “acute respiratory infections”, “severe respiratory infections”, “short of breath”, “dyspnoea”, “dyspnea”, “laboured breathing”, “breathless”, “oxygen”, “die”, “dying”, “end of life” and the following MeSH terms: Coronavirus, Coronavirus Infections, Dyspnea, Oxygen, and Death. A detailed search strategy is provided at the end of the review.

Alongside searching databases, five online resources developed for COVID-19 relevant literature were searched:

Identified evidence

Systematic reviews
Five systematic reviews were identified. This included one Cochrane systematic review [6] of oxygen therapy for dyspnoea in adults. The review has been withdrawn as it is out of date, and the original author team were not available to update the review. The remaining four systematic reviews [7-10] are summarised below.

1) A systematic review [7] outlined evidence for the management of dyspnea in the terminally ill: This narrative review on the management of dyspnea in the terminally ill explores all treatments for dyspnea and includes a section on standard oxygen use. The evidence for supplemental oxygen as palliative treatment in end-stage patients is outlined from two different perspectives: (1) the use of standard oxygen via nasal cannula, Venturi, or non-rebreathing masks, and (2) high-flow nasal therapy via a specially modified soft, loose-fitting nasal cannula. The studies which explore standard oxygen use vary widely in terms of the study populations (most participants have either cancer or COPD), the design of the studies and the methods used to evaluate the effect of oxygen. Of studies included, a randomized controlled trial [11] involving a range of conditions reported that palliative   oxygen   does   not   provide   incremental   benefit    over  room   air   delivered   by   nasal   cannula   in   improving   morning  or  evening  breathlessness  for  patients  with  advanced  disease  who  are  not  hypoxic.[12] The review does not appraise the quality of included studies. The findings of the reported studies are conflicting and the review authors conclude the evidence to support the use of standard oxygen in terminal patients is not compelling and further trials are needed.

2) A systematic review [8] examined oxygen and airflow effect on relief of dyspnea at rest in patients with advanced disease of any cause: This systematic review appraises the scientific basis for oxygen therapy to manage dyspnea at rest in patients with advanced disease. Five studies were included and a total number of participants across the studies was 83. The study designs were case series and case control studies. The studies included both cancer patients and patients with advanced lung disease of obstructive and restrictive pathology. Although the review is well conducted according to the AMSTAR checklist, the quality of the studies included in this review is very low.  The authors conclude that there is low grade evidence to suggest that airflow and oxygen can improve dypsnea at rest in some patients with advanced disease however there is no evidence to identify which patients may benefit.

3) A systematic review [9] focused on the etiology and pharmacological management of intractable breathlessness in patients with advanced cancer: One paragraph in the review is dedicated to oxygen therapy and the authors refer to 2 studies which have demonstrated that oxygen and air can reduce dyspnea in patients with cancer. However, the recommendation is that patients with cancer who are hypoxic should be offered and taught how to use a fan before being offered oxygen. In common with Gallagher et al [8] the authors state there are no predictive factors established to identify which patients may benefit most from oxygen and recommend that, if it is used, systematic evaluation of its effectiveness for each patient must be undertaken.

4) A systematic review [10] to determine the efficacy of palliative oxygen for relief of dyspnea in cancer patients: Four studies reporting on a total of 134 patients were included in the review. Quality of included studies was assessed using Jadad score, which has a maximum score of 5.  3 of the included studies scored 2 and one scored 5). The studies provided oxygen at rest or during a 6-minute walk. Oxygen failed to improve dyspnoea in mildly or non-hypoxemic cancer patients (SMD=-0.09,95% confidence interval -0.22 to 0.04; p=0.16).  The authors recommend further study of the use of oxygen in this population is warranted given its widespread use.

Guidelines
Three evidence-informed guideline documents were identified relevant to palliative care and the management of breathlessness, but not specific to COVID-19, including consideration of the possible adverse effects arising from oxygen therapy:

  1. British Thoracic Society (April 2015): Guidelines for home oxygen use in adults: accredited by NICE

Palliative oxygen therapy may on occasion be considered by specialist teams for patients with intractable breathlessness unresponsive to all other modalities of treatment. In those instances, individual formal assessment of the effect of palliative oxygen on reducing breathlessness and improving quality of life should be made.

The type of portable device selected for oxygen therapy if to be delivered in community should balance patient factors with cost effectiveness, resources and safety.

  1. British Thoracic Society (June 2017): Guideline for oxygen use in adults in healthcare and emergency settings.

General guidance is provided on the use of oxygen in palliative care settings, not related specifically to COVID-19 patients.

  • Oxygen use in palliative care patients should be restricted to patients with SpO2 consistently <90% or patients who report significant relief of breathlessness from oxygen. In non-hypoxemic patients, opioids and non-pharmacological measures should be tried before oxygen.
  • In general, there is no role for the monitoring of oxygen saturation or PO2 in comfort-focused care in the last few days of life. If the patient appears comfortable, oxygen levels are irrelevant and should not influence care.
  • Oxygen use has to be tailored to the individual and a formal assessment made of its efficacy for reducing breathlessness and improving quality of life for that person.
  • Oxygen therapy should not be continued in the absence of patient benefit or where its disadvantages (e.g., discomfort of masks or nasal cannula, drying of mucous membranes) outweigh any likely symptomatic benefit.
  1. Scientific Committee of the Association of Palliative Medicine (January 2004): The use of oxygen in the palliation of breathlessness

Despite limited evidence for its effectiveness, oxygen therapy is widely used across palliative care. An older report from 2004 by an expert working group [13] reported multiple factors that should also be taken into account in the use of oxygen in the palliation of breathlessness, beyond the patient’s perspective. This included an outline of potential adverse effects of oxygen therapy in the context of palliative care:

  • A restriction of activities.
  • Oxygen apparatus is cumbersome and for an already disabled patient may act as a disincentive to going out and living as normally as possible.
  • Impaired communication between patient and family.
  • If patients become psychologically dependent on oxygen they may attend too much on the mechanics of having their oxygen therapy. Some will not even remove their mask for even a minute and conversation may be impeded. They may even become frightened when there is any interruption in the oxygen supply and refuse to go out without a continuous supply from a cylinder. This may have a deleterious impact on quality of life.
  • Fire hazard: Oxygen promotes combustion. Patients who smoke during oxygen therapy are in great danger of facial burns and some fatalities have been reported.
  • Hypercapnic respiratory failure: The dangers of oxygen therapy in those patients with Type II respiratory failure are well known.
  • Withdrawing oxygen: Once oxygen has been given to a patient it is often difficult to stop its use even when it is on longer relieving breathlessness or being used appropriately.
  • The cost of oxygen: Oxygen is not cheap and should be used appropriately rather than universally.

Additional literature searching
Backward and forward reference searching was used to identify additional studies that may be relevant to inform the review. No randomised controlled trials, case control or cohort studies were identified.

Randomised Controlled Trials
None.

Case Control and Cohort Studies
None.

Additional primary research and commentary
From additional hand searching of research literature, one publication relating to oxygen therapy and COVID-19 were identified. A letter published in The Lancet Respiratory Medicine [14], written in response to a study describing clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China. The letter highlights that the pathophysiology of severe viral pneumonia is acute respiratory distress syndrome (ARDS). Non-invasive ventilation is not recommended for patients with viral infections complicated by pneumonia because, although non-invasive ventilation temporarily improves oxygenation and reduces the work of breathing in these patients, this method does not necessarily change the natural disease course [15].

Limitations of the Identified Studies
No evidence was identified that can inform whether oxygen may be an effective treatment for alleviating symptoms of breathlessness for patients dying with COVID-19. Across the included reviews the evidence to support the use of standard oxygen in terminal patients is very limited and based on low grade evidence. Further research is required to provide clarification on which patients with advanced disease may benefit from the use of oxygen therapy.

The strength of included systematic reviews is mixed. One review included studies of a low quality with non-randomised studies and low numbers of participants [8]. Remaining reviews included a narrative review [7] preventing AMSTAR criteria being applied, a review meeting several of the AMSTAR checklist [9], and one review that met most of the criteria of the AMSTAR checklist.   [10]. The included research letter [14] was developed based on expert opinion and cites related research literature.

EMERGING EVIDENCE IN COVID-19
Nine existing guidelines were identified that contain information relevant to the management of patients with COVID-19. Guidance below numbered 1 – 6 relates to symptom management as part of palliative care for patients with COVID-19. Guidance numbered 7 – 9 discusses critical care, non-invasive respiratory support and clinical management of patients with COVID-19. Guidance listed below that is clearly underpinned and supported by evidence is marked with an asterisk (*). Extracts of relevant content from the guidance is outlined below.

  1. National Institute for Health and Care Excellence (NICE) (22nd April 2020)*: COVID-19 rapid guideline: managing symptoms (including at the end of life) in the community

As part of recommendations for managing symptoms, including end of life in the community, the following are suggested as approaches to managing breathlessness as part of supportive care:

  • keeping the room cool
  • encouraging relaxation and breathing techniques and changing body positioning (see table 3 for techniques to help manage breathlessness)
  • encouraging patients who are self-isolating alone, to improve air circulation by opening a window or door (do not use a fan because this can spread infection)
  • when oxygen is available, consider a trial of oxygen therapy and assess whether breathlessness improves.

This guidance is being reviewed and updated regularly.

  1. NHS England and NHS Improvement (updated 22nd April 2020): Clinical guide for the management of palliative care in secondary care during the coronavirus pandemic, Version 1

Management of breathlessness suggests that “Treatment of underlying causes of dyspnoea should be considered and optimised where possible.” Under reversible causes, non-pharmacological and pharmacological approaches are provided. Non-pharmacological approaches include humidified oxygen, but it is noted that there is no evidence of benefit to its use in the absence of hypoxemia.

  1. NHS England and NHS Improvement (22nd April 2020): Clinical guide for the management of palliative care in hospital during the coronavirus pandemic

Management of breathlessness includes a focus on reversible causes, non-pharmacological measure and pharmacological measures. Oxygen therapy is not included in the guidance.

  1. NHS Scotland: End of Life Care Guidance when a Person is Imminently Dying from COVID-19 Lung Disease

For the management of breathlessness, the guidance suggests considering whether the patient is benefiting from any oxygen prescribed. If not, consider discontinuing non-beneficial oxygen and using medication and non-pharmacological measures for symptom control.

  1. ScotPalCovid*: Dyspnoea (breathlessness) management near the end of life in COVID-19 infection

If breathlessness accompanies cough, expectoration, chest tightness and cyanosis then oxygen therapy should be commenced, if possible. Respiratory support techniques should be selected according to the degree of hypoxia, patient tolerance and the doctor’s advice. Specific, in-depth recommendations about oxygen therapy for elderly people with COVID-19 is available [16]  and more general oxygen therapy recommendations [17].

  1. International Association for Hospice and Palliative Care (IAHPC): Palliative Care in the COVID-19 Pandemic: Recommendations for Symptom Control of Patients with COVID-19: Briefing note

The guidance suggests that, if dyspnoea persists despite optimal treatment of the acute disease, medical and non-medical measures should be used for symptom control.

Suggested non-pharmacological interventions include body positioning (leaning forward position, pillow support for arms etc.), relaxation or cooling of the face with a cool towel (no hand-held fans to prevent dissemination of the aerosol) may alleviate mild breathlessness.

It is suggested that oxygen or high flow oxygen (with oxygen reservoir) may also relieve breathlessness if intensive care and invasive ventilation are not indicated.

  1. NHS England and NHS Improvement (8th April 2020): Clinical guide for the management of critical care for adults with COVID-19 during the coronavirus pandemic

The focus of the guidance is predominantly in the context of critical care/ICU. The guidance notes, however, that there may be a role for non-invasive ventilation or continuous positive airway pressure, including in patients who have had tracheostomies, to wean them from ventilator support (and the requirement for sedation). However, there is insufficient evidence from the UK experience to provide any guidance on this at this stage.

  1. NHS England and NHS Improvement (6th April 2020): Guidance for the role and use of non-invasive respiratory support in adult patients with COVID19 (confirmed or suspected)

This guidance was developed using published evidence, clinical guidelines and personal communications with colleagues in China and Italy. The guideline is not designed to be prescriptive but to provide a useful aid to use alongside clinical judgement. It can be adjusted to suit individual clinical environments.

  • Non-invasive ventilation with bilevel positive airway pressure (BiPAP) is usually not needed in those with otherwise normal lungs; compliance is usually maintained in COVID-19 patients. However, excessive work of breathing is a possible indicator for intubation. The use of non-invasive ventilation (BiPAP) should be reserved for those with hypercapnic acute on chronic ventilatory failure.
  • Continuous positive airway pressure (CPAP) is the preferred form of non-invasive ventilatory support in the management of the hypoxemic COVID-19 patient. Its use does not replace invasive mechanical ventilation (IMV), but early application may provide a bridge to IMV.

Technical considerations:

  • Guidance on the management of masks:
    • Well-fitting oronasal face masks, masks over the whole face, or helmets should produce the least droplet dissemination.
    • Vented masks could worsen contamination of the environment.
    • Any patient on acute NIV should be managed with a non-vented mask and an exhalation port in the circuit.
    • Ensure that the ventilator mode employed supports the use of non-vented masks and exhalation ports.
    • Sequence of actions: NIV mask on → ventilator on; ventilator off → NIV mask off.

For patients already managed under home ventilation services who are admitted to hospital with suspected or confirmed coronavirus infection:

  • Check if their usual mask is a vented or non-vented mask. Vented masks should be changed for a non-vented mask and an exhalation port put into the circuit.
  • A viral/bacterial filter should be placed between the mask and the exhalation port in exactly the same way as for acute NIV.
  • For any patient who has a humidifier in the community, the humidifier should be removed from the circuit.
  • Patients remaining at home should continue with their usual method of ventilation.
  • Contact home ventilation service for further advice as needed.
  1. World Health Organization (13th March 2020): Clinical management of severe acute respiratory infection when COVID-19 is suspected

No guidance is provided specific to those dying from COVID-19 or potential harms.

Summary of guidance
NICE and a rapid review by ScotPalCovid suggest that if oxygen is available, trialling oxygen therapy to assess whether breathlessness improves for a patient could be explored. In guidance from the IAHPC, oxygen is suggested as an option that could be explored alongside non-pharmacological approaches if dyspnoea persists despite optimal treatment of the acute disease. However, NHS England and NHS Improvement guidelines outline that there is no evidence of benefit of oxygen therapy to alleviate the symptom of breathlessness in the absence of hypoxemia. There may, however, be a role for use of oxygen therapy to wean patients from ventilator support.

Pertinent factors to consider for oxygen use for patients dying of COVID-19 are included across the guidance. For those currently receiving oxygen therapy, NHS Scotland guidance suggests considering whether a patient is benefiting from any oxygen prescribed. If not, consider discontinuing non-beneficial oxygen and using medication and non-pharmacological measures for symptom control. Where oxygen therapy is used, technical guidance is available on the management of oronasal face masks fitted over the whole face. Guidance that suggests trailing or use of oxygen therapy also stipulates that this is possible where oxygen is available. Numerous non-pharmacological approaches to the management of breathlessness are also included within the identified guidance.

CONCLUSIONS
There is no available evidence to inform the use of oxygen therapy in the management of breathlessness for patients dying with COVID-19. The use of oxygen therapy to manage breathlessness in patients receiving palliative care remains a controversial topic, with limited and low-quality evidence of its effectiveness in conditions where published research exists (i.e. cancer and COPD).

Whilst research literature is limited, guidance is emerging from multiple sources that focuses specifically on the management of patients with COVID-19. Emerging guidelines outline that there is no evidence of benefit of oxygen therapy in the absence of hypoxemia and adverse effects in the palliative care setting need to be considered. However, there may be a role for its use in patients with COVID-19 to wean patients from ventilator support and where hypoxemia is present and dyspnoea cannot be controlled by other means. When used in the hospital or home setting, technical guidance is available to inform the management of oronasal face masks fitted over the whole face.

Where oxygen therapy is considered, it should be tailored to the individual and a formal assessment made of its efficacy for reducing breathlessness and improving quality of life for that person. Where there is an absence of patient benefit or where its disadvantages (e.g. discomfort of masks or nasal cannula, drying of mucous membranes) outweigh any likely symptomatic benefit, it should be discontinued. If palliative oxygen therapy is considered for the community setting, it should balance patient factors with cost effectiveness, resources and safety.

Oxygen in many LMIC settings has limited availability. Even when available health care facilities may have to be selective in its use due to limited supply. Its use may have substantial cost implications for the health care facility and for the patient and their relatives. Oxygen may be prescribed inappropriately because of the mistaken view that “giving oxygen = giving life.” Lack of evidence of the effectiveness of oxygen in palliating breathlessness in non-hypoxic patients should be sensitively communicated to patients and carers. Palliation of breathlessness should be through other pharmacological and non-pharmacological means with useful guidelines available in the Pallium India e-book on palliative care guidelines for Covid-19 pandemic.

End.

Disclaimer:  The article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice.

Authors: All authors are based in the Academic Unit of Palliative Care, part of Leeds Institute of Health Sciences except for Sarah Rudd, who is a clinical librarian at North Bristol NHS Trust. Dr Matthew Allsop is a University Academic Fellow, Dr Lucy Ziegler is an Associate Professor in Palliative Care, Dr Yu Fu is a Research Fellow, and Professor Michael Bennett is St. Gemma’s Professor of Palliative Medicine and Head of the Academic Unit of Palliative Care.

We thank the Oxford CEBM COVID-19 Palliative Care Rapid Review coordinating team for their contribution in review development and in providing internal peer review for this manuscript. 

Dr Jo Elverson
Professor Bridget Johnston
Dr Nicholas Jones
Dr Susie Lapwood
Dr Sarah Mitchell
Dr Dan Munday
Professor Sandy Oliver
Dr Lucy Selman
Bridget Candy

Louise Jones

We thank Frank Arrojo and Helen Findlay our PPI representatives for helping to develop the research question.

SEARCH TERMS
Example of terms used to search PubMed for COVID-19 literature:

(coronavirus*[Title] OR coronovirus*[Title] OR coronoravirus*[Title] OR coronaravirus*[Title] OR corono-virus*[Title] OR corona-virus*[Title] OR “Coronavirus”[Mesh] OR “Coronavirus Infections”[Mesh] OR “Wuhan coronavirus” [Supplementary Concept] OR “Severe Acute Respiratory Syndrome Coronavirus 2″[Supplementary Concept]  OR COVID-19[All Fields] OR CORVID-19[All Fields] OR “2019nCoV”[All Fields] OR “2019-nCoV”[All Fields] OR WN-CoV[All Fields] OR nCoV[All Fields] OR “SARS-CoV-2”[All Fields] OR HCoV-19[All Fields] OR “novel coronavirus”[All Fields])AND (“short of breath”[All Fields] or “dyspnoea”[All Fields]  or “laboured breathing” [All Fields] OR “dyspnea”[MeSH Terms] OR “dyspnea”[All Fields] OR “breathless”[All Fields])

(coronavirus*[Title] OR coronovirus*[Title] OR coronoravirus*[Title] OR coronaravirus*[Title] OR corono-virus*[Title] OR corona-virus*[Title] OR “Coronavirus”[Mesh] OR “Coronavirus Infections”[Mesh] OR “Wuhan coronavirus” [Supplementary Concept] OR “Severe Acute Respiratory Syndrome Coronavirus 2″[Supplementary Concept]  OR COVID-19[All Fields] OR CORVID-19[All Fields] OR “2019nCoV”[All Fields] OR “2019-nCoV”[All Fields] OR WN-CoV[All Fields] OR nCoV[All Fields] OR “SARS-CoV-2”[All Fields] OR HCoV-19[All Fields] OR “novel coronavirus”[All Fields])AND (“oxygen”[MeSH Terms] OR “oxygen”[All Fields]) AND (“death”[MeSH Terms] OR “death”[All Fields])

[ AND (“oxygen”[MeSH Terms] OR “oxygen”[All Fields]) OR o2[All Fields]) AND (die[All Fields] OR dying[All Fields] OR (“death”[MeSH Terms] OR “death”[All Fields])]

Example of terms used to search PubMed for SARS/MERS relevant literature:

(bronchitis OR common cold OR influenza OR pneumonia OR SARS OR MERS ” OR “Respiratory Tract Infections”[Mesh]) AND (“oxygen”[MeSH Terms] OR “oxygen”[All Fields] OR o2[All Fields]) AND (die[All Fields] OR dying[All Fields] OR “death”[MeSH Terms] OR “death”[All Fields])

(bronchitis OR common cold OR influenza OR pneumonia OR SARS OR MERS ” OR “Respiratory Tract Infections”[Mesh]) AND (“short of breath”[All Fields] or “dyspnoea”[All Fields]  or “laboured breathing” [All Fields] OR “dyspnea”[MeSH Terms] OR “dyspnea”[All Fields] OR “breathless”[All Fields]) AND (die[All Fields] OR dying[All Fields] OR “death”[MeSH Terms] OR “death”[All Fields])

Example of terms used to search PubMed for oxygen therapy relevant literature:

(oxygen or o2) AND (end of life care or palliative care or palliation) and (breathless or short of breath or Dyspnoea or dyspnic or laboured breathing)

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