Dexamethasone reduces mortality in patients seriously ill with COVID-19

Outline of the currently available evidence for the use of dexamethasone in the management of COVID-19 | Updated 26 October 2021

Current Australian guidelines for clinical care of people with COVID-19

Current Australian guidelines for the clinical care of people with COVID-191 recommend:

  • Use dexamethasone 6 mg daily intravenously or orally for up to 10 days (or acceptable alternative regimen) in adults with COVID-19 who are receiving oxygen (including mechanically ventilated patients).
  • Use dexamethasone 6 mg daily intravenously or orally for up to 10 days in pregnant or breastfeeding women with COVID-19 who are receiving oxygen (including mechanically ventilated patients).

In both groups the guidelines have also identified alternative corticosteroid medicines considered acceptable if dexamethasone is not available.

A conditional recommendationa has also been made for considering the use of dexamethasone (and acceptable alternative corticosteroids) in children and adolescents with acute COVID-19 who are receiving oxygen (including mechanically ventilated patients).

For all three populations mentioned above, these same guidelines have issued a conditional recommendation against the routine use of dexamethasone (or other corticosteroids) to treat COVID-19 when oxygen (supplemental) is not required.

Read more about the detailed information supporting these recommendations, as well as further guidance for other disease-modifying treatments and COVID-19.

a A conditional (weak) recommendation for an intervention is one where treatment benefit probably outweighs harm for the majority. Uncertainty exists but most patients would likely want this option. In general, clinicians should ‘think twice’ and consider individual patient factors within a shared decision-making model (eg, patient’s values, preferences, comorbidities, polypharmacy, burden of care or personal limitations) that may result in an alternative course of action.

This article is written for health professionals.

In June 2020, preliminary results from UK-based trial RECOVERY reported that the glucocorticoid dexamethasone reduced death by up to one-third among hospitalised patients requiring ventilation for severe respiratory complications of COVID-19.2 

The trial published subsequent results in The New England Journal of Medicine in February 2021, which are consistent with those detailed in the preliminary report.

The news was welcomed by the global health community including the World Health Organisation (WHO), the UK Department of Health and Social Care, the Australian National COVID-19 Clinical Evidence Taskforce and the Australian Health Protection Principal Committee (AHPCC).

The RECOVERY trial published their preliminary report about dexamethasone on 17 July 2020.3 A WHO-led meta-analysis looking at the effect of systemic corticosteroids in critically ill people hospitalised with COVID-19 was published in September 2020.4 This analysis included the RECOVERY findings, and concluded that the use of systemic corticosteroids in critically ill hospitalised people with COVID-19 reduced 28-day mortality, compared with placebo or usual care.

 

What is the evidence for dexamethasone in COVID-19?

RECOVERY is a randomised clinical trial established during the SARS-CoV-2 outbreak to test a range of potential treatments for COVID-19, including low-dose dexamethasone.1

COVID-19 (coronavirus disease) is the infectious disease caused by the virus SARS-CoV-2.

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is a new strain of coronavirus that first started causing severe disease symptoms in humans around December 2019.

Coronaviruses are a large family of viruses known to cause respiratory infections. These can range from the common cold to more serious diseases such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS).5

Since March 2020 over 20,000 patients have been enrolled in the RECOVERY trial from more than 176 public hospitals across the UK6 (as at 16 November 2021, 44,944 patients have enrolled in the trial from 188 global active sites). In addition to low-dose dexamethasone, RECOVERY is examining and regularly assessing multiple other treatments. Some medicines such as hydroxychloroquine, azithromycin and lopinavir with ritonavir are no longer under investigation, while others such as tocilizumab and convalescent plasma continue to be trialled.2,6,7

In the dexamethasone arm, a total of 2,104 patients were randomised to receive usual care (for the participating hospital) plus a daily dose of dexamethasone 6 mg for 10 days (oral or intravenous). This group was compared with 4,321 patients randomised to usual care alone.2,3

Primary outcome was all-cause mortality at 28 days after randomisation, and follow-up was completed for 99.9% of participants.3

Dexamethasone was associated with a reduction in mortality in patients with more severe COVID-19 disease. It reduced deaths by one-third in ventilated patients (rate ratio [RR] 0.64, 95% CI 0.51 to 0.81) and by one-fifth in other patients receiving oxygen without invasive mechanical ventilation (RR 0.82, 95% CI 0.72 to 0.94) compared to standard care alone.3

The RECOVERY chief investigators pointed to the public health importance of the preliminary data stating that, ‘Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.’2 Professor Peter Horby, one of the chief investigators noted, ‘Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.’2

In the RECOVERY trial there was no clear effect for dexamethasone when given to patients who were not receiving any respiratory support at randomisation (RR 1.19, 95% CI 0.91 to 1.55).3

The authors suggest that beneficial effect of corticosteroid treatment in severe viral respiratory infections may be dependent on the treatment being initiated later in the disease, once active viral replication has declined and inflammation is the dominant pathology.

This might explain why hospitalised patients with COVID-19 who did not require oxygen therapy or respiratory support and those recruited after the early stages of illness received no benefit (and possible harm) from dexamethasone.3 Assessment of the RECOVERY findings for dexamethasone, alongside the results from the WHO meta-analysis and some additional (indirect) studies of corticosteroids have suggest that use of dexamethasone in patients may increase the risk of hypoglycaemia and death.1

Read more about the RECOVERY trial

 

About dexamethasone

Dexamethasone is a prescription-only synthetic adrenocorticosteroid with glucocorticoid activity.8

Corticosteroids regulate gene expression which can produce;

  • glucocorticoid effects eg, glucogenesis, proteolysis, lipolysis, suppression of inflammation and immune responses, and
  • mineralocorticoid effects eg, hypertension, sodium and water retention, potassium loss.9

Dexamethasone is one of the more potent glucocorticoids – about 25 to 30 times as potent as hydrocortisone. Unlike hydrocortisone, dexamethasone exerts little if any mineralocorticoid activity effects.8,9

Due to their anti-inflammatory and immunosuppressant effects, corticosteroids such as dexamethasone are used to manage a wide range of symptoms and conditions including:8-10

  • chemotherapy-induced and post-operative nausea and vomiting
  • collagen diseases eg, systemic lupus erythematosus (SLE)
  • endocrine disorders eg, adrenal insufficiency
  • gastrointestinal disorders eg, ulcerative colitis
  • leukaemia and lymphoma
  • certain paediatric respiratory infections eg, croup
  • oedema eg, cerebral oedema due to malignancy, neurosurgery or stroke
  • pulmonary disorders eg, chronic asthma and respiratory insufficiency
  • rheumatic diseases eg, rheumatoid arthritis and osteoarthritis
  • skin diseases eg, psoriasis and dermatitis.

Dexamethasone may also be used in prevention eg, neonatal respiratory syndrome, and as an adjunct in the treatment of shock.

 

Adverse effects and common side effects of dexamethasone

Dexamethasone can be associated with adverse effects eg, allergic reactions, as well as side effects associated with prolonged therapy and/or high-dose therapy. These effects can include:8

  • anti-inflammatory and immune suppression eg, increased susceptibility to and severity of infections with masking of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis
  • cardiovascular effects eg, thromboembolism, hypertension, myocardial rupture following recent cardiac infarction
  • endocrine effects eg, adrenal suppression, hyperglycaemia, increased requirements for insulin or oral hypoglycaemic agents
  • fluid and electrolyte imbalances eg, sodium retention with oedema and hypertension, potassium loss, hypokalaemia alkalosis, hypocalcaemia
  • neurological effects eg, increased intracranial pressure
  • other adverse effects include anaphylaxis and hypersensitivity reactions, dermatological effects, gastrointestinal effects, leucocytosis, metabolic effects, musculoskeletal effects, ocular effects, psychiatric effects.

Precautions for dexamethasone use

In the context of COVID-19, the following precautions for dexamethasone should be considered where applicable.8,11

  • Corticosteroids may increase susceptibility to or mask the symptoms of infection.
  • The immunosuppressive effects of glucocorticoids may result in activation of latent infection or exacerbation of intercurrent infections eg, varicella, measles.
  • While immunosuppression is most likely to occur in patients on long-term, high-dose systemic corticosteroid treatment, patients receiving moderate doses for short periods, or low doses over a prolonged period may also be at risk.
  • The effects of anticoagulant agents are usually decreased (but may be increased in some patients) with concurrent corticosteroid treatment. Close monitoring of the INR or prothrombin time is recommended.
  • Concurrent administration of dexamethasone with anticoagulants, heparin, streptokinase, urokinase, alcohol or non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin may increase the risk of gastrointestinal ulceration or haemorrhage.
  • Potassium loss may occur as a result of dexamethasone administration. Monitoring of serum potassium is recommended.
  • Glucocorticoids may increase blood glucose concentrations. Dose adjustments of medicines such as antidiabetic agents may be necessary.
  • There is the also potential for severe psychiatric reactions. Symptoms typically emerge within a few days or weeks of starting treatment. Most psychiatric effects resolve after either dose reduction or withdrawal.

Find out more about dexamethasone and potential medicine interactions

 

What do your patients need to know?

Patients with confirmed COVID-19

  • In the RECOVERY trial, dexamethasone was given to hospitalised patients with serious respiratory complications from COVID-19.
  • Dexamethasone did not provide any benefit for hospitalised patients with less serious illness associated with COVD-19, ie, those who did not need ventilation or oxygen.
  • The reported findings suggest that use of dexamethasone in addition to usual hospital care could prevent 1 death for every 8 patients with COVID-19 on mechanical ventilation, or 1 death for every 25 patients with COVID-19 on supplemental oxygen.
  • The RECOVERY trial did not test dexamethasone on patients with COVID-19 who had not been hospitalised and so it is difficult to draw conclusions as to what this means for those with COVID-19 being managed in the community.
  • Dexamethasone was not used to prevent the risk of COVID-19 infection.
  • Dexamethasone can have serious side effects and should only be used for approved conditions.

Patients who have been prescribed dexamethasone for approved conditions

  • Dexamethasone has not been shown to prevent infection with COVID-19.
  • Continue to take dexamethasone as prescribed.
  • If you have tested positive for COVID-19, speak to your doctor about your dexamethasone prescription.
  • Do not change your dose of dexamethasone unless instructed by your doctor.
  • Do not share your dexamethasone with anyone else, even if they are in hospital with COVID-19.
  • There is no need to stockpile dexamethasone, but if you are concerned about supply speak to your pharmacist.
 
 

References

  1. National COVID-19 Clinical Evidence Task Force. Australian guidelines for the clinical care of people with COVID-19. Canberra: Australian Government Department of Health, 2020 (accessed 26 October 2021).
  2. Nuffield Department of Population Health RECOVERY Trial. Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19. Oxford, UK: University of Oxford, 16 June 2020 (accessed 27 October 2021).
  3. Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N Engl J Med 2020.
  4. WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: A meta-analysis. JAMA 2020;324:1330-41.
  5. Australian Government Department of Health. What you need to know about coronavirus (COVID-19). Canberra, Australia: Australian Government, 2020 (accessed 27 October 2021).
  6. Nuffield Department of Population Health. Randomisation. Oxford, UK: University of Oxford, 2020 (accessed 27 October 2021).
  7. US National Library of Medicine - ClinicalTrials.gov. Randomised evaluation of COVID-19 therapy (RECOVERY). Bethesda, Maryland, USA: NLM, 2020 (accessed 27 June 2021).
  8. Alphapharm Pty Ltd. Australian Product Information: Dexamethasone Mylan. Millers Point, NSW: Alphapharm Pty Ltd, 2011 (revised 2019) (accessed 27 June 2021).
  9. Australian Medicines Handbook. Dexamethasone. Adelaide: AMH Pty Ltd, 2020 (accessed 17 June 2020).
  10. Expert Group for Respiratory. Therapeutic Guidelines: Management of croup version 5. West Melbourne: Therapeutic Guidelines Ltd, 2020 (accessed 27 October 2021).
  11. National COVID-19 Clinical Evidence Task Force. Statement for the National COVID-19 Clinical Evidence Taskforce on media release of results of dexamethasone arm of the UK RECOVERY trial. Melbourne: NC19CETF, 17 June 2020.