Dexamethasone reduced death by one-third in ventilated COVID-19 patients

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In March 2020, the RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial was established as a randomised clinical trial to test a range of potential treatments for COVID-19, including low-dose dexamethasone (a steroid treatment).

Over 11,500 patients have been enrolled from over 175 NHS hospitals in the UK.

On 8 June, recruitment to the dexamethasone arm was halted since, in the view of the trial Steering Committee, sufficient patients had been enrolled to establish whether or not the drug had a meaningful benefit.

A total of 2104 patients were randomised to receive dexamethasone 6 mg once per day (either by mouth or by intravenous injection) for ten days and were compared with 4321 patients randomised to usual care alone.

Among the patients who received usual care alone, 28-day mortality was highest in those who required ventilation (41%), intermediate in those patients who required oxygen only (25%), and lowest among those who did not require any respiratory intervention (13%).

Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021).

There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75; p=0.14).

Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.

Given the public health importance of these results, the researchers are now working to publish the full details as soon as possible.

Peter Horby, Professor of Emerging Infectious Diseases in the Nuffield Department of Medicine, University of Oxford, and one of the Chief Investigators for the trial, said, ‘Dexamethasone is the first drug to be shown to improve survival in COVID-19.

This is an extremely welcome result. The survival benefit is clear and large in those patients who are sick enough to require oxygen treatment, so dexamethasone should now become standard of care in these patients. Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.’

Martin Landray, Professor of Medicine and Epidemiology at the Nuffield Department of Population Health, University of Oxford, one of the Chief Investigators, said, ‘Since the appearance of COVID-19 six months ago, the search has been on for treatments that can improve survival, particularly in the sickest patients.

These preliminary results from the RECOVERY trial are very clear – dexamethasone reduces the risk of death among patients with severe respiratory complications. COVID-19 is a global disease – it is fantastic that the first treatment demonstrated to reduce mortality is one that is instantly available and affordable worldwide.’

The UK Government’s Chief Scientific Adviser, Sir Patrick Vallance, said, ‘This is tremendous news today from the Recovery trial showing that dexamethasone is the first drug to reduce mortality from COVID-19.

It is particularly exciting as this is an inexpensive widely available medicine. This is a ground-breaking development in our fight against the disease, and the speed at which researchers have progressed finding an effective treatment is truly remarkable.

It shows the importance of doing high quality clinical trials and basing decisions on the results of those trials.’


Indications
Dexamethasone has a wide variety of uses in the medical field. As a treatment, dexamethasone has been useful in the treatment of acute exacerbations of multiple sclerosis, allergies, cerebral edema, inflammation, and shock. Patients with conditions such as asthma, atopic and contact dermatitis, and drug hypersensitivity reactions have benefited from the use of dexamethasone.[1]

In endocrinology, dexamethasone has been found useful as a test for Cushing syndrome.[2] This test begins with a low dose test. There are two versions of this test: the standard two-day test and the overnight test. With the standard test, 0.5 mg oral dose of dexamethasone is given every 6 hours for two days. Six hours after giving the final dose, serum cortisol levels are measured.

The overnight test begins with a 1 mg oral dose of dexamethasone at 11:00 PM with a second 1 mg oral dose at midnight. The following morning, serum cortisol levels are tested between 8:00 AM and 9:00 AM.

The test is read as a positive screening test for Cushing syndrome if the final cortisol reading is high, signaling that the more specific confirmative high dose dexamethasone suppression test should follow. The high dose dexamethasone suppression test has three forms: the standard 2-day test, the overnight test, and the intravenous (IV) test. With all three versions of the test, baseline serum cortisol levels need to be determined before commencing with the test. Baseline serum is measurable with a 24-hour urinary free cortisol test.[3]

The standard 2-day test uses 2 mg of oral dexamethasone given every 6 hours for two days. During the 2-day exam, urine is collected and tested for free cortisol and 6 hours after the final dose of dexamethasone; blood is drawn to measure the serum cortisol level.

The overnight test begins with an 8 mg oral dose of dexamethasone at 11:00 PM. The following morning between 8:00 AM, and 9:00 AM, serum cortisol is measured. The IV test is the shortest of the tests. The patient receives one milligram of dexamethasone via continuous intravenous infusion per hour for 7 hours. Serum cortisol is measured at the end of 7 hours.

Off-label indications are as follows. Dexamethasone is useful in the treatment of chemotherapy-induced nausea and vomiting. It is also used in the prevention and treatment of altitude sickness. It has also seen use in the treatment of spinal cord compression due to metastases in oncological cases.[4]
Mechanism of Action

Dexamethasone is a potent glucocorticoid with very little, if any, mineralocorticoid activity.[5] Dexamethasone’s effect on the body occurs in a variety of ways. It works by suppressing the migration of neutrophils and decreasing lymphocyte colony proliferation. The capillary membrane becomes less permeable, as well. Lysosomal membranes have increased stability.

There are higher concentrations of vitamin A compounds in the serum, and prostaglandin and some cytokines (interleukin-1, interleukin-12, interleukin-18, tumor necrosis factor, interferon-gamma, and granulocyte-macrophage colony-stimulating factor) become inhibited.

Increased levels of surfactant and improved pulmonary circulation have also been shown with dexamethasone use. Dexamethasone is metabolized by the liver and excreted in the urine mainly. Dexamethasone has a half-life of approximately 3 hours.

Administration
Dexamethasone is available in various formulations. As a tablet, it is available in strengths ranging from 0.5 mg to 6 mg. Other forms of administration are as an injectable suspension or as an oral solution.[6]

In the treatment of inflammation, it is advisable to start with low doses of 0.75 mg/day, which may titrate to 9 mg/day, with dosing divided into 2 to 4 doses throughout the day. This applies to intravenous, intramuscular, and oral administrations. Less may be used when directly administered to the lesion or tissue with dosing ranging from 0.2 to 6 mg per day.[7]
As therapy for acute multiple sclerosis exacerbations, 30 mg oral daily doses taken for seven days is the recommended regimen followed by one month of 4 to 12 mg oral daily doses.
As cerebral edema may be a life-threatening condition, aggressive treatment is necessary. The recommendation is for 10 mg of intravenous dexamethasone, followed by 4 mg of intramuscular administration given every 6 hours. In this instance, it is necessary to titrate down over 7 days to discontinue dexamethasone therapy.[8]

In the treatment of circulatory shock, the regimen is 1 to 6 mg/kg of intravenous dexamethasone as a one-time bolus. This regimen may be substituted with 40 mg given intravenously every 2 to 6 hours as needed. Treatment with high dose dexamethasone is not recommended beyond 2 to 3 days.

Research has shown that allergic reactions improve with a 6-day regiment beginning with 4 to 8 mg intramuscular injection on the first day. This dose is followed by oral doses on days 2 to 6 beginning with 1.5 mg every 12 hours for days 2 and 3, 0.75 mg every 12 hours for the third day, and finally 0.75 mg daily for days 5 and 6. The patient should appropriately be titrated down by day 7 with no dosing necessary on day 7.

Adverse Effects
Although dexamethasone is generally well tolerated, it does have its drawbacks as a medication. The most frequently reported adverse effect by patients is the presence of insomnia after use. Some other frequent adverse effects reported by patients include acne, indigestion, weight gain, increased appetite, anorexia, nausea, vomiting, acne, agitation, and depression. There have been reports of adrenal suppression, arrhythmias, spermatogenic changes, glaucoma, hypokalemia, pulmonary edema, pseudotumor cerebri, and increased intracranial pressure.[9]

Contraindications
Dexamethasone use is contraindicated if patients have systemic fungal infections, hypersensitivity to dexamethasone, or cerebral malaria. Another contraindicated to administer live or live-attenuated vaccines during the use of dexamethasone as the immune system is being suppressed and will less like form a strong enough immune response placing the patient at risk.

It is still permissible to administer killed or inactivated vaccines, although it bears mentioning that immune response may be attenuated, and it is unpredictable if immunity with developing as a result.[10]

In patients with cirrhosis, diverticulitis, myasthenia gravis, renal insufficiency, or ulcerative diseases such as peptic ulcer disease or ulcerative colitis, it is important to use caution when prescribing dexamethasone. Recommendations include using dexamethasone cautiously during pregnancy as there is an increased risk of oral cleft formations.

Clinical experience has shown that large doses can increase blood pressure. In patients with recent myocardial infarction, it is advised to proceed with caution as an increase in free wall rupture of the left ventricle has been reported with the use of dexamethasone.

Suppression of the hypothalamus-pituitary-adrenal axis (HPA axis) occurs with use, and therefore the rapid withdrawal of dexamethasone is not recommended. It is important to gradually increase and/or decrease any corticosteroid due to its effect on the HPA axis.

Latent diseases such as fungal (Candida, Cryptococcus, Pneumocystis), parasitic (Toxoplasmosis, Amebiasis, Strongyloides), and bacterial (Mycobacterium, Nocardia) infections may become active due to suppression of the immune system.[11]

Steroid use may inhibit bone formation and may lead to the formation of osteoporosis. Caution is necessary when prescribing dexamethasone to populations at higher risk for osteoporosis.

Enhancing Healthcare Team Outcomes
Dexamethasone is a widely prescribed drug by many healthcare professionals, including the nurse practitioner. However, it is essential to know that this potent steroid has many adverse effects, and patient monitoring is critical. In general, clinicians should avoid long-term prescriptions, and the drug tapered quickly if the patient is improving. If chronic use is warranted, then the patient must be educated about the potential side effects of the steroid. Healthcare workers must monitor the patient for mood changes, development of osteoporosis, weight gain, hyperglycemia, electrolyte changes, and depression.


Source:
Oxford University

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