Is there any additional benefit to extended length dexamethasone (>10 days) for covid-19 hospitalized patients?

Comment by InpharmD Researcher

There is limited information regarding the use of dexamethasone beyond 10 days for the treatment of COVID-19 in hospitalized patients. A few clinical trials have observed hydrocortisone and methylprednisolone beyond 10 days for the management of ARDS/COVID-19 with negative results. However, there have been concerns that extended use of corticosteroids may further increase the risk of coagulation adverse events in COVID-19 patients.

The 10-day duration of dexamethasone for COVID-19 patients was primarily established by the RECOVERY trial, a study that had been scrutinized for its limitations (i.e., the trial was pragmatic and investigators could exclude patients with documented reasons). The use of corticosteroids in general for COVID-19 is mired by a great deal of heterogeneity between studies that have also called into question the proper dosage of therapy and the patient population that would benefit. Some authors express concerns regarding the extended use of corticosteroids during the procoagulant state of COVID-19. They noted that dexamethasone 6 mg/day can increase the level of clotting factors and fibrinogen complications. The physical and mental fatigue from post-COVID-19 recovery may also be complicated by the extended corticosteroid use related to its adverse events in myopathy, neuromuscular weakness, and psychiatric symptoms. For acute respiratory distress syndrome (ARDS), methylprednisolone use beyond 2 weeks after onset of ARDS is associated with an increased risk of death. [1-3]


[1] Mishra GP, Mulani J. Corticosteroids for COVID-19: the search for an optimum duration of therapy. Lancet Respir Med. 2021;9(1):e8. doi:10.1016/S2213-2600(20)30530-0
[2] Sarzani R, Spannella F, Giulietti F, et al. Possible harm from glucocorticoid drugs misuse in the early phase of SARS-CoV-2 infection: a narrative review of the evidence [published online ahead of print, 2021 Oct 31]. Intern Emerg Med. 2021;1-10. doi:10.1007/s11739-021-02860-3
[3] Matthay MA, Thompson BT. Dexamethasone in hospitalised patients with COVID-19: addressing uncertainties. Lancet Respir Med. 2020;8(12):1170-1172. doi:10.1016/S2213-2600(20)30503-8

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is there any additional benefit to extended length dexamethasone (>10 days) for covid-19 hospitalized patients?

Please see Tables 1-3 for your response.


Effects of Hydrocortisone on 21-day Mortality or Respiratory Support Among Critically Ill Patients with Covid-19


Multicenter, randomized, double-blind study

N= 149


To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure

Study Groups

Hydrocortisone (n= 76)

Placebo (n= 73)

Inclusion Criteria

Age > 18 years; admitted for acute respiratory failure and biologically confirmed for COVID-19; treated within 24 hours of onset of prespecified first severity criterion or within 48 hours if referred from another hospital

Severity criteria. One of 4 must be present for inclusion:

1) Need for mechanical ventilation with a positive end-expiratory pressure (PEEP) of 5 cm H20 or more

2) Ratio of Pao2 to fraction of inspired oxygen (Fio2) < 300 on high-flow oxygen therapy with an Fio2 value of at least 50%

3) for patients receiving oxygen through a reservoir mask, a Pao2:Fio2 ratio < 300, estimated using prespecified charts

4) Pulmonary Severity Index > 130

Exclusion Criteria

Non-covid-19 related pneumonia, septic shock, do-not-intubate orders


Patients were randomized (1:1) to receive hydrocortisone initial dose 200 mg/day until day 7, then decreased to 100 mg/day for 4 days and 50 mg/day for 3 days, for a total of 14 days; or matching placebo. A shorter treatment of a total of 8 days is utilized if patients sufficiently improve by day 4 (patient breathing spontaneously; Pao2:Fio2 ratio greater than 200; Sequential Organ Failure Assessment [SOFA] score on day 4 less than or equal to SOFA score on day 1; and strong probability of being discharged from the ICU before day 14, according to the physician of record). Patients also received standard care for acute respiratory failure with adjunctive treatments allowed based on primary physician's discretion.


Enrollment period: March 1 to June 20, 2020

Follow-up: 21 days

Outcome Measures

Primary outcome: Treatment failure on day 21 defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy

Secondary outcome: Need for tracheal intubation if patient was not intubated at baseline, cumulative incidences until day 21

Baseline Characteristics


Hydrocortisone (n= 76)

Placebo (n= 73)


Age, years (interquartile range [IQR])

63.1 (51.5 to 70.8) 66.3 (53.5 to 72.7)  



22 (28.9%)

54 (71.1%)

23 (31.5%)

50 (68.5%)


Never smoked

57/75 (76%)

57/72 (79.2%)


Chronic obstructive pulmonary disease (COPD) or asthma

7 (9.2%)

4 (5.4%)

Diabetes 13 (17.1%)

14 (19.2%)

Mechanical ventilation 62 (81.6%)

59 (80.8%)

High-flow oxygen therapy 10 (13.2%)

9 (12.3%)

Symptom duration, days 9 (7.0 to 11.5)

10 (8.0 to 12.0)




Hydrocortisone (n= 76)

Placebo (n= 73)


Treatment failure on day 21

 32 (42.1%)  37 (50.7%) 0.29

Endotracheal intubation

8/16 (50%)

12/16 (75.0%)


Prone position

Nosocomial infection on day 28


36 (47.4%)

28 (37.7%)

11 (14.7%)

39 (53.4%)

30 (41.1%)

20 (27.4%)




Discharged from ICU

43 (57.3%)

32 (43.8%)


Adverse Events

Serious Adverse Events: Three in the hydrocortisone group: cerebral vasculitis possibly related to SARS-CoV-2; cardiac arrest related to a pulmonary embolism; and intra-abdominal hemorrhage related to anticoagulant therapy for pulmonary embolism

Study Author Conclusions

In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome.

InpharmD Researcher Critique

The trial was terminated early based on the lack of perceived benefits in treatment failure shortly after the press-release of the RECOVERY trial. Because the planned number of 290 patients was not met, the study is likely underpowered.


Dequin PF, Heming N, Meziani F, et al. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(13):1298-1306. doi:10.1001/jama.2020.16761


Efficacy and Safety of Corticosteroids for Persistent Acute Respiratory Distress Syndrome


Multicenter, randomized, controlled trial

N= 180


To determine the efficacy and safety of moderate dose methylprednisolone when administered to patients with persistent acute respiratory distress syndrome (ARDS)

Study Groups

Methylprednisolone sodium (n= 89)

Placebo (n= 91)

Inclusion Criteria

Age > 13 years, intubated and receiving mechanical ventilation with presence of persistent bilateral opacities

Exclusion Criteria

Immunosuppressant, previous use of corticosteroids, chronic respiratory disease, chronic liver disease, ongoing septic shock, pregnancy


Patients were randomized (1:1) to receive intravenous methylprednisolone sodium succinate diluted in 50 mL of 5% dextrose in water (single dose: 2 mg/kg, followed by 0.5 mg/kg Q6H for 14 days, then 0.5 mg/kg Q12H for 7 days, and then tapering of dose) or a matching placebo. All patients underwent weaning from the ventilator under a protocol. 


Study period: August 1997 to November 2003

Follow-up: discharged without assistance, death, or 180 days

Outcome Measures

Primary: Mortality 60 days after enrollment

Secondary: Number of ventilator-free days,number of days without organ failure, ICU-free days at day 28, serious adverse events from myopathy/neuropathy, 180-day mortality in patients receiving treatment > 14 days after ARDS onset

Baseline Characteristics


Methylprednisolone (n= 89)

Placebo (n= 91)


Age, years

49.0 ± 19 49.2 ± 16.5  








Days in hospital prior to study inclusion

12.4 ± 6.2 12.3± 6.6  

Category of lung injury
















Direct lung injury

Indirect lung injury








Metylprednisolone (n=89)

Placebo (n=91)



25.6 (29.2 %)

26 (28.6%)


Ventilator-free days at day 28




Organ failure-free days




Coagulation abnormalities


20.7 ± 8.9

21.2 ± 10.2

22.8 ± 8.7

22.2 ± 8.3


17.9 ± 10.2

21.4 ± 10.2

21.4 ± 10.2

22.1 ± 8.6






ICU-free days at day 28

8.9 ± 8.2

6.2 ± 7.8


Serious adverse events associated with myopathy or neuropathy




180-day mortality in patients receiving treatment > 14 days after ARDS onset

23 (44%)

25 (12%)


Adverse Events

25 reported in the placebo group versus 33 in the methylprednisolone group (p=0.27). All 9 patients who experienced serious adverse events related to myopathy/neuropathy were in the methylprednisolone group which mainly reflected as bilateral weakness of the arms (71%).

Study Author Conclusions

The results do not support the routine use of methylprednisolone for persistent ARDS despite the inprovement in cardiopulmonary physiology. In addition starting metylprednisolone therapy more than two weeks after onset of ARDS may increase risk of death

InpharmD Researcher Critique

Patients in the study were intubated and/or on mechanical ventilation. This indicates the potential for comorbid complications being concomitantly treated. For the concerning outcome of patients treated after 14 days of symptom onset, the authors hypothesize that patients may be less-responsive to corticosteroid therapy due to lower active fibroproliferation (denoted by a lower baseline lung level of procollagen peptide type III). The optimal timing of methylprednisolone therapy remains to be seen.




Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354(16):1671-1684. doi:10.1056/NEJMoa051693


Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19


Ongoing, international, multicenter, open-label trial



To determine whether hydrocortisone improves outcomes for patients with severe Coronavirus Disease (COVID)-19 

Study Groups

Fixed-dose hydrocortisone (n= 143)

Shock-dependent hydrocortisone (n= 152)

No hydrocortisone (n= 108)

Inclusion Criteria

Adults with presumed or confirmed COVID-19 infection who were admitted to an intensice care unit (ICU) for respiratory or cardiovascular organ support

Exclusion Criteria

Presumption of imminent death, systemic corticosteroid use, more than 36 hours elapsed since ICU admission


Patients were randomized to receive a fixed dose of intravenous hydrocortisone, 50 mg every six hours for seven days; intravenous hydrocortisone, 50 mg every 6 hours while in shock for up to 28 days; or no hydrocortisone. Hydrocortisone was discontinued in the shock-dependent group once shock was considered to have resolved or vasopressors had been discontinued for 24 hours.


Up to 21 days

Outcome Measures

Primary outcome: respiratory and cardiovascular organ support–free days up to day 21

Secondary outcomes: Hospital mortality, Median organ support-free days among survivors

Baseline Characteristics


Fixed-dose hydrocortisone (n= 137)

Shock-dependent hydrocortisone (n= 146)

No hydrocortisone (n= 101)

Age, years

60.4 ± 11.6

59.5 ± 12.7

59.9 ± 14.6


98 (71.5%)

103 (70.6%)

72 (71.3%)

Confirmed SARS-CoV-2 Infection

109/134 (81.3%)

87/125 (69.6%)

79/100 (79.0%)

Time to Enrollment (IQR)

From hospital admission, days

From ICU admission, hours


1.2 (0.8-2.6)

15.1 (7.5-19.8)


1.0 (0.7-2.8)



1.1 (0.7-2.0)

13.5 (8.1-17.5)

Acute Respiratory Support


High-flow nasal cannula

Noninvasive MV

Invasive MV


Vasopressor support



17 (12.4%)

33 (24.1%)

87 (63.5%)

1/137 (0.7%)

56 (40.9%)


1 (0.7%)

23 (15.8%)

49 (33.6%)

73 (50.0%)


47 (32.2%)



16 (15.8%)

32 (31.7%)

53 (52.5%)

2/99 (2.0%)

30 (29.7%)



Fixed-Dose Hydrocortisone (n= 137)

Shock-Dependent Hydrocortisone (n= 146)

No Hydrocortisone (n= 101)

Median organ support-free days

In-hospital deaths

Median Organ support-free days among survivors

0 (-1 to 15)

41 (30%)

11.5 (0 to 17)


0 (-1 to 13)


37 (26%)

9.5 (0 to 16)

0 (-1 to 11)

33 (33%)

6 (0 to 12)

Patients with >1 serious adverse events

4 (3%)

5 (4%)

1 (1%)

Study Author Conclusions

In patients with severe COVID-19, treatment with a 7 day fixed course of hydrocortisone or shock-dependent dosing of hydrocortisone was 93% and 80% superior, respectively, to no hydrocortisone treatment in improvement of organ support free days. However, this study was stopped early and no statistical superiority was met.  

InpharmD Researcher Critique

The use of hydrocortisone in patients with severe COVID-19 may be superior to no hydrocortisone treatment in terms of organ support-free days including respiratory and cardiovascular support. These results were reported before meeting any prespecified internal trigger. This trial was open-label and 15% of patients in the “no hydrocortisone” group received systemic corticosteroids.




Writing Committee for the REMAP-CAP Investigators, Angus DC, Derde L, et al. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial [published online ahead of print, 2020 Sep 2]. JAMA. 2020;10.1001/jama.2020.17022. doi:10.1001/jama.2020.17022