Rethinking Corticosteroid/Glucocorticoid Dosing in COVID-19

SARS-CoV-2 is a virus that kicks off an inflammatory disorder in certain individuals. That’s what data says and that’s what most of us have seen. Inflammatory markers through the roof on the sicker patients, those who end up in my ICU. We start glucocorticoid therapy such as dexamethasone or methylprednisolone and the inflammatory markers drop, patients sometimes get better. After starting the first wave hit my neck of the woods in March of 2020, I checked numerous labs on patients and found consistently elevated ferritin, CRP, and d-dimer.

Given that we had no data to guide our management outside of what folks were trying in other countries, we were flying blind while trying to save people. We took a shot and started giving these patients glucocorticoid therapy. Some got better, some didn’t. There was historical precedence to give glucocorticoid therapy in ARDS from Meduri’s old work. Although we knew it wasn’t beneficial and harmful to give glucocorticoid in influenza. Again, we were flying blind.

Then the RECOVERY trial was published. We rejoiced as our inclinations were confirmed in a fantastic large trial that has changed the management of COVID moving forward. The team found that 6mg of dexamethasone for 10 days saved lives in patients who required oxygen and had COVID-19. I went on to create content on this trial. Although the RECOVERY trial gave us great information, we have to be academically honest in admitting that the authors could have chosen a different glucocorticoid, a different dose, and a different duration of therapy.

This is where the fine tuning comes in and where I am trying to reconcile what to do next. I was always curious if we were under-dosing the glucocorticoid or keeping it on for too short a period of time in certain folks. Over the last two years I have read and dissected numerous papers on other glucocorticoid regimens for COVID-19.

For a period of time I believed the right way to go was to give patients methylprednisolone 1mg/kg IV twice a day or 125mg IV twice a day (whichever was higher) right off the bat and then taper down. Hit them hard up front and knock down the inflammatory response. This was based on numerous papers supporting this notion. It wasn’t just me making things up. Now, I am rethinking my approach. This has further come to mind since we’ve metaphorically been putting tocilizumab and baricitinib in the drinking water which have not necessarily been reflected in these trials. Have we perhaps gone too far on suppressing the immune system?

Since the RECOVERY trial there have been so many trials published looking at different regimens on different patient populations that it has been challenging to keep up. Heck, even one of the most respected cardiac anesthesia journals is weighing in on what to do. But what should we do? Even today (7/18/22), the NIH recommends a blanket 6mg of dexamethasone daily for up to 10 days or hospital discharge. This includes patients who are on supplemental oxygen all the way to ECMO patients.

I believe it is the right time to backtrack on my prior sentiments. There is significant heterogeneity in COVID patients at the end of the day. There’s variation in their presentation, oxygen requirement, clinical picture, etc. Systematic review and meta-analyses definitely have value, but they miss nuance. Tan et al. high-dose was defined as methylprednisolone >100 mg/day or equivalent and dexamethasone >20 mg/day. Low dose was anything less than that. Out of 12 studies and 2759 patients, high-dose did not decrease mortality. It seemed odd to me that there was no increase in hyperglycemia nor infection rates. Looking through the studies they reviewed, I did notice that there were a number of studies which showed a methylprednisolone benefit that they did not include amongst the twelve. Examples of those studies are noted HERE.

Torres et al. recently looked to tease out a way to personalize corticosteroids from data taken from 55 ICU’s in Spain. After 4226 patients were analyzed, they noted that “no effect was found regarding the dosage of corticosteroids”. At least here they found that a duration greater than 10 days was associated with decreased mortality. Bouadama et al. performed an RCT looking at 6mg per day of dexamethasone versus 20mg for 5 days then 10mg for 5 days. They found no benefits in any of their outcomes.

This all leads me to the recent work of two authors who I’ve followed their work for years. Annane was the lead author for two landmark trial looking at glucocorticoid therapy in septic shock. Meduri was mentioned earlier for doing corticosteroid work in ARDS. The two legends teamed up for an Editorial in Intensive Care Medicine that is free for you to download. If they had a chance to criticize my work, they’d pick apart my “one-size fits all” dosing. I have also stopped checking daily inflammatory markers on patients. The vast majority of the time it did not change management anyway. Then I would just pray the therapy worked and my patient would get better. (More to come…)

Citations for Glucocorticoid Therapy in COVID

Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, Gibson M, Umberger R. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007 Apr;131(4):954-63. doi: 10.1378/chest.06-2100. PMID: 17426195.
Link to (NOT FREE) Article

Ni YN, Chen G, Sun J, Liang BM, Liang ZA. The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis. Crit Care. 2019 Mar 27;23(1):99. doi: 10.1186/s13054-019-2395-8. Erratum in: Crit Care. 2020 Jun 23;24(1):376. PMID: 30917856; PMCID: PMC6437920.
Link to Article

RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.
Link to Article

Tan RSJ, Ng KT, Xin CE, Atan R, Yunos NM, Hasan MS. High-Dose versus Low-Dose Corticosteroids in COVID-19 Patients: a Systematic Review and Meta-analysis. J Cardiothorac Vasc Anesth. 2022 May 13:S1053-0770(22)00336-6. doi: 10.1053/j.jvca.2022.05.011. Epub ahead of print. PMID: 35715291; PMCID: PMC9101704.
Link to Article

Torres A, Motos A, Cillóniz C, Ceccato A, Fernández-Barat L, Gabarrús A, Bermejo-Martin J, Ferrer R, Riera J, Pérez-Arnal R, García-Gasulla D, Peñuelas O, Lorente JÁ, de Gonzalo-Calvo D, Almansa R, Menéndez R, Palomeque A, Villar RA, Añón JM, Balan Mariño A, Barberà C, Barberán J, Blandino Ortiz A, Boado MV, Bustamante-Munguira E, Caballero J, Cantón-Bulnes ML, Carbajales Pérez C, Carbonell N, Catalán-González M, de Frutos R, Franco N, Galbán C, Gumucio-Sanguino VD, de la Torre MDC, Díaz E, Estella Á, Gallego E, García Garmendia JL, Gómez JM, Huerta A, García RNJ, Loza-Vázquez A, Marin-
Corral J, Martin Delgado MC, Martínez de la Gándara A, Martínez Varela I, López Messa J, Albaiceta GM, Nieto M, Novo MA, Peñasco Y, Pérez-García F, Pozo-Laderas JC, Ricart P, Sagredo V, Sánchez-Miralles A, Sancho Chinesta S, Serra-Fortuny M, Socias L, Solé-Violan J, Suarez-Sipmann F, Tamayo Lomas L, Trenado J, Úbeda A, Valdivia LJ, Vidal P, Barbé F; CIBERESUCICOVID Project Investigators. Major candidate variables to guide personalised treatment with steroids in critically ill patients with COVID-19: CIBERESUCICOVID study. Intensive Care Med. 2022 Jul;48(7):850-864. doi: 10.1007/s00134-022-06726-w. Epub 2022 Jun 21. PMID: 35727348; PMCID: PMC9211796.
Link to Article

Bouadma L, Mekontso-Dessap A, Burdet C, Merdji H, Poissy J, Dupuis C, Guitton C, Schwebel C, Cohen Y, Bruel C, Marzouk M, Geri G, Cerf C, Mégarbane B, Garçon P, Kipnis E, Visseaux B, Beldjoudi N, Chevret S, Timsit JF; COVIDICUS Study Group. High-Dose Dexamethasone and Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure: The COVIDICUS Randomized Clinical Trial. JAMA Intern Med. 2022 Jul 5. doi: 10.1001/jamainternmed.2022.2168. Epub ahead of print. PMID: 35788622.
Link to Article and FULL FREE PDF

Annane D, Meduri GU. Precision medicine for corticotherapy in COVID-19. Intensive Care Med. 2022 Jul;48(7):926-929. doi: 10.1007/s00134-022-06751-9. Epub 2022 Jun 22. PMID: 35732834; PMCID: PMC9216292.
Link to Article

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