When should I consider systemic corticosteroids in my patient with Covid-19?

As of July 30, 2020, The National Institute of Health (NIH) Coronavirus Disease 2019 (COVID-19) Guidelines Panel recommends using dexamethasone 6 mg per day for up to 10 days for the treatment of Covid-19 in patients who are mechanically ventilated (“Strong” recommendation based on 1 or more randomized trials) with a a less strong recommendation (“Moderate”) in those who require supplemental oxygen but who are not mechanically ventilated.1

These recommendations appear to primarily stem from a multicenter, open label randomized controlled trial of dexamethasone vs standard of care in hospitalized patients in United Kingdom, 2 with treated group receiving dexamethasone 6 mg IV or orally daily for 10 days or until hospital discharge (whichever came first).  Mortality at 28 days was significantly lower among patients on mechanical ventilation who received dexamethasone (29.3% vs 41.4%, rate ratio 0.64, 95% CI, 0.51-0.81) and in those receiving supplemental oxygen without mechanical ventilation (23.3% vs 26.2%). The risk of progression to invasive mechanical ventilation was also lower in the dexamethasone group. No significant difference in mortality was found in patients who did not require supplemental oxygen. 

Retrospective and case series studies have reported conflicting results on the efficacy of corticosteroid for the treatment of covid-19. 3-10 That’s why despite its limitations (open label, wide range of 02 supplementation, few patients receiving remdesvir), the randomized controlled trial discussed above should guide our decision making on the use of corticosteroids in patients with Covid-19.

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References

  1. NIH. The Coronavirus Disease 2019 (COVID-19) Guidelines. https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/corticosteroids/ Accessed August 6, 2020.
  2. Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19—Preliminary report. N Engl J Med 2020; July 17, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2021436
  3. Keller MJ, Kitsis EA, Arora S, et al. Effect of systemic glucocorticoids on mortality or mechanical ventilation in patients with COVID-19. J Hosp Med 2020;15(8):489-493. https://www.journalofhospitalmedicine.com/jhospmed/article/225402/hospital-medicine/effect-systemic-glucocorticoidsmortalityor-mechanical
  4. Wang Y, Jiang W, He Q, et al. A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduct Target Ther. 2020;5(1):57. https://www.ncbi.nlm.nih.gov/pubmed/32341331
  5. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020. https://www.ncbi.nlm.nih.gov/pubmed/32167524
  6. Corral L, Bahamonde A, Arnaiz delas Revillas F, et al. GLUCOCOVID: A controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia. medRxiv. 2020. https://www.medrxiv.org/content/10.1101/2020.06.17.20133579v1
  7. Fadel R, Morrison AR, Vahia A, et al. Early short course corticosteroids in hospitalized patients with COVID-19. Clin Infect Dis. 2020. https://www.ncbi.nlm.nih.gov/pubmed/32427279
  8. Fernandez Cruz A, Ruiz-Antoran B, Munoz Gomez A, et al. Impact of glucocorticoid treatment in SARS-CoV-2 infection mortality: a retrospective controlled cohort study. Antimicrob Agents Chemother 2020. https://www.ncbi.nlm.nih.gov/pubmed/32571831
  9. Yang Z, Liu J, Zhou Y, Zhao X, Zhao Q, Liu J. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis. J Infect. 2020;81(1):e13-e20. https://www.ncbi.nlm.nih.gov/pubmed/32283144

 10. Lu X, Chen T, Wang Y, Wang J, Yan F. Adjuvant corticosteroid therapy for critically ill patients with COVID-19. Crit Care. 2020;24(1):241. https://www.ncbi.nlm.nih.gov/pubmed/32430057

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

When should I consider systemic corticosteroids in my patient with Covid-19?

Does my patient on chronic prednisone need stress doses of corticosteroids perioperatively?

There are wide-ranging opinions on stress doses of corticosteroids (CS) in patients on chronic prednisone undergoing surgery, largely due to lack of adequately-sized randomized controlled studies.  Most experts seem to agree, however, that the age-old practice of routinely administering very high doses of hydrocortisone (eg, 100 mg IV every 8 hours) with prolonged taper postoperatively is excessive. 1-7

Couple of questions to consider before you decide on stress doses of CS for your patient with CS-induced (not primary) adrenal suppression. First, is your patient likely to have a suppressed adrenal function? And if so, what type of surgery is he or she about to undergo?

As for the first question, keep in mind that exogenous CS suppress the production of corticotropin (ACTH) and can induce adrenal atrophy that may persist for up to 12 months, an effect that’s dependent not only on their dose but also on their duration and may vary greatly from person to person. 2,4

Generally, a daily prednisone dose of 5 mg or less —irrespective of the duration— is considered unlikely to cause adrenal suppression (unless it’s given at bed time) and therefore should not require stress doses of CS.1 Conversely, clinical features of Cushing’s syndrome and prednisone doses of 20 mg or more daily for more than 3 weeks are likely to be associated with hyphothalamic-pituitary-adrenal (HPA) axis suppression.  Due to possible delay in the recovery of the HPA axis after discontinuation of exogenous CS, you should review not only your patient’s current dose and duration of CS but his or her regimen during the previous year. 2

When in doubt, particularly in patients receiving intermediate doses (eg, between 5 to 20 mg of prednisone daily) or duration of CS, testing the HPA axis (eg, by cosyntropin stimulation) has been suggested by some with the caveats that it’s a grade 2C (weak recommendation, low quality evidence) recommendation,7 and the results may not necessarily predict clinical adrenal insufficiency or be available before surgery. 4  

Once you have decided that your patient may be at risk of adrenal insufficiency during the perioperative period, the stress dose and duration of CS will likely depend on the type of surgery: “minor” (eg, inguinal herniorrhaphy); “moderate” (eg, total joint replacement, peripheral vascular surgery) and “major” (eg, pancreatoduodenectomy, cardiac surgery with cardiopulmonary bypass). 

A popular online resource suggests the following:4

  • Minor surgery or local anesthesia: Give only the morning maintenance dose of CS without any stress doses
  • Moderate surgery: Give the usual morning dose plus hydrocortisone IV 50 mg (or equivalent) just before the procedure followed by 25 mg IV every 8 hours for 24 hours, followed by the maintenance regimen
  • Major surgery: Give the usual morning dose plus hydrocortisone 100 mg IV before anesthesia induction, followed by 50 mg IV every 8 hours for 24 hours, tapering the dose by half each day to maintenance.

Alternatively, for minor and moderate procedures, other authors suggest usual daily dose plus hydrocortisone 50 mg IV before incision, followed by hydrocortisone 25 mg IV every 8 h for 24 h, then the usual daily dose.1  Yet others have recommended giving IV hydrocortisone 25 mg/day for 1 day for minor surgeries, 50-75 mg/day x 1-2 days for moderate surgeries, and 100-150 mg/day for 2-3 days for major surgeries.2-4 Whichever regimen you chose, make sure to give the morning maintenance dose.  

Why is less aggressive stress dosing being favored in these patients? Several reasons come to mind, including:

  •  In normal subjects, endogenous cortisol production rarely rises above 150-200 mg /day even in response to major surgery 2-4   
  • High doses of CS, particularly with long taper, may unnecessarily subject patients to adverse effects, such as hyperglycemia and poor wound healing 3,4
  • Published reports of CS-treated patients having complications such as hypotension or even death in the postoperative period have generally only implicated, not proven, adrenal insufficiency as a cause. 1-4

 

Bonus pearl: Did you know that the hypotension of secondary adrenal insufficiency in patients treated with CS is not caused by mineralocorticoid deficiency? Instead, it may in part be related to the action of CS in enhancing vascular responsiveness to vasopressors (eg, catecholamines).2 

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References

  1. Liu MM, Reidy AB, Saatee S, et al. Perioperative steroid management: Approaches based on current evidence. Anesthesiology 2017;127:166-72. https://anesthesiology.pubs.asahq.org/article.aspx?articleid=2626031
  2. Axelrod L. Perioperative management of patients treated with glucocorticoids. Endocrinol Metab Clin N Am 2003;32:367-83. http://pggweb.com/doc/glucocorticoids.pdf
  3. Salem M, Tainsh RE Jr, Bromberg J, et al. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg 1997;219:416-25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1243159/
  4. Shaw M. When is perioperative ‘steroid coverage’ necessary? Clev Clin J Med 2002;69:9-11. https://www.ncbi.nlm.nih.gov/pubmed/11811727
  5. Urmson K. Stress dose steroids: the dogma persists. Can J Anesthe 2019;September 23. https://www.ncbi.nlm.nih.gov/pubmed/31549340
  6. Wax DB. One size fits all for stress-dose steroids. Anesthesiology 208;128:674-87. https://anesthesiology.pubs.asahq.org/article.aspx?articleid=2672525
  7. Hamrahian AH, Roman S, Milan S. The management of the surgical patient taking glucocorticoids. Uptodate 2019, accessed October 21, 2019. https://www.uptodate.com/contents/the-management-of-the-surgical-patient-taking-glucocorticoids
Does my patient on chronic prednisone need stress doses of corticosteroids perioperatively?

Despite taking higher doses of warfarin, my patient’s INR won’t budge. What am I missing?

Poor compliance is probably the most common and least “exciting” explanation for low INRs despite seemingly adequate or high warfarin doses.  Otherwise, consider the following: 

Increased vitamin K intake: Since warfarin acts by inhibiting vitamin K recycling by VKORC1 (Vitamin K epOxide Reductase Complex), find out if your patient takes multivitamins or loves foods or products rich in vitamin K, ranging from leafy green vegetables to nutritional supplements( eg, Ensure) and even chewing tobacco!1 

Drug interactions: Warfarin is notorious for interacting with many drugs, although its effect is more often enhanced than counteracted. Run the patient’s med list and look for “counteractors” of warfarin,  including carbamazepine, phenobarbital, phenytoin, rifampin, and dexamethasone.2 

Hypothyroidism: Thyroid hormone seems to be necessary for efficient clearance of the vitamin K-dependent clotting factors (II, VII, IX, and X). Thus, larger doses of warfarin may be needed when patients are hypothyroid.3 

Hyperlipidemia and obesity: High lipid levels may allow for high vitamin K levels (since it’s lipid-soluble and carried in VLDL), especially at the start of therapy.4,5 

What if the INR is falsely low? This is usually not the problem although one major trial took a lot of heat for using a point of care INR device that gave low readings in anemic patients.6  When in doubt, check a chromogenic factor Xa test to confirm; 20-30% activity correlates with a true INR of 2-3.7

If none of these explanations fit the bill, consider genetic testing for warfarin resistance.8,9

Bonus Pearl: Did you know that use of warfarin (introduced in 1948 as a rodenticide) has already led to some selective pressure for VKORC1 mutations in exposed rat populations.10

References

  1. Kuykendall JR, et al. Possible warfarin failure due to interaction with smokeless tobacco. Ann Pharmacother. 2004 Apr;38(4):595-7. https://www.ncbi.nlm.nih.gov/pubmed/14766993
  2. Zhou SF, et al. Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. https://www.ncbi.nlm.nih.gov/pubmed/19515014
  3. Bucerius J, et al. Impact of short-term hypothyroidism on systemic anticoagulation in patients with thyroid cancer and coumarin therapy. Thyroid. 2006 Apr;16(4):369-74. https://www.ncbi.nlm.nih.gov/pubmed/16646683
  4. Robinson A, et al. Lipids and warfarin requirements. Thromb Haemost. 1990;63:148–149. https://www.ncbi.nlm.nih.gov/pubmed/16646683
  5. Wallace JL, et al. Comparison of initial warfarin response in obese patients versus non-obese patients. J Thromb Thrombolysis. 2013 Jul;36(1):96-101. https://www.ncbi.nlm.nih.gov/pubmed/23015280
  6. Cohen D. Rivaroxaban: can we trust the evidence? BMJ 2016;352:i575. https://www.bmj.com/content/352/bmj.i575/rapid-responses
  7. Sanfelippo MJ, et al. Use of Chromogenic Assay of Factor X to Accept or Reject INR Results in Warfarin Treated Patients. Clin Med Res. 2009 Sep; 7(3): 103–105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757431/
  8. Rost S, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004;427:537–41. https://www.ncbi.nlm.nih.gov/pubmed/14765194
  9. Schwarz UI, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008 Mar 6;358(10):999-1008. https://www.ncbi.nlm.nih.gov/pubmed/18322281
  10. Rost S, et al. Novel mutations in the VKORC1 gene of wild rats and mice–a response to 50 years of selection pressure by warfarin? BMC Genet. 2009 Feb 6;10:4. https://bmcgenet.biomedcentral.com/articles/10.1186/1471-2156-10-4

Contributed by Nicholas B Bodnar, Harvard Medical School student, Boston, MA.

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Despite taking higher doses of warfarin, my patient’s INR won’t budge. What am I missing?

My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?

The most helpful lab data favoring corticosteroid-induced granulocytosis (CIG) is the absence of a shift to the left in the peripheral WBC (ie, no more than 6% band forms) and toxic granulation.1 Although the total WBC itself is less helpful, experimental studies have reported a mean maximum neutrophil counts 2.4 times the base line after IV injection of hydrocortisone (200 mg) 2, and a mean increase of 4,000 neutrophils/mm3 after prednisone (20-80 mg). 3

Several possible mechanisms for CIG revolving around altered neutrophil characteristics and dynamics have been proposed4, including

  • Reduced egress from blood into tissues
  • Demargination from vascular endothelial surfaces
  • Delayed apoptosis
  • Enhanced release from the bone marrow.

An experimental animal study reported that only 10% of CIG is related to bone marrow release of neutrophils with the rest related to demargination (61%) and reduced egress from blood or delayed apoptosis (29%).4 This study may explain why high percentage of band forms would not be expected in CIG.

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References

  1. Shoenfeld Y, Gurewich Y, Gallant LA, et al. Prednisone-induced leukocytosis: influence of dosage, method, and duration of administration on the degree of leukocytosis. Am J Med 1981;71:773-78. Link
  2. Bishop CR, Athens JW, Boggs DR, et al. Leukokinetic studies: A non-steady-state kinetic evaluation of the mechanism of cortisone-induced granulocytosis. J Clin Invest 1986;47:249-60. https://www.ncbi.nlm.nih.gov/pubmed/5638121
  3. Dale DC, Fauci AS, Guerry DuPont, et al. Comparison of agents producing a neutrophilic leukocytosis in man. J Clin Invest 1975;56:808-13. PDF
  4. Nakagawa M, Terashma T, D’yachkova YD, et al. Glucocorticoid-induced granulocytosis: Contribution of marrow release and demargination of intravascular granulocytes. Circulation 1998;98:2307-13. PDF

 

 

My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?