CME INDIA Presentation by Admin

CME INDIA Second Wave Vital Inputs

(A) Steroids in Covid – Double Edged Sword

Dr. S. K. Gupta, MD(Med), FICP, CFM(France), Clinical Asst. Professor GS Medical College CCSU Uttar Pradesh India. Visiting Consultant Max Super Speciality Hospital, New Delhi shares:

When to start Steroids in Covid-19?

1. All patients with oxygen saturations below 94% should be started on Steroids irrespective of day of illness.

To detect oxygen level below 94% use pulse oximeter. Oxygen saturation dipping to less than 94% after 5 min walk test or even during sleep could be early indicator of worsening disease.

Many patients may try to report higher Spo2 levels for fears of worsening disease. Care provider should try to elicit the lowest possible persistent reading of correctly measured Spo2 and give benefit of doubt to patient by starting early steroids.

2. If the symptoms (fever and/or cough) persist beyond five days: one may use Inhalational Budesonide (given by Nebulization or inhalers or with spacer at a dose of 800 mcg twice daily or more for five to seven days).

Avoid adding Levolin/ Asthalin/ Duolin in inhalation/nebulization because these agents may cause dryness of secretions tremors and loss of sleep.

3. If symptoms (persistent fever, cough worsening, myalgia, weakness etc. Suggestive of hyperinflammation) persist beyond seven days, the treating doctor may decide to add treatment with low-dose oral steroids e.g., Methyl prednisolone 4 to 8 mg twice a day or Prednisolone 5 to 10mg twice a day.

4. Treating physician may also choose to start oral Steroids if patient complains of sudden increasing weakness associated with high levels of rising CRP in second week of illness. Not even being able to go to toilet could be a common symptom of weakness.

5. If the patients are worsening steroid should be initiated early in the pulmonary phase to counter the immune dysregulation. Ideal time for steroid initiation is after eighth day of symptoms, when virus has very low tendency to replicate and inflammatory response is persistent.

Which steroid to be used in what doses?

• Dexamethasone Sodium phosphate 8mg is equal to dexamethasone 6mg *oral/iv/im per day.
• One may need to double the dose in severe cases.
• Dexamethasone is Tried, tested, affordable and easily available.
  • Or Methyl prednisolone 32 mg per day oral or IV
  • Or Prednisone/ Wysolone 40mg per day oral
• Methylprednisolone shown to offer no significant advantage over Dexamethasone except in short trials.

Precautions while giving steroids?

1. Blood sugar levels should be measured even in those with no previous history of diabetes because Covid itself is Diabetogenic disease. Stress of disease coupled with steroids can lead to early hyperglycaemia. 

2. Watch for secondary Bacterial/Fungal infection.

3. One may choose to add antibiotic cover to treatment.

How to manage high Blood sugar levels?

Insulin under care of a physician remains best choice, but if patient is on home isolation with random blood sugar levels in range of 150 to 200mg% one may choose to start with DPP4 inhibitors like Vildagliptin 50mg with/out Metformin 500mg twice a day. If still not controlled add Insulin.

Avoid SGLT2 inhibitors like Dapagliflozin and sulphonyl urea like glimepiride.

How long to give steroids?

5 to 10 days. No need to taper steroids after a short course of 5 days.

Steroids should be strictly avoided in

1. Asymptomatic.

2. Mild symptoms less than 7 days.

3. CT score less than 8 with disease duration less than 5 to 7 days.

4. Viremia phase (high fever with normal CRP and CT).

Second Wave ALERTS

(B) When early initiation of steroids becomes a Game Changer: Second Wave Solution

ALERT by Dr. Dhiren Gupta, MD (Pediatric), Sir Ganga Ram Hospital, Delhi (Personal Observations).

Few points want to share – which I learned over past 4 weeks (regarding Covid)

1) Not only incubation period has shortened but duration between first symptom and pneumonia. Last year it was 8 to 10 days but this time 6 to 8.

2) Loss of smell no more indicator of benign (means less severe disease) disease. Three of my patients last week had severe pneumonia.

3) Many adolescent behaving like adult – same pattern, similar pneumonia.

4) If you target drop in SpO2 to 94 and less for starting steroids probably you are late. It Takes 5 to 7 days to settle. But if u target persistence of fever (even if low grade – 99) after 6 days – You can save lot of patients from hypoxia.

5) Severe chills and rigor, 103 plus fever on day 2 to 3 indicates likely severe pneumonia. Treat them with steroids and Remdesivir (if available).

6) On sixth day of symptoms- if CRP more than 70 to 90 even with normal spo2- indication of cytokines storm. Almost all land up in ICU within 24 to 48 hours (without exception).

7) CTSS more than 11 with persisting fever – treat aggressively despite normoxia.

8) Detection of progressive inflammation before hypoxemia is the key.

9) Avoid use of steroids during first 5 days unless patient is hypoxic.

CME INDIA Learning Points

Timing Blues

There is no confusion

• The Ideal time for steroid initiation is after eighth day of symptoms, when virus is very low replicable and inflammatory response is about to settle down.
• If steroid is started in the early viral replicable phase i.e., early phase of symptoms then there is a chance that the virus will replicate more.
• In pulmonary phase steroid has to be given and start early with the standard dose, then after 24-hour dose can be increased seeing the clinical and biochemical response and this is the ideal approach as suggested by many experts. There is profound inflammation in pulmonary phase, so anti-inflammatory steroid has huge role to counter the process.

Then why expert now advocating to start early

• Second wave is behaving in very unpredictable way. Young cases with rapid deterioration are being observed.
• Dr. D. Ramesh, MD (Med), Coimbatore, tabulates it aptly:

• It is possible due to very subtle symptoms we are not able to pin point DAY 1 of the Covid Infection. This could be one major reason why early involvement of pulmonary phase being observed. All patients with oxygen saturations below 94% should be started on Steroids irrespective of day of illness. So, apart from general recommendations, applying your own wisdom is the need of the time.
• AIIMS 3^rd May new recommendations includes use of steroid in mild cases in specific situations.

Mild cases

• Inhalational Budesonide (given via DPI/MDI with Spacer at a dose of 800 mcg BD for 5 to 7 days) to be given if symptoms (fever and/or cough) are persistent beyond 5 days of disease onset
• Systemic Steroids NOT indicated in mild disease; HOWEVER, may be considered in cases with high grade fever and worsening cough beyond 7 days ONLY in consultation with the treating physician for a duration of 3-5 days. Tab Dexamethasone 0.1-0.2 mg/kg OD OR Tab Methylprednisolone 0.5-1 mg/kg in 2 divided doses.

Moderate cases

• Inj. Methylprednisolone 0.5 to 1 mg/kg in 2 divided doses (or an equivalent dose of dexamethasone – 0.1 to 0.2 mg/kg per day) usually for a duration of 5 to 10 days.
• Patients may be initiated or switched to oral route if stable and/or improving.

Severe cases

• Inj Methylprednisolone 1 to 2mg/kg IV in 2 divided doses (or an equivalent dose of dexamethasone – 0.2 to 0.4 mg/kg per day) usually for a duration 5 to 10 days.

Choice of Steroids, Use Any?^1-5

Choice of Steroid as per CDC

• Whether use of prednisone, methylprednisolone or hydrocortisone for the treatment of COVID-19 provides the same benefit as dexamethasone is unclear.
• The total daily dose equivalencies for these drugs to dexamethasone 6 mg (oral or intravenous [IV]) are:
  • Prednisone 40 mg.
  • Methylprednisolone 32 mg.
  • Hydrocortisone 160 mg.
• Half-life, duration of action, and frequency of administration vary among corticosteroids.
  • Long-acting corticosteroid: dexamethasone; half-life: 36 to 72 hours, administer once daily.
  • Intermediate-acting corticosteroids: prednisone and methylprednisolone; half-life: 12 to 36 hours, administer once daily or in two divided doses daily.
  • Short-acting corticosteroid: hydrocortisone; half-life: 8 to 12 hours, administer in two to four divided doses daily.

What about this statement? Is Methylprednisolone better?

• In the United Kingdom, a major randomized clinical trial (RCT) indicated that the use of low-dose dexamethasone in ventilated COVID-19 patients, and to a lesser degree in patients in need of supplemental oxygen, reduced the mortality.⁶
• Evidence for the intermediate-acting corticosteroid, methylprednisolone, has been limited to date.
• Mechanistically, methylprednisolone achieves higher lung tissue-to-plasma ratios in animal models than dexamethasone, which may thus be more effective for lung injury.
• In a recent study in hospitalized patients suffering from COVID-19 pneumonia, the administration of 2 mg/kg per day of intravenous methylprednisolone compared to treatment with 6 mg/day of dexamethasone, led to a reduction in the hospital length of stay, need for mechanical ventilation, and improved clinical status at days 5 and 10.⁸

Bottom Line

• USE ANY but use Steroid treatment at right time, right dose and maintain  right duration
• Most important factor is the timing of the steroid therapy; if not used early enough to prevent CARDS (Covid related adult respiratory distress syndrome), the effect of steroids will not be as effective as it would be if used before the onset of CARDS.
• Dexamethasone has a greater anti-inflammatory effect than does other commonly used corticosteroids of note is that dexamethasone has been shown to inhibit TSST-1 – induced cytokine production and T cell proliferation If a superantigen phenomenon is responsible for the hyperinflammatory response seen in some COVID-19 patients, dexamethasone would be expected to be an effective agent.
• Some studies do favour Methylprednisolone.

References

1. Liu J, Zheng X, Huang Y et al. Successful use of methylprednisolone for treating severe COVID-19. J Allergy Clin Immunol 2020. 183.
2. Meduri GU, Bridges L, Shih MC et al. Prolonged glucocorticoid treatment is associated with improved ARDS outomces: analysis of individual patients’ data from four randomized trials and trial-level metaanalysis of the updated literature. Intensive Care Med 2016; 42:829-40. 184.
3. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19. A meta-analysis. JAMA 2020. 185.
4. Ruiz-Irastorza G, Pijoan JI, Bereciatua E et al. Second week methyl-prednisolone pulses improve prognosis in patients with severe coronavirus disease 2019 pneumonia: An observational comparative study using routine care data. medRxiv 2020.
5. https://www.evms.edu/media/evms_public/departments/internal_medicine/Marik_Critical_Care_COVID-19_Protocol.pdf
6. Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693–704. https://doi.org/10.1056/NEJMoa2021436
7. Annane D, Pastores SM, Arlt W, Balk RA, Beishuizen A, Briegel J, et al. Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med. 2017;43(12):1781–92. https://doi.org/10.1007/s00134-017-4914-x.
8. Ranjbar, K., Moghadami, M., Mirahmadizadeh, A. et al. Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial. BMC Infect Dis 21, 337 (2021). https://doi.org/10.1186/s12879-021-06045-3

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