CME INDIA Presentation by Admin.

“If what you are doing isn’t working, change what you are doing” – Laurie Buchanan

We all use some drugs of unproven efficacy due to mad rush in COVID management. Are we ignoring the science and art of medicine? Many bells are ringing but which bells bring harmony in music is a great challenge today in physicians’ mind. This presentation of CME INDIA will clear most of your myths.

CME INDIA face à face:

Face-to-Face with Dr Chandrakant Tarke, DM (Pulmonology from New Delhi), MD, DNB, MNAMS, EDRM(Italy), Consultant and Interventional Pulmonologist and Sleep Disorder Specialist, Apollo Hospitals, Hyderabad.

Q. What is your experience with Favipiravir?

I have not found useful. (Seen many patients who deteriorated on Favipiravir as compared to Ivermectin and Doxy combination). Ivermectin better than Favipiravir. Many trials also came in favour of Ivermectin.

Q. How your feel about Remdesivir?

Remedesivir works better in first 10 days. Can be considered in mild cases also where fever persists beyond 4-5 days. CT score more than 8. Can use in CT score less than 8 with dense consolidation (rather than GGO), high fever without raised CRP especially in elderly and with co-morbidities even with normal CT too.

Q. Lots of cry for early use of steroids, do you think, it is justified?

• Steroids should be strictly avoided in:
  • Asymptomatic
  • Mild symptoms less than 7 days
  • CT score less than 8 with disease duration less than 5 to 7 days
  • Viremia phase (high fever with normal CRP and CT)
• Steroids should be used in all moderate and severe cases i.e. all patients with SPO2 less than 94 irrespective of day of onset of symptoms. All these patients should receive 80 to 120 mg MP/day.

Q. Dr P R Parthsarathy, Internist, Chennai asks: I have a question regarding the steroids. Agreed that it should not be used in the viraemic phase but sometimes it’s difficult to identify – the history may not be proper; the CRP may be normal but the CT shows abnormalities. In such a situation, how to proceed? Is there any way other than monitoring the markers on a daily basis in such a situation?

• Steroid is double edged sword, use carefully in COVID.
• Mild cases first week: AVOID
• Mild cases second week (fever, malaise, myalgia etc): can use low dose such as DEFLAZACORT 6 to 12 mg per day…If you want suppress inflammation further then DEXA 4 to 12 mg per day etc
• Moderate cases: Hospitalized patients: Methylprednisolone 40 to 120 mg per day,
• Non-hospitalised patients: Tab DEXA 6 BD or Tab. METHYLPRED 40 BD etc
• Severe cases: Methylprednisolone 120 mg per day…If no response in 2-3 days. Then consider 125, 250, 500 mg per day…
• Sharing my experience here with high dose steroids in selected cases. Used 500 mg per day of methylprednisolone for 1 to 3 days (on top of of 120 mg usual dose) in almost 40 patients, all on HFNC 50 to 80 litre requirement or NIV with 80 to 100% FiO2 requirement. Almost all in second week of illness. Not improved with tocilizumab/plasma etc. Almost all improved with high dose of steroid. Within 2-4 days post high dose steroid shifted to nasal prongs…!
• Right time and Right dosage make difference…!

Q. Please suggest how to advice Inflammatory markers, many poor people cannot afford it.

• Most important lab investigation for COVID is CRP (from reliable lab). CRP should be guide for steroid dose. If High CRP, Use higher dose of steroid. (Remember increased CRP in some cases can be because of bacterial infection, UTI, line sepsis etc. In such cases, don’t escalate steroids. Taper steroids and cover with appropriate antibiotic. Use Procalcitonin, WBC, cultures as a guide.
• IL 6 results are very unreliable due to following reasons:
  • Lab method are not standardized. Same sample can give different readings in different labs.
  • Collected blood sample transport delays, temperature exposure alters IL 6 values.       
  • Many stable patients can erroneously have IL 6 values in hundreds or thousands too.
• Clinico-radiologic findings and CRP (from reliable lab) should be the main criteria to use steroids.
• Almost all patients with CRP above 100 should be considered in cytokine storm and higher doses of steroids should be considered. In such cases daily CRP monitoring should be done.
• Other markers such as ferritin, LDH etc. are not so specific. Ferritin seem to rise with delay (CRP rises earlier than Ferritin). Repeating CRP is more useful than ferritin or LDH.
• D Dimer also important marker for treatment decision after CRP and Procalcitonin. All hospitalised patients should receive LMWH 40 mg daily. If CRP above 500 then consider 60 OD to 60 BD. If above 1000, then 60 BD. Look for creatinine, platelets etc. and dose adjustment in LMWH. Patients on 60 BD, daily Hb, occurrence of melena etc. should be observed.

Q. Does the patient give clue before going into cytokine storm?

• Yes. We can predict. If patient in second week having SOB (even with previous normal CT), rising CRP above 50, CT worsening etc. points towards impending cytokine storm. Daily CRP monitoring and steroids dose adjustment is crucial here. Selected patients improved with pulsed steroid i.e.500 mg of MP once daily for 3 days etc.

CME INDIA Discussion

Dr Meena Chhabra Diabetologist, Delhi:

• Recovery trial randomised evaluation of COVID 19 therapy showed that dexamethasone reduced deaths in patients on ventilator or receiving oxygen therapy. The dose used in RECOVERY is 6 mg daily for 10 days is 5 to 6-fold than the therapeutic glucocorticoid replacement dose. High glucocorticoid dose can exacerbate hyperglycaemia in people with established diabetes unmask undiagnosed diabetes, precipitate hyperglycaemia or new onset diabetes and can cause HHS (hyperglycaemic hyperosmolar state)
• High CRP does not mean higher dose of steroid. Doubling of CRP in 24 hours is a very good clinical marker.
• If CRP is more than 5 and is doubling in 24 hours-Steroids are indicated.

Dr Hem Shankar Sharma, Asso. Prof of Medicine and Nodal officer, Bhagalpur Medical College:

• Favipiravir – not that useful. In majority, why to give for 14 days?? The virus has not been multiplying beyond 10 to 12 days. Patients reported usually on day 4 to 5! Then purposes of giving a drug till 19 to 20th days!!!
• Ivermectin with Doxycycline is a good combination.
• Ramdesivir…agreed with the description.
• Steroids. No in asymptomatic or very mild cases, not requiring O2..support.
• CRP…YES, an important tool.
• IL6…confusing, reliability, lab references, cost!!!
• Clinical experience, with CBC, CRP, and Radiological evidence, important.
• All breathing problems cases, should have D DIMER, or CRP equivalent, LMWH important, Protocol as above.

Dr Swati Srivastava, Asso. Prof Medicine, SMS Medical College, Jaipur:

• Steroids – What about dexamethasone?
• Regarding steroids – I would not mention where it should not be given, rather we could mention where it will be useful. As per literature, they stress that, it is useful in sickest patients. But in clinical experience, it has good results
• Hyperglycaemia in diabetics is an important factor to be anticipated and managed accordingly
• Novel anticoagulants to follow up after discharge??

Dr Atri Gangopadhyay, Pulmonologist, Ranchi:

• Everything in COVID is still investigational and any proper RCT requires minimum two years to give a consensus.
• In such cases, when the disease is so prominent, we have to extrapolate from other existing viral diseases (logical) and often from experience (definitely not scientific)
• Steroids have always been used in viral pneumonias with good results.
• Two things that sets apart COVID from previous viral pneumonias are Cytokine storm and thromboembolism.
• Again, steroids have been shown to be beneficial in preventing/ postponing/ mitigating Cytokine storm.
• Symptomatic embolism cases do benefit from steroids.
• So, any COVID who is beyond mild/ asymptomatic, who has a decreased saturation is a case for steroid
• Exact monitoring yet has no consensus in COVID, so anyone admitted in an intensive care, must have daily markers, other people once every 3-4 days.
• COVID is a disease where I would always put more dependency on labs for follow up rather than clinical examination.
• Try proper examination with a PPE – ineffective and risky.
• There is no clinical sign detecting Cytokine storm or other worsening of COVID yet,
• So, for safety as well as efficiency please trust your labs currently for follow up of COVID.

Dr Ravi Kirti, HoD, Dept. of Medicine, AIIMS, Patna:

• Ivermectin – only observational data. No RCT. At this stage, not enough evidence to support its use.
• Steroids – only criteria should be oxygen requirement. All moderate and severe cases (I.e. patients unable to maintain saturation >94% without supplemental oxygen) should receive steroids.
• WHO recommends dose equivalent to 6 mg dexamethasone OD. The equivalent dose of methylprednisolone would be 32 mg per day. So, using doses higher than 80 mg per day is not advisable.
• CRP, D-dimer, LDH, Ferritin – all are markers of severity. But it is unclear how they can guide in treatment.
• Agree, IL6 results can be unreliable.
• Agree, LMWH should be used in all hospitalised patients (unless there is a contraindication). For example, Enoxaparin 40 mg SC OD. Who should receive higher doses (e.g. 1 mg/kg BD) is unclear. Many centres use such higher doses when d-dimer is 4 or 5 times the upper limit of normal. We use this dose in all patients who require supplemental oxygen. This is based on our understanding of the pathophysiology rather than evidence.

Dr V P Youmash, Assistant Professor, KAPV Medical College, Trichy:

• With my reasonable experience within our hospital for past 6 months, the most useful life saving drugs practically are Adequate oxygen support through various modalities, timely steroids and anticoagulation.
• HCQ, Ivermectin, Favipravir, Azithromycin and Doxycycline are all found useful in asymptomatic/ mild symptomatic pts or as prophylaxis too sometimes. They might shorten the symptomatic period and hasten the recovery, but most of the times the individual’s own immune regulation does the same job. We need more comparative studies for its usefulness against placebo management to prove its efficacy.
• Remedesevir for 5 days has been useful in mild symptomatic patients to hasten recovery. It is proven to be better than favipravir. Needs platelet, renal and liver function monitoring. Remedesevir in hypoxic moderate COVID pts does help to wean from oxygen faster, but only when given along with steroids and enoxaparin. We don’t know whether patient  improves with remedesevir or due to steroids/enoxaparin or synergistic effect of all three drugs. Even I have seen pts improve only with steroids and enoxaparin before the availability of remedesevir.
• Tocilizumab has been useful in selective pts, after ruling out active bacterial infections, but owing to the risk of flare up of TB and invasive fungal infections. Young pts and pts without much comorbidities respond well to tocilizumab when given at appropriate time.
• Timing of steroids is very crucial. First 5-7 days, it should be avoided. Even if given earlier, shorter duration doesn’t do much harm. But prolonged steroids started early in the course leads to hyperglycemia, secondary bacterial infections, prolonged symptoms, delays recovery and worsens the course at times. Steroids in hypoxic pts with extensive GGOs does wonders in a matter of 3-4 days. Oxygen requirement decreases and pts recover well within a week.
• Insulin by IV infusion or SC doses is another drug which has helped a lot in newly detected or known diabetic pts as many go into DKA due to multiple factors. Blood sugars in critically ill patient should be maintained 140-180 mg/dl.
• Addressing to sleep, diet and psychological support all helps in shortening the hospital stay and recovering patients earlier.

Dr Santosh Malpani, Diabetologist, Nanded, Maharashtra:

• Dr Chandrakant is from Nanded.  He has worked hard in COVID. He has narrated his experience in a lucid and simple way. It appears authentic. My experience is almost the same. Here in COVID hospitals we are having same protocol.

Dr Subhash Kumar, Diabetologist, Patna:

• In the Pandemic situation, evidence based medicine is given rest. Pharma and other agencies have taken the front seat in deciding the protocol. The COVID-19 treatment has been decided as per personal case based experience. We are missing the oath “Don’t do Harm if you can’t improve.” None of the anti-viral drugs have shown any statically significant benefits – they are more of pharma gimmicks.
• Other than Steroids in moderate to sever condition, none of the oral drugs have done any good.
• For sever COVID cases, a skill of intensivist and immediate protocol bases management can be life saviour. We still need a long way to go before we can tame the situation.
• I strongly believe pharma nexus is ruling the world. None of the evidence based protocols like NICE guideline, Australian guideline and others have ever advocated HCQS or any anti-viral drug for their population.
• Hope we get a clear RCT based evidence without pharma or any GOVT. intervention. Will give clear insight on use of drugs.

CME INDIA Learning Points:

• Shoot the Target in Time:
  • Patients transition through a number of different phases (clinical stages). The treatment of each phase is distinct … this is critically important.
  • Targeting the key pathologic processes has been highly successful, if begun within 6 hours of a COVID19 patient presenting with shortness of breath and/or arterial desaturation and requiring supplemental oxygen.
  • If such early initiation of treatment could be systematically achieved, the need for mechanical ventilators and ICU beds will decrease dramatically. EVMS Guideline Sept 28th.

• Remember MATH+ as Initial Hospital Protocol as per EVMS (East Virginia Medical School Guideline)
  • Methylprednisolone IV
  • Ascorbic Acid High dose IV
  • Thiamine
  • Heparin Low Molecular weight
  • + Zinc, Famotidine, Melatonin, Vitamin Magnesium

• Salvage treatments of unproven benefit.
  • Tocilizumab (IL-6 inhibitors)-It should be noted that Il-6 inhibitors may increase the risk of opportunistic infections.  IL-6 is required for a normal antibody response.
  • Convalescent serum: the role and timing of convalescent serum are uncertain.  COVID-19 pulmonary disease is immune mediated. It appears paradoxical to enhance the antibody response with convalescent serum.  Antibodies directed against SARS-CoV-2 appears pointless when the virus is DEAD.
  • In patients with progressive fibrosis the combination of anti-fibrotic therapy with corticosteroids should be considered
  • ECMO – Unlike “typical ARDS” patients do not progress into a resolution phase. Rather, patients with COVID-19 progress to a severe fibro-proliferative phase and ventilator dependency. ECMO in these patients would likely serve little purpose.

• Must Give Extended Anti-Coagulant Post discharge
  • Patients have an increased risk of thromboembolic events post-discharge.
  • Extended thromboprophylaxis (? with a DOAC) should be considered in high risk patients.
  • Risk factors include:
  •  Increased D dimer (> 2 times ULN)
  •  Increased CRP (> 2 times ULN) [200]
  •  Age > 60 iv. Prolonged immobilization

• Do not opt for Steroid Premature Discontinuation
  • Premature discontinuation of corticosteroids (after 4 day) and the effect of reinitiation of this combination on the CRP profile has been shown here. Message is crystal clear.

• Difficult to predict the disease
  • COVID-19 patients present with a variety of phenotypes.
  • It is dependent on inoculum size and viral load, genetic heterogeneity mutations and polymorphisms, blood type, sex and androgen status, age, race, BMI (obesity), immunological and nutritional status, and co-morbidities.
  • The phenotype at presentation determines the prognosis and impacts the optimal approach to treatment.

• The pulmonary phase of COVID-19 is a treatable disease
  • There is no single “silver bullet” to treat severe COVID-19 disease.
  • Patients will require treatment with multiple drugs/ interventions that have synergistic and overlapping biological effects

• LMWH-Any non-coagulant properties?
  • YES
  • Anti-inflammatory effects and inhibition of histones.
  • Vitro studies demonstrated that heparin inhibits SARS-CoV-2 interaction with the ACE-2 receptor and viral entry as well as viral replication
  • Most importantly LWWH inhibits heparanase (HPSE). HSE destroys the endothelial glycocalyx increasing endothelial leakiness, activating clotting and potentiating endothelialitis. (HPSE levels have been reported to be increased in patients with severe COVID-19 infection.)

• LMWH of UFH, which one better?
  • LMWH has
  • Ease of administration,
  • Greater anti-Xa activity
  • Better safety profile in comparison with unfractionated heparin (UFH)

• EVMS guidelines Golden views
  • The historically high levels of morbidity and mortality from COVID-19 is due to a single factor: the widespread and inappropriate reluctance amongst hospitalists and intensivists to employ anti-inflammatory and anticoagulant treatments, including corticosteroid therapy early in the course of a patient’s hospitalization.
  • It is essential to recognize that it is not the virus that is killing the patient, rather it is the patient’s overactive immune system.
  • The flames of the “cytokine fire” are out of control and need to be extinguished. Providing supportive care (with ventilators that themselves stoke the fire) and waiting for the cytokine fire to burn itself out simply does not work… this approach has FAILED and has led to the death of tens of thousands of patients.

CME INDIA Tail Piece:

7 TIPS by Dr Atri Gangopadhyay, Pulmonologist, Ranchi seems smooth sailing in untidy sea:

• Any chest / throat symptomatic, go for COVID testing first. Don’t wait for 2-3 days.
• If COVID positive, advice CT chest, D dimer, CRP.
• Extensive chest lesions – admit, Remdesivir, Antibiotics (doxycycline is the best friend whatever others may say).
• Limited CT findings – NO ANTIVIRALS, no antibiotics, only micronutrient and antiallergic.
• If COVID negative – Xray, treat for pharyngitis, with repeat COVID test after three days if deterioration.
• In admitted moderate – severe COVID, repeat CT only after 72 hrs if deterioration/ no improvement. No repeat CT if improvement. You may repeat CT at discharge to know about post-COVID.
• Xray may be repeated in ICU admitted patients based upon clinical judgement.

(Presented by DR. N.K.SINGH)

Source:

https://www.evms.edu/media/evms_public/departments/internal_medicine/EVMS_Critical_Care_COVID-19_Protocol.pdf

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