CME INDIA Presentation by Dr N K Singh, Admin.

At that time, two philosophical quotes motivated me to rewrite the rejected letter from Lancet: “Medicine is the science of uncertainty and the art of probability” (William Osler) and “Nothing belongs to you more than your dreams” (Friedrich Nietzsche). I decided to resubmit the letter now, considering that COVID-19 should be a methylene blue “promoter”, and the dye can get the lifesaving status it deserves. – Paulo Roberto B. Evora, MD, PhD DOI: 10.21470/1678-9741-1-2020-0607 Braz J Cardiovasc Surg 2020;35(4):604-5

CME INDIA Feature

Dr Subodh Banzal, endocrinologist, Indore posted a YouTube video in CME INDIA group on 10th September 2020. He says: Dr Sunil Garge and Dr Mahashabde are my classmates and both are senior citizens. Dr Garge is Post renal transplant and Dr Mahashabde is diabetic. Both were seriously ill and had a good recovery after Methylene Blue. I am not directly involved in treatment of COVID patients. I forwarded their experiences to take opinion of all colleagues who are involved in corona patients care. Listen to the message:

This is an audio by Dr Sunil Garge – an anecdotal miraculous narration of Methylene Blue’s use and its benefit. It authenticates one more experience by another doctor too. I too contacted Dr Sudhir Mahashabde, ophthalmologist at Indore.

He responded as: My experiences are anecdotal. When I was admitted for COVID, my friend Dr. Sunil Garge was also admitted. He insisted on the use of Methylene Blue nebulization. He himself was taking it. Simultaneously, my 2 other doctor classmates who were under COVID treatment were also taking Methylene Blue. We all took this treatment. We all are better. I shared it with my doctor friends & groups. We got reference from Dr. Golwalkar from Bhavnagar, who was treating with this method. It is great that you are keen to study it scientifically.

Dr Taresh Patel, DTCD, Surat: One interesting case of happy hypoxia:

34 year’s male patient referred by well-known family physician with SpO2 only 85% in all 4 limbs without any symptoms and HRCT was normal. Basic blood reports were normal. I admitted patient and first done ABG that was normal so I suspected Methemoglobinemia and send blood for the same. To rule out COVID as a cause of methemoglobinemia, I sent Rapid Antigen Test that was positive.

I started oxygen and gave one injection of Methylene Blue after G6PD normal and in next morning Spo2 was 98% without oxygen. Patient discharged after 2 days. His methaemoglobin was high. In COVID happy hypoxia is due to methemoglobinemia.

Dr Sanjeev R Pathak, Diabetologist, Ahmedabad: Yes may be true for some cases but not in most – according to one of the critical care experts in Ahmedabad.

Dr Akash Kumar Singh, Internist, Vadodara:

The Vadodara experience with Methylene Blue. Posted after discussion with 3 tertiary care set ups treating COVID19 with the countries most advanced facilities in place. 2 of the 3 centres have not used it as they are not convinced about its usefulness in COVID19. Our centre’s experience which I am sharing after discussion with our Chief Intensivist Dr. Ankur Bhavsar FCCM, EDIC. My personal view:

It is not to be used. No rationale behind it. No study. Not even case series also, Of course no RCT. Not recommend by any of major scientific associations. We have used in 3 patients (100 mg in 250ml NS IV over 2-3 hours for 3 days on request of relatives) without any benefits. 2 patients have been transferred from other setups who were on MB inhalation and IV therapy respectively. Both have persistent oxygen requirement.
So the medical fraternity of Vadodara which is one of the best centre for medical education and has the most evidence based and rational medical practice in place is not at all convinced about this treatment modality for COVID19 and it is not used here

Dr Niranjan, Haematologist, Kolkata: Thank u Sir for this very interesting and informative case. I would ask our COVID Physicians whether they noticed higher PaO2 by ABG than what is suggested by Pulse Oximeter – in their COVID patients also? Because that is the hallmark of methemoglobinemia and very astutely picked up by the physician in this case, and whether they have any report of methaemoglobin level of COVID patients.

Dr Basab Ghosh, Internist, Agartala: Methemoglobinemia could be a possible complication in COVID-19, maybe HCQ is the culprit, so sufficient Vit C is suggested in the initial cocktail of treatment for any COVID-19 case.

What are doses of Methylene Blue based on spO2 level or PO2 level? Indications and contraindications?

Dr Subrahmanyam Karuturi, Rajahmundry, AP: IV: 1 mg/kg over 5 to 30 minutes, may repeat dose 1 hour later if methaemoglobin level remains above 30% or symptoms persists.

Methylene Blue use by Dr Deepak Golwalkar, Bhavnagar, Gujrat:

• I’ve achieved remarkable success in treating my patients with Methylene Blue and with documented evidence. When used in sub lingual and nebulised form M.B. helps remarkably in clearing alveolar capillary block.
• COVID causes a silent hypoxia wherein patients despite having acute hypoxia (low oxygen saturation spO2) show no clinical symptoms. Patient is not dyspnoeic in spite of having very low oxygen saturation. These soon escalate to a cytokine storm and patient goes in the irreversible phase of the respiratory distress.
• There are multiple reasons why M.B. is effective; the chief is Nitric Oxide mediated reduction in inflammatory cascades in addition to inhibiting canonical inflammasomes. COVID patients show resemblance to methemoglobinemia. M.B. is considered an approved drug of choice for methemoglobinemia. Additionally, M.B. has a strong antifibrotic action and is very fast acting.
• Primary course of administration is in Nebulized form and Sublingually together. For patients with severe Cyanosis (oxygen levels less than 85%), IV may be required based on the clinical condition of the patient.
• Administration steps as below (under medical supervision only as MB is known to be toxic in incorrect dosages):
  • 0.1% Methylene Blue to be administered as inhalation through a nebulizer (Primary line of treatment).
  • Nebulization to be given through a nasal mask.
  • Sublingual administration will be as a supportive line of treatment.

Methylene blue may have a role in the treatment of COVID-19 (Published online 2020 Aug 6. doi: 10.1016/j.mehy.2020.110163)

Article Highlights:

• We are focusing on possible role of an old albeit “mysterious” drug namely Methylene Blue. This medication may abort effects of Bradykinin by inhibition of Nitric Oxide synthase inhibitor and promote oxygen saturation while it is inexpensive and ubiquitously accessible. Clinical studies cannot be over emphasized.
• M.B. is a derivative of phenothiazine. It converts ferric iron in methaemoglobin to ferrous iron of normal haemoglobin and is a well-known medication for methemoglobinemia at doses of 1–2 mg/kg in repeatable single dose infusion shots. Administered intravenously, it is turned into leucomethylene blue in the body which can reduce the heme group from methaemoglobin to haemoglobin 
• Individuals with Glucose-6-Phosphate Dehydrogenase(G6PD) deficiency are at risk for haemolytic anaemia, while receiving M.B.
• Theoretical pivotal role of kininogen system in SARS-CoV-2 scenario is also in focus to imply that Kininogen-kallikrein system, may be not “a bean in the bean pot” among all the events of the disease.

Clinical Trial

[1]  Eur J Pharmacol. 2020 Oct 15; 885: 173494.Published online 2020 Aug 20. doi: 10.1016/j.ejphar.2020.173494

Application of methylene blue -vitamin C –N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial

“Preliminary results of this clinical trial showed the treatment of severe COVID-19 with a mixture of MB, vitamin C, and N-acetyl Cysteine is safe and feasible. The reduced MB has rapid and delayed effects. The rapid effect increases the SPO2% (All patients have been received 100% oxygen) by reducing met-Hb. Delayed effects are through the acceleration of normally slow NADPH–methemoglobin reductase, the improvement of inflammatory markers such as CRP level and LDH, decreasing severity of disease that may be also due to antimicrobial effect. We suggest the optimal time of reduced methylene blue (LMB) administration should be before entering the patient to a very severe stage of the disease and multi-organ involvement and failure. It is the opinion of the authors that the observed results if verified in more patients and a randomized multicenter clinical trial could significantly reduce the mortality of COVID-19 infection and ICU stay average length.”

CME INDIA Learning Points:

• Methylene Blue as an inexpensive ubiquitously available medication.
• It may have a considerable potential role in the treatment of COVID-19.
• Ministry of health/ICMR/AIIMS etc at present strictly do not advice to use it. There are preliminary trial reports from few centres, this cannot be taken as evidence-based science.
• This medication can be considered in this critical health emergency, either as compassionate/informed voluntary treatment for individuals.
• Paradoxical and unexpected effects have been observed in M.B. administration in other diseases if not meticulously done with proper dosage.
• Watch for adverse reaction that may happen in patients with a history of serotonergic medications as anti-depressants.
• G6PD deficiency must be ruled out before M.B. administration.
• Concomitant NSAID administration may block alternative pathways of BRK activity. In the condition of NO synthesis block, these pathways may be over activated and continue the disease process. Hence NSAIDs may add a benefit to M.B.
• Any clinical step must be taken cautiously.
• Other side of coin is that we are in a scrambling global health emergency. Too much obsessive and procrastinating methodology may leave us with many dead patients.

CME INDIA Tail Piece

By Dr Prabhat Agarwal, Agra.

What is shown in red circle ara in ABG report?

tHb is defined as the sum of HHb+O2Hb+COHb+MeHb.

COHb(carboxyhemoglobin) and MetHb(methemoglobin)are called dyshemoglobins as they are incapable of oxygen transport.

total hemoglobin, ctHb (cO2Hb + cHHb + cCOHb + cMetHb)

fractionated carboxyhemoglobin, FCOHb (cCOHb / ctHb × 100)

fractionated methemoglobin, FMetHb (cMetHb / ctHb × 100)

fractionated oxyhemoglobin FO2Hb (cO2Hb / ctHb × 100

[Note: If local availability is a problem, online sites are selling it]

Further Reading:

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409924/

2. https://deemagclinic.com/2020/09/22/methylene-blue-may-have-a-role-in-the-treatment-of-COVID-19/

3. J Anaesthesiol Clin Pharmacol. 2010 Oct-Dec; 26(4): 517–520

4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440159/

Discover CME INDIA

• Explore CME INDIA Repository
• Examine CME INDIA Case Study
• Read History Today in Medicine
• Register for Future CMEs

Get CME INDIA Highlights

Curated articles in your inbox.

SUBSCRIBE!

You have Successfully Subscribed!