Clinical guidelines are systematically developed statements of good practice in clinical medicine. They set out the problem, explain the issues, and make clear and unambiguous recommendations on the treatment choices available to health workers and the public at large. Busy doctors and nurses seldom have the time to put in the work involved and many find such guidelines invaluable in their clinical practice.
When done well, they are immensely useful even in routine healthcare settings. In the midst of a widespread health emergency such as we have witnessed in India during the second wave of the SARS-Cov2 epidemic, clinical practice guidelines are vital. Getting them right is crucial; equally getting them wrong could lead to damaging consequences.
Clinical guidelines are by no means new. The movement towards systematically promoting effective healthcare is at least 40 years old now. Many countries have invested public money in building up academic expertise in critical appraisal of the research evidence and in the science and art of developing clinical guidelines. A few well-known examples from around the world are:
- The UK’s National Institute of Health and Clinical Excellence (NICE)
- The Scottish Inter-collegiate Guidelines Network
- The Canadian Medical Association Clinical Practice Guidelines Infobase
- The New Zealand Clinical Guidelines Group Clinical Practice Guidelines
- The US Agency for Healthcare Research and Quality’s National Guidelines Clearing House
There is also rich literature on best practice in developing and disseminating clinical practice guidelines.
Summary of Good Practice
|Be systematically evidence-based.|
|State the strength of evidence when making practice recommendation.|
|Quantify the health-gain from implementing the practice recommendations.|
|Be written by experts with domain knowledge and experience of developing guidelines.|
|Involve practicing clinicians as well as patient groups by a process of consultation.|
|Be mindful of resources available to a health system.|
| Balance the needs of individual patients and the population served.|
|Be regularly and quickly revised in the light of emerging evidence.|
How has India used clinical practice guidelines as a tool in the Covid pandemic?
We discuss the Indian experience in the recent pandemic with respect to four situations.
First, the use of convalescent plasma; second, the use of a range of drugs believed to have anti-viral properties; third, the role of steroids in reducing mortality; and fourth, the possible contribution of overuse of treatments recommended in guidelines to the Mucormycosis epidemic.
India has overused plasma, attracted possibly by its biological plausibility and early support for treatment of Covid-19 afflicted patients. Social media is replete with appeals for blood donors to come forward and rescue someone in hospital with severe form of the disease. But whereas many other countries changed practice as soon as evidence of lack of efficacy emerged, Indian doctors persisted with this line.
In November 2020, the Indian Council of Medical Research made a half-hearted attempt to limit the use of plasma by suggesting strict criteria for its use, but clearly this sent the wrong message to practicing clinicians and demand for plasma mushroomed.
It was only after a group of clinicians and bioethicists wrote an open letter to Principal Scientific Adviser K Vijayraghavan that the ICMR revised the Guidelines for treatment of Covid-19, removing convalescent plasma as a treatment option. But despite the revision, there was a backlash from those who would potentially lose out from the lucrative trade in plasma.
Antiviral and antiparasitic agents
There is as yet little to no evidence that widely used antiviral agents save lives during this pandemic. These include favipiravir, remdesivir, hydroxychloroquine, ivermectin, and more recently the latest from India’s Defence Research and Development Organisation and Dr Reddy’s Labs, 2-Deoxy D Glucose (2-DG), which is an analog of the glucose molecule. And yet, the latest iteration of National Covid Task Force Guidelines provides for the use of remdesivir, ivermectin and hydroxychloroquine, albeit with supposed caution, and in specified and limited circumstances.
In his April 25 Mann Ki Baat radio address, Prime Minister Narendra Modi interviewed Dr Shashank Joshi who decried the overuse of remdesivir. However, five days later, the government of India announced plans to import just short of half-a-million vials of the drug from the United States and Egypt. A few days later, on May 4, it was patting itself on the back by announcing a ramping up of production of remdesivir locally. Such mixed messaging sends confusing signals about how seriously the guidelines should be taken by practicing healthcare workers.
The one drug that has definitely been shown to save lives in Covid-19 is dexamethasone. The original trial used this specific steroid in a dose of 6 mg once a day orally for 10 days, after which it was stopped without dose-tapering. The ICMR guidelines recommends injectable methylprednisolone for moderately severe disease in a dose of 0.5 am-1 mg per kg body weight per day for 5-10 days; and in severe disease in a dose of 1-2 mg per kg body weight.
It is unclear where and how the switch occurred from dexamethasone to methlyprednisolone. Pharmacologically, 6 mg of dexamethasone is equivalent in steroid strength to 30 mg of methylprednisolone, or 150 mg of hydrocortisone. The ICMR recommendation of a dose between 0.5 to 2 mg of methylprednisolone per kg body weight would, for an 80 kg adult, deliver the equivalent of between 8 mg and 32 mg of dexamethasone.
This is clearly an excessive dose of steroid, and that is if the dose and duration recommended is strictly adhered to. We are all aware of rampant systematic overuse of this drug even in mild to moderate conditions.
Did the guidelines result in complications?
As cases begin to wane in our cities, India has witnessed an alarming rate of increase in fungal infections called Mucormycosis which is both hugely expensive to treat and carries a relatively high morbidity and mortality. Patients who recover from Covid-19 present themselves with nasal blockage, congestion, bloody nasal discharge and localised facial pain, numbness, swelling, and blurred or double vision. Many states have declared it an epidemic and made the disease notifiable.
Mucormycosis is a much-feared complicating infection in people with debilitating diseases such as cancer where treatments such as radiation and chemotherapy lower immunity of the patient. To account for the dramatic rise in incidence following Covid-19 in India, we have many theories but little hard evidence. Overuse of steroids and poorly controlled diabetes are believed to be the most likely pre-disposing factors but excessive and indiscriminate prophylactic off-label use of antibiotics, contaminated water to humidify oxygen, repurposing of industrial grade oxygen, and the widespread prescription of zinc have all been suggested as potential risk factors.
If steroid overuse is a likely risk factor, then the ICMR guidelines may have at least contributed, even if only inadvertently, to indiscriminate over-use in treating patients with Covid-19. It does not explicitly restrict steroids to patients who are either on high flow nasal oxygen or are being mechanically ventilated. By recommending injectable methylprednisolone at high and varying doses, it may have led doctors to draw their own conclusion that more severe disease calls for higher doses.
The World Health Organisation and the US-Centre for Disease Control guidelines explicitly call out the risks associated with use of such drugs which are not backed up by robust clinical evidence. By not explicitly discouraging the use of antibiotics such as ivermectin, hydroxychloroquine, and azithromycin, the guidelines may have lost an opportunity to educate doctors that indiscriminate use of drugs without good evidence of effectiveness has real consequences for their patients.
The recently issued guideline for Mucormycosis makes but weak recommendations on prevention, focusing on hygiene to the exclusion of more relevant steps such as not to prescribe or overuse drugs that predispose the patient.
In a country like ours, where powerful medicines are available often without a prescription; where doctors have a tendency to over-prescribe; and where off-label use of drugs is rampant, one has to ask: why we are unable to run properly designed and well-conducted clinical studies to establish evidence to make categorical recommendation of therapies in our National Treatment Guidelines? Why do we continue to have qualifiers like “experimental use” and “clinical trial mode” giving physicians who are already under pressure to “do something” an easy way out using these unproven therapies?
We seem to have no hesitation in spending almost Rs 3,000 crore to promote questionable products like Coronil by cabinet-rank ministers. Clearly it is not a question of budgetary resources. Rather it is a question of priorities.
The development of treatment guidelines is a disciplined and deliberative process as was explained in this interview with clinicians from Christian Medical College, Vellore. Ideally it needs a multidisciplinary team of experts who understand clinical trials and research evidence. They need to have the time to consider the evidence, write a draft, and consult widely with clinicians and other users of the service, before issuing the guideline.
Treatment guidelines issued by the ICMR in July 2020, were revised only in April 2021. The National Task Force did not even meet for two months between January 2021 and April 2021, a crucial time when genomic sequencing and disease surveillance data began to emerge that a second wave of Covid-19 was all but certain.
The ICMR, for its part, needs to have an apex body of experts to independently oversee the process and take responsibility for drafting well considered treatment guidelines. For this role it must first choose experts known for their subject knowledge and expertise in infectious diseases, epidemiology, and public health; and not “celebrity names” just because they hold senior positions of power in institutions like AIIMS or Niti Aayog or some private hospitals to develop our pandemic response.
Second, we must not shy away from drawing on international expertise. There are many expert doctors of Indian-origin and academics working in the same field, albeit abroad, who would be willing to help on such an expert committee.
Third, these guidelines ought to be written in such a way that they should leave very little to the individual interpretation of a practicing healthcare worker.
Fourth, the guidelines should be continually reviewed and promptly updated upon the availability of additional evidence. It serves no purpose to issue a set of guidelines and have no follow up or revisions when new evidence emerges on therapies such as convalescent plasma, for example.
Fifth, there must be effective communication of updates and revisions to practicing healthcare workers across the country in a timely and efficient manner. Just posting the new revisions on a website without holding a session to explain what changed, what evidence was considered and evaluated and how the changes need to be incorporated in patient care should to be addressed clearly.
Unless we develop the discipline and stick to a deliberative process of generating, evaluating, and revising clinical evidence to support the treatments that are recommended on the National Treatment Guidelines, we will have to tolerate the pervasive off-label use of questionable drugs that in the end, do more harm than good to patients who have already suffered much.
Dr Jammi Nagaraj Rao is a public health physician, independent researcher and epidemiologist in the UK.
Dinesh Thakur is a public health activist.