27/12/2020
മൃത്യോർമാ അമൃതം ഗമയ
Author: Dr Premanand, MD
Director (Ph: 8139877600)
Dr Prem's Centre for Diabetes & Medical Specialties, Thalassery
Part II
'I would especially commend the physician who, in acute diseases, by which the bulk of mankind are cut off, conducts the treatment better than others'. HIPPOCRATES
It is said that fools learn from experience, while the wise learn from history. In the scientific world, in order to be able to learn from history, archives of accurate, unbiased and well organized data has to be collected, peer reviewed and analyzed to share and use in future scenarios. Kerala has a robust and renowned primary care system under its government, one which provides immense safety to its population. It is this world class primary care system that we have to thank for successfully containing the infamous Nipah outbreak of 2018. This being said, when we compare similar Nipah outbreaks in other developing countries like Malaysia and Bangladesh, the mortality in the 2018 Kerala outbreak was quite high in contrast (Tan & Chua, Current Infectious Disease Reports). The data published on the past outbreak in medical literature has been few and far between. This high mortality has never been addressed and no medical audit has been published in the public domain.
The age old notion that prevention is better than cure holds true in regards to our current situation. It should come as no surprise that epidemics do emerge in this temperate climate every three or four years. As with the case of COVID-19, animal slaughterhouses with their often unhygienic environment are a prime breeding ground for viruses to thrive and spread among people from all walks of life. Establishing stringent public health and safety policies along with regular inspections from a central authority will pay rich dividends when it comes to curbing these outbreaks. It is the responsibility of the government and the public health departments to ensure that the number of people who have to see the insides of an intensive care unit is kept to an absolute minimum.
Oxygen is a drug, and as with any drug should be used only when needed, however its use must be warranted without any hesitation whenever the prerequisites to do so are met. You’d be hard pressed to stumble upon any ICU patient who was without an oxygen mask or tube. Laborious use of oxygen without a clear understanding of its effects on the body under various pathological conditions can have disastrous consequences, including sudden unexpected death. This is especially important to take into consideration when managing obese patients with respiratory compromise. In the hands of an experienced physician with learned brains, intensive care units equipped with advanced life support machines can bring the acutely sick back to life and save patients. Unfortunately, it is extremely sad that the public health system in our state lacks all of these in its entirety. It is imperative that the medical teaching and training system of the state undergo conscious revamping and rejuvenation to improve this very concerning state of affairs. Years of supervised dedicated intensive care training cannot be replaced by any short-cuts. It is no surprise that a haphazardly put together team of niche specialists who lack the proper training for managing acute critical care scenarios will have poorer outcomes as they lack the expertise and know-how that is required of a competent critical care team.
Closed glass doors are a curse to any society. Barring procedures and isolation precautions, ICUs should be open to patient’s loved ones. Transparent communication, whether it be verbal, non verbal, or even digital, and proper documentation of all medical records and data are of immense value, on top of offering medical workers a layer of legal protection if needed. On top of preventing potential litigation, truthful and open communication adds beauty to the art of medicine. It has been scientifically proven that the very sick patients do recognize people who care for them even beyond the language of communication. De-escalation of futile treatment and experimental therapy, when the patient is at the point of no-return, will only add respect to the treating physician and will never equate to euthanasia. It isn’t hard too farfetched for the doctors to see themselves in their patient’s shoes. Infection control and safe practices should be stringently implemented and must be, ideally, entrusted as the responsibility of a separate infection control team, independent of the doctors managing critical care patients. This, as proven in countless infection control studies, will minimize the number of medical personnel contracting the disease every day. All aerosol producing procedures especially NIV be instituted cautiously in all facilities with no negative pressure rooms, as PPEs are likely ineffective.
ARDS is the conglomeration of all the organ insultsin any acute infection as do Covid-19. ARDS onset is often rapid and progressive, appearing approximately nine days after the onset of a severe COVID‐19 infection. On average, patients with ARDS died approximately twenty days after the onset of the symptoms or about ten days after ICU admission. ARDS is difficult to manage at a late stage of the disease and early recognition is crucial in arresting progression. With a SARS-CoV2 infection, the lung protective mechanism is lost due to virus damaging the lung epithelium through its influence on ACE-2 receptors. 83% of cells expressing ACE receptors are in alveolar epithelial cells, forming a nidus for the virus, and ensuing more lethality. The alveolus begins to fill with neutrophils, cytokines and exudate. In this state, the lungs cannot provide enough oxygen to the blood for the body's organs, leading to a stage of hypoxia, a point where the vital organs such as the brain and kidneys are starved of oxygen. Inflammation also alters the clotting system to a state prone for clot formation known as a hypercoagulable state, allowing for lethal thrombotic complications to occur. One of the worrying things that mortality statistics overlook are the devastating, everlasting consequences patients who have survived severe COVID infections have to live with. TV channels and politicians love to flash a low percentage of infected patients dying, but what they fail to mention are the alarming number of patients who have permanently impaired lung functions, fibrosis, and other associated morbidities caused by compromised COVID infection.
Dual modes of transmission makes Covid spread dangerously easy. When unchecked, the virus can spread as easily as the scent of cigarette smoke. Immune modulation and inflammation makes Covid potentially fatal in victims with pro-inflammatory conditions like heart disease, cancers or diabetes. A deranged immune system with advanced age makes them further vulnerable as aging can lead to weakening of the innate immune system leading to a higher viral load in these populations. This in turn results in an over-activation of the adaptive immune system, leading to an increased level of cytokine production, commonly called a cytokine storm. There is anecdotal evidence from pilot studies, retrospective and experimental studies stating that there are varying levels of benefits in the prevention and control of COVID-19 by vitamin D, vitamin C, Zinc and Selenium supplementation. Vitamin D has been of specific interest among many physicians and researchers alike, as it stabilizes the protective mechanism in the alveolar epithelium.
Vitamin D is the most widely studied and probably the most promising agent. Recent European studies highlight the immune-modulatory properties of Vitamin D and calls attention to the fact that its deficiency has been well documented in patients who have contracted covid and subsequently progressed into its more severe stages. The authors suggest to keep the serum Vit D level above 100 nmol/L, with supplementation of 100,000 IU in the 1st week and 50,000 IU weekly after for slowing disease progression and improving survival. Dark skinned people have lower levels of Vit D and are more prone for complications. Intake of Vit D upto 15,000 IU/day is found to be safe in view of the authors. Another recent study reports ARDS may be aggravated by vitamin D deficiency due to unregulated cytokine production and inflammation and tapered down by activation of the vitamin D receptor. Lung epithelial cells have an abundance of Vit D receptors, suggesting a possible preventive role of Vit D by improving lung epithelial protective mechanism thereby preventing viral invasion and replication. Vitamin D deficiency is more common in older patients and in patients with obesity and hypertension, both being predispositions for poorer prognosis upon infection. The rationale for using vitamin D is based largely on immunomodulatory effects that could potentially protect against COVID-19 infection or decrease the severity of illness. Vitamin D can suppress cytokine production by simultaneously boosting the natural immune system, thus reducing the viral load in the early stage of infection, and decreasing the over-activation of the acquired immune system, potentially cushioning the cytokine storm and ARDS. Most immune cells express the receptors for Vit D and most cytokines, produced by or regulating these immune cells, are under the coherent control of the active vitamin D. Most studies have reported that VitD supplementation is inversely associated with CRP levels.
Despite the potential effects of Vit D on ARDS or lung injury, serious caution is needed before concluding that vitamin D supplementation may improve the outcome of SARSCoV-2 infections. Vit D receptors regulate a very large number of genes, mostly in cluster patterns, and there has been a lot of speculation on the beneficial effects of vitamin D supplementation for a wide variety of major diseases with inconclusive evidence. It is assumed that 65% of the Indian population is deficient in Vit D. Correction of vitamin D deficiency is relatively easy by either increased exposure to sunlight (unlikely for patients with ARDS), oral or parenteral vitamin D supplementation. To correct vitamin D deficiency in severely sick patients much higher doses than usual are needed, probably related to impaired hepatic conversion. Vit D may reduce the incidence of ARDS, possibly benefiting patients later on in the disease course upon admission to ICUs and improving mortality rates. We are at an early stage in understanding the heterogeneity of COVID-19-associated ARDS, it’s pathophysiological features, clinical course, biomarkers, and phenotypes based on respiratory mechanics. ARDS is a heterogeneous syndrome, presenting with variable mechanical and gas exchange disturbances. These features make it an important but ubiquitous finding in various disease processes. This clinical and biological heterogeneity contributes substantially to the complexity of managing COVID-19 in the ICU.
Several observational and interventional studies are currently running including early Aspirin and Vitamin D to reduce COVID-19 Hospitalizations, Phase II Pilot Study of Hydroxychloroquine, Vitamin C, Vitamin D, and Zinc for the Prevention of COVID-19 Infection, impact of Zinc and Vitamin D3 supplementation on the survival of aged patients infected with COVID-19, COVID-19 and Vitamin D Supplementation - High Dose Versus Standard Dose Vitamin D, just to name a few. More affirmative conclusions are likely in the months to come and several randomized control trials in the pipeline
COVID-19 has been associated with inflammation and a prothrombotic state with increases in fibrin, fibrin degradation products, fibrinogen, and D-dimers, all associated with worse clinical outcomes. Heparin in prophylactic and therapeutic doses are strongly indicated. Autopsy studies have proven clinically significant hypercoagulability in 15-30% of patients. Covid-19 being a hypercoagulable state, all hospitalized patients should be on prophylactic LMW heparin and clinically judged for therapeutic anticoagulation. Use of regular Aspirin is also under clinical trial.
Vitamin C has beneficial effects in patients with critical illnesses as it is an antioxidant and a free radical scavenger. It has anti-inflammatory properties, influences cellular immunity and vascular integrity. In ARDS, high doses of vitamin C ameliorates inflammation and vascular injury in patients with COVID-19. High dose IV Vit C, 12 to 24 gm/day has been tried in ICUs with varying benefits. Though Zinc has been shown to have impact on RNA viral replication, its long term supplementation is not advisable due to negative effects on hematologic and neural systems. Remdesivir, an antiviral agent, cripples enzymes that viruses need to replicate themselves. Dexamethasone, through its anti-inflammatory effects, has proven benefits in hypoxemic patients. Drawing from conclusions based on the English Recovery Trial and various other similar findings from countries such as China and the United States, approximately one in every twenty critically ill patients who received treatment (Remdesivir or Dexamethasone) were likely to survive.
It is far too soon to believe that surviving the virus means you are safe. You still need to avoid gathering and keep your distance from people outside your immediate household. And you still need to wear a mask.COVID-19 is a zoonosis, first transferred from infected bats in the wet markets of Wuhan. Now, it seems that we have returned the favour, millions of minks have been ordered to be culled as they have been reported to have a mutated version of the virus that they are now transferring to humans. Everyone has the right to live- change is inevitable in our attitude towards the living world. As Karl Marx quotes, 'History repeats itself, first as tragedy, second as farce'.
