A drug that is familiar to mountaineers finds mention in humanity’s ongoing tussle with COVID-19. We use the juncture as an opportunity to reacquaint ourselves with Acute Mountain Sickness (AMS) and the drug in question.
Dexamethasone has been part of medicines used to treat high altitude illness for several years. Notwithstanding the lives it may have quietly saved so, its moment in the limelight happened in mid-June 2020 when news reports from the UK said, it was proving to be a life-saver in the battle with COVID-19. The drug’s name wouldn’t have escaped the attention of mountaineers and outdoor enthusiasts. Proper acclimatization, hydration, descent to safe altitude when beset with discomfort and having acetazolamide and dexamethasone in the first aid kit, form the classic defence against high altitude illness.
Colonel (Dr) S. P. Singh (Retd) is currently Additional Professor, Department of Physiology, All India Institute of Medical Science (AIIMS), Rishikesh. He runs India’s first course in High Altitude Medicine there. A product of the Armed Forces Medical College (AFMC), Pune, Dr Singh has been working in the field of high altitude medicine and physiology since 2008 when he was posted to the Indian Army’s High Altitude Medical Research Centre, in Leh (Ladakh). He has a number of publications in the field and was a member of the team that wrote the latest edition of the army’s guidelines for prevention and treatment of high altitude illness. Dr Singh responded to questions posed by this blog.
“ Dexamethasone is a medicine that is used for treating a large number of illnesses, including those due to inflammation (within that, auto-immune diseases where the body’s immune system attacks its own cells; for example: rheumatoid arthritis) and allergy; for example: skin allergies, eye allergies etc. It is also used as a life-saving drug when severe inflammation threatens dire consequences. The body produces corticosteroid hormones (better known to doctors as glucocorticoids) which are essential for life and continuously regulate a host of functions including energy production, water content of the body, immune regulation and behavior. An important function of glucocorticoids is to help us overcome stress. The term stress implies any shift in the environment that changes or threatens to change the existing optimal state of the body. Thus, extreme heat, cold, low environmental oxygen ere all examples of stress. Large amounts of glucocorticoids are secreted by the adrenal glands of the body to help overcome stress, ‘’ he said.
Dexamethasone in the context of AMS
In mountaineering, dexamethasone is spoken of in the context of Acute Mountain Sickness (AMS). According to Dr Singh, AMS is the most common illness to occur in un-acclimatized sojourners arriving at High Altitude (>2700m/9000ft). It consists of a constellation of symptoms viz., headache, decreased appetite, nausea, vomiting, giddiness / dizziness and weakness / fatigue. Most people who develop these symptoms recover spontaneously or with symptomatic therapy (pain killers, anti-vomiting drugs and rest) within 2-3 days. Thus, AMS is a harmless illness, in terms of no threat to life and limb. Yet, it is important that people with AMS not ascend higher till their symptoms resolve completely. This is so, because we believe that approximately one per cent of people with AMS will develop High Altitude Cerebral Edema (HACE) if they ascend higher while symptomatic. HACE involves collection of excess water in the brain (brain edema) and can kill a person within hours of onset.
Hypoxia (the condition in which, the body or a portion of the body is deprived of adequate oxygen supply at the tissue level) is the direct cause of AMS. It leads to an increase in the pressure of Cerebro-Spinal Fluid (CSF – a derivative of blood in which the brain and spinal cord float) inside the skull. This is associated with increased leakiness of brain capillaries, which allows excess water to enter the brain from the blood causing very mild brain edema (in contrast to the florid edema of HACE). The cause of the increased leakiness of capillaries might be mild inflammation due to low oxygen at high altitude. Dexamethasone appears to prevent / treat AMS / HACE by inhibiting inflammation, preventing / reducing capillary leakiness and improving blood oxygen levels by salutary effects on the lungs. Because steroids have a general action to help us overcome stress, dexamethasone helps overcome the stresses of high altitude in the first few days while the body responds to and settles down in the new environment.
Since dexamethasone decreases capillary leakiness and has positive effects on the lungs to improve blood oxygen levels, it is of benefit in the prevention and treatment of AMS, HACE and HAPE. However, dexamethasone is a synthetic corticosteroid. “ It is important to remember that much higher doses of (synthetic) corticosteroid are given, than are naturally present in the body, to suppress inflammation and allergy. These high doses also carry the risk of significant adverse effects. For instance: when given in the case of pneumonia due to a bacterial infection, dexamethasone will suppress fever and symptoms of lung infection but if the infection is not treated simultaneously with antibiotics it will spread throughout the body. Therapeutic doses must, therefore, be given with great caution, under strict supervision, along with other therapy,’’ Dr Singh said.
Descent is the definitive cure for all high altitude illness
The other major drug for AMS is acetazolamide (Diamox). According to Dr Singh, acetazolamide creates a mild acidosis in the body. This counters the alkalosis (the normal pH of blood is 7.35 – 7.45. pH<7.35 is acidosis and pH>7.45 is alkalosis) that is inherent on ascent to altitude. As a result of the acidosis caused by acetazolamide the rate and depth of breathing increases and the water content of the body reduces (due to excess urination). These effects are bound to be beneficial because more breathing means more oxygen in the body. Also, since AMS / HACE / HAPE are all conditions of excess water in the brain / lungs; maybe less water in the body helps. Acetazolamide also has a mild direct effect of decreasing the pressure inside the skull by reducing formation of CSF. “ Acetazolamide is best known for preventing AMS / HACE and has a smaller role (as dexamethasone) in the treatment of these conditions too, although dexamethasone is far superior for treatment. Clinical experience and some scientific studies suggest that acetazolamide may have a role in the prevention of HAPE too. This is, however, not yet established,’’ Dr Singh said.
In the context of AMS, both these drugs – acetazolamide and dexamethasone – are typically talked of as prophylactic treatment. Dr Singh explained it. “ Prophylaxis means to administer a drug before the occurrence of an illness, when the chances of the illness occurring are high, to prevent the occurrence of the illness. For example: hydroxychloroquine (HCQ) has been touted for prophylaxis / prevention of COVID-19. As already brought out, dexamethasone is effective in the cure of AMS but is usually not necessary. AMS is amenable to symptomatic therapy (pain killer for headache, anti-vomiting drugs for nausea / vomiting) and if needed some oxygen supplementation for a short period (usually 30-60 minutes helps significantly). Descent is not necessary for the treatment of AMS, but the decision must be guided by local conditions, tour itinerary and logistics. For example: if the rest of the team has no option but to ascend and the person with AMS can’t be left alone, it is better to send him down with one more person rather than risk HACE by ascent. Cases of HACE and HAPE must descend as soon as possible, unless, of course, institutional care is available at the altitude of occurrence. For instance: people arriving in Leh, who develop HAPE or HACE are treated in the hospitals there. After recovery, the patient with HACE should not ascend further but the person with HAPE may, with exercise of due caution. Descent is the definitive cure for all high altitude illness,’’ he said.
In general, acetazolamide (Diamox) would seem more popular with the outdoor fraternity as a means to check AMS. It is a good drug for prevention of AMS / HACE and may be of benefit for prevention of HAPE too. “ More importantly acetazolamide is a safe drug. It is given to some patients with eye problems (glaucoma) for months and years with minimal adverse effects. So, we know it is safe. With dexamethasone one must be careful of the dose and duration it is taken and even so, some people might develop adverse effects at lower doses or shorter durations,’’ Dr Singh said. He feels that a first aid kit for mountaineering should contain both the drugs. “ Acetazolamide is our old friend that will prevent all three acute high altitude Illnesses – AMS, HACE and HAPE; whereas dexamethasone is the life saver in an emergency situation. No medical supervision is required for ingesting acetazolamide. If you know you have no drug allergy to sulfonamides (an antibiotic with structural similarity to acetazolamide) go ahead and take acetazolamide. A dose of 125mg (Diamox) twice a day or 250mg sustained release preparation (Iopar) once a day, starting the day before you ascend to altitude and continued to the second day there, is a great way to prevent / reduce the severity of AMS / HACE. If you intend to continue climbing and know you are prone to AMS, continue acetazolamide to the second day of reaching your target altitude. Should you find the benign side-effects such as a metallic taste in the mouth or tingling of the lips, hands and feet troublesome you could shift to dexamethasone tablet 4mg twice a day. But it would be good to not take dexamethasone in this dose for more than 10 days. A combination of both drugs in the same doses may also be used if you want to go high (from sea-level to >3500m in one day) very fast and have to indulge in strenuous activity there without time to acclimatize. Given in these doses for the recommended duration, medical supervision is not needed, provided the cautions mentioned above are adhered to,’’ Dr Singh said.
None of this however takes anything away from the merit in patiently acclimatizing to high altitude. That is the safest method. Patience – respecting the time needed for the body to gradually acclimatize – is, key. “ In my experience, there is nothing that can replace natural acclimatization,’’ Dr Tsering Norbu of Ladakh Institute of Prevention (LIP), said. Based in Leh, the retired physician is known well to visiting mountaineers. “ If you are not allergic to sulfa drugs, then we prescribe Diamox. We don’t approach dexamethasone in a similar fashion because it is typically used as a life saver in cases of AMS where the situation is bordering HACE,’’ he said. Being a tourist destination 11,500 feet up from sea level, Leh gets its fair share of high altitude illness. LIP is a NGO working in the domain of health. When patients require formal medical intervention, he refers them to the district hospital, Dr Norbu said.
COVID-19 and dexamethasone
On June 16, 2020, amid world battling COVID-19, BBC reported that dexamethasone “ cut the risk of death by a third for patients on ventilators. For those on oxygen, it cut deaths by a fifth.’’ This was a finding from the UK. What made dexamethasone significant beyond its stated life-saving ability was the fact that it was available in good supply and was affordable. The name of the drug must have struck a bell immediately with mountaineers worldwide. Asked what likely made dexamethasone relevant in the treatment of COVID-19 patients on ventilator support and whether medically there is any parallel in the stress the body underwent with what happens during AMS, Dr Singh said, “ since dexamethasone helps combat stress it could possibly help in COVID-19 pneumonia or Acute Respiratory Distress Syndrome (ARDS). COVID-19 involves inflammation which damages the lungs even as it fights the virus. Dexamethasone can suppress inflammation and because it reduces capillary leakiness it should reduce the severity of the symptoms caused by ARDS. The caution that needs to be kept in mind, I believe, is that dexamethasone is not the definitive cure (it does not kill the virus) and by suppressing inflammation which controls the infection even as it causes symptoms, it might worsen the infection. If, however, adjunctive therapy to kill the virus is available then dexamethasone could help tide over the critical time in ARDS when inflammation does more harm than good to our body. The disease process of ARDS in COVID-19 involves increased capillary leakiness. Other than that, there is little in common with HAPE. Having said that, I believe a respiratory physician may be able to help you better with this question,’’ Dr Singh said.
Colonel Muthukrishnan Jayaraman is an endocrinologist with the Indian Army. A regular runner, he has contributed in the past to articles related to health on this blog. “ Dexamethasone in COVID-19 is as an anti-inflammatory to counter the cytokine storm that happens especially in the more severe forms of the disease,’’ he said. Further on June 17, BBC followed up with another report explaining how dexamethasone works in the case of COVID-19. “ This drug works by dampening down the body’s immune system. Coronavirus infection triggers inflammation as the body tries to fight it off. But sometimes the immune system goes into overdrive and it’s this reaction that can prove fatal – the very reaction designed to attack infection ends up attacking the body’s own cells. Dexamethasone calms this effect. It’s only suitable for people who are already in hospital and receiving oxygen or mechanical ventilation – the most unwell. The drug does not work on people with milder symptoms, because suppressing their immune system at this point would not be helpful,’’ the report said.
For a pulmonologist’s view, this blog reached out to Dr Jacob Baby, Lead Consultant (Pulmonology), Aster Medcity, Kochi. “ Dexamethasone is a synthetic corticosteroid; they are naturally occurring chemicals produced by the adrenal glands located above the kidneys. Corticosteroids affect the function of many cells within the body and suppress the immune system. They also block inflammation and are used in a wide variety of inflammatory diseases affecting many organs. Dexamethasone is 20-30 times more potent steroid action than naturally occurring cortisol. It reduces inflammation by blocking an enzyme named phospholipase A2, which breaks cell wall phospholipid and releases inflammatory mediators. Glucocorticoids function through interaction with the glucocorticoid receptors by up-regulating the expression of anti-inflammatory proteins and down-regulating the expression of pro-inflammatory proteins. It is cheap and easily available and used as effective anti-inflammatory in many inflammatory diseases like asthma and rheumatological disorders like inflammation of muscles, inflammation of blood vessels, chronic arthritis, and lupus. It also exerts excellent anti-edema (reducing swellings) action enabling its use in cancerous conditions, brain swelling and also swelling in the spinal cord,’’ Dr Baby said.
On how dexamethasone works in the case of COVID-19, he said, “ Recovery Trial in the UK – for treating COVID 19 – had an arm investigating dexamethasone. Oxford researchers announced the results of the dexamethasone trial, in which 2104 enrolled patients were administered 6 mg of the drug for 10 days. Dexamethasone reduced deaths by one-third in ventilated patients and by one-fifth in patients receiving only oxygen. One death would be prevented by treatment of around eight ventilated patients, or around 25 patients requiring oxygen alone. The drug reduced the 28-day mortality rate by 17 per cent with significant benefit among patients requiring ventilation. COVID-19 causes accumulation of cytokines mainly IL-6 in the lungs. IL-6 increases inflammation in the lung cavity which causes the production and accumulation of fluids in the lungs. Dexamethasone reduces inflammation and suppresses immune activation of immune agents. The drug induces anti-inflammatory effects by reducing the secretion of cytokines into the lungs.’’
(Compiled and edited by Shyam G Menon, freelance journalist based in Mumbai.)