Being a respiratory physiologist in times of a respiratory pathogen pandemic means getting lots of questions from my colleagues and the public about all sorts of stuff. The beauty of being a physiologist is that, in the absence of sound clinical trials, one can at the very least evaluate whether something is plausible. You may recall not long ago I cautioned everyone about taking hydroxychloroquine based on a half-assed clinical trial, little physiological plausibility, and overwhelming evidence of a serious side effect profile. It’s not always rewarding to be so right, but I’m afraid I was right.
I’m proud that my respiratory physiology students are using these crazy times as a learning opportunity and one of my students sent me the following question, which I am sharing with her permission. It might be that I’m only writing this for that student, which is totally fine. But, maybe everyone else will learn something too.
Hi Dr. Bates I wanted to reach out and ask you a question or two about COVID 19. I just finished watching a YouTube video (I know it’s not very credible) but basically what this lady was talking about is that the symptoms of COVID 19 were similar to high altitude sickness and she was saying that acetazolamide a medication that treats high altitude sickness specifically edema could help do you think this is plausible? I just wanted to ask you about it cause it obviously came from a random person on YouTube but I found it interesting maybe you would know more.
I do, in fact, know more and I’ll tell you what I know. First and foremost, Here is the video this student is referencing in their email:
COVID-19 is scary, no doubt. People are looking to medicine for creative treatments, and people become more likely to try wacky things when they are afraid of dying. There is no doubt in my mind, the person in the video is scared. There is no doubt in my mind that the doctor she references is scared, based on his video. Fear is a powerful motivator which is why one of my defining principles is that I never make a decision based on fear. Only data. Here’s the data.
Is there evidence that acetazolamide is useful in ARDS-like pathologies?
There is no clinical evidence that acetazolamide is useful in acute respiratory distress syndrome (ARDS). There is a single theoretical paper with a single author that compares high altitude pulmonary edema, a consequence of altitude ascent, with COVID-19 symptomology. So, there is not even a use for acetazolamide in a clinically similar situation. There are lots of papers (1643 to be exact) that acetazolamide can be useful in the intensive care setting, but not in situations that are analogous to this. Because there are no clinical data, we can only evaluate the physiological plausibility of acetazolamide to treat COVID-19.
What is acetazolamide and how does it work?
Acetazolamide, or Diamox, is used to treat and prevent acute mountain sickness. Exactly how it works is an area of ongoing debate, but are some things we know. It inhibits an enzyme called carbonic anhydrase, which converts carbon dioxide and water to hydrogen and bicarbonate. Here’s my doodle of the reaction and how it is impacted by acetazolamide:
This all is key to the next part of our discussion. When you travel to altitude, perhaps because you’re going skiing or to enjoy the mountain views, the atmospheric pressure falls. People often comment that the “air is thinner.” The result is that the partial pressure of oxygen, which is a major regulator of all things physiological, also falls. This means that there is less oxygen in your blood, and less oxygen bound to the hemoglobin in your red blood cells. But, your body has a way to deal with this. The fall in oxygen in your blood stimulates specialized tissue in your carotid arteries called chemoreceptors, which leads to an increase in your ventilation. The relationship between oxygen and breathing looks like this (doodled by yours truly)…
When the oxygen in your arterial blood falls, it stimulates your chemoreceptors to cause an increase in breathing. That’s great when you’re going to altitude. I’ve done a lot of simulated altitude in my own work (see this, for example) and I’ve been hypoxic an awful lot. It doesn’t feel that bad. What feels terrible, is when your CO2 changes and increasing your breathing changes your CO2 like this…
So, decreasing your oxygen increases your ventilation, which conversely lowers your CO2. Bear with me, we’re almost through the physiology. All of these adaptations are good, so far, because they increase oxygen delivery to the lung and to the blood. But, lowering your CO2 also causes your blood pH to increase, causing what is called an “alkalosis.” This alkalosis is bothersome because it prevents your breathing from continuing to increase, further improving oxygen delivery. An alkalosis puts a brake on ventilation. Acetazolamide works, in part, by causing your kidney to excrete the basic part of the reaction I drew above – the HCO3. Here’s a great reference if you’re interested in learning more about how this specifically works in kidney. Removing the brake lets your ventilation increase even more, improving oxygen delivery to the blood. There are other effects, but this is the major one.
So, why would it work/not work in COVID-19 patients
Reports from clinicians caring for these patients suggest that the pathophysiology is different from typical ARDS in that these patients are profoundly hypoxic without the same degree of lung structure changes. COVID-19 seems to be impacting the ability of the lung vasculature to respond to hypoxia. Just like at altitude, low oxygen in their blood causes them to increase their ventilation and they may report being short of breath. That’s where the similarities seem to end, though.
If they were arriving at the emergency room short of breath, with low CO2 and an alkalosis, there is every plausible reason to think that acetazolamide would increase their ventilation and increase their oxygenation. That doesn’t seem to be consistent with the data. Data from 82 patients in Wuhan suggests that respiratory failure is the primary cause of death in most patients. Like your biceps or quads, your diaphragm is a skeletal muscle and can fatigue when stressed. When it’s taxed for too long, it starts to fail. Even though a patient is hypoxic, their primary muscle of respiration loses the ability to generate force, and ventilation falls. The next steps are the opposite of what I described above. When ventilation falls, the PCO2 rises. When the CO2 rises, the blood becomes more acidic. This acidosis is further compounded by their hypoxia. Data from Wuhan support that this classic respiratory failure is present in many of their patients. The rising CO2 and acidosis both normally increase ventilation, but not when the diaphragm is failing. Ventilation can’t increase. It feels terrible. Having your CO2 climb feels like you’re drowning. Giving acetazolamide would only worsen the acidosis. In a patient with respiratory failure, it would only make things worse.
To put it simply, there is not good evidence that acetazolamide would be effective here. There is good evidence that it would be harmful, particularly in the context of acidosis and respiratory failure.
Physiology is the study of how organisms respond to stress. You can’t suggest things without understanding the physiology, my friends. The physiology is pretty clear here.
**Note: I’ve used hypoxia throughout here because it’s the sloppy shorthand being bantered around the internet. If you’re a respiratory physiologist, it’s hypoxemia. Also, I can’t figure out how to subscript my 2’s in WordPress. Good enough. Fin.