I think that acetazolamide and nifedipine may have a role in slowing the progression of #COVID19

Yes you read that right.

In this #thread we will explore the atypical ARDS that COVID-19 patients present with and dive into some pathophysiology that may just explain it.

#FOAMed

Disclaimer: this thread is intended to stimulate discussion, it is NOT medical advice.

This is a theoretical physiologic explanation for the atypical ARDS that we are seeing and a pharmacologic theory that may slow that process.

These therapies are NOT proven.

So let’s begin: The primary driver of mortality in the COVID-19 population has been Acute Respiratory Distress Syndrome (ARDS), yet early reports suggest that the actual patient presentation has seemed to be atypical for what we usually see in an ARDS patient.

Patients are presenting with severe hypoxia, yet their level of hypoxia doesn’t seem to have a direct relationship with their well-preserved lung mechanics and mentation. Their lung compliance indicates that they have preserved lung gas volume, not something typical of ARDS.

Why might this be? Well, in response to hypoxia we can see pulmonary vasoconstriction. This vasoconstriction aims to increase perfusion in hopes of improving gas exchange.

Unfortunately, with increased perfusion you see additional capillary leak and pulmonary edema formation.

This increased pulmonary capillary pressure and potential capillary leak is the same as what causes High Altitude Pulmonary Edema.

If we begin to compare the presentation of patients with HAPE and patients with COVID19, we don’t need to look too far to see similarities.

In both presentations we see significant hypoxia and tachypnea, this tachypnea leads to low carbon dioxide levels, and in many of our covid patients, respiratory alkalosis.

But obviously if a patient is experiencing tachypnea, they may lose carbon dioxide. What else is there?

A early reported radiologic marker of COVID-19 appears to be ground glass opacities with patchy infiltrates, these obviously can be found in pneumonia, but ground-glass opacities are actually most commonly a manifestation of hydrostatic pulmonary edema.

There are also consistent reports of covid19 patients being started on anticoagulation, due to a potential hypercoagulable state. But with significant pulmonary edema formation, we also see elevated fibrinogen levels. We see this in HAPE.

In addition, early autopsy results have found evidence of pulmonary edema in COVID19 patients.

In both HAPE and COVID, these pulmonary changes can lead to alveolar damage, deterioration and ultimately ARDS and intubation/ventilation in severe cases.

This is a huge problem, we are seeing early reports of mortality rates from 50-80% in our COVID patients who are placed on ventilators and we don’t have proven/effective antiviral therapy.

So what can we do to reduce the risk of patients desaturating and requiring ventilation?

Well so far we have seen evidence that proning can help improve oxygenation and resolve hypoxia, staving off ventilation requirements.

Likely, because this process helps improve overall gas exchange rather than simply treating overall respiratory failure.

The effectiveness of proning seems to line up with the theory that this hypoxia and hypocapnia may be related to capillary leak, pulmonary edema and inhibited gas exchange.

Okay, so now that the pathophysiology has been discussed, how does that relate to acetazolamide and nifedipine?

That’s a great question, allow me to delve into my favorite topic, pharmacology.

Acetazolamide is a carbonic anhydrase inhibitor, the inhibition of carbonic anhydrase leads to decreased hydrogen ion secretion in the renal tubule. This ultimately results in an increase in bicarbonate excretion.

This excretion of bicarbonate begins to reverse a patients alkalosis, in addition, the decrease in bicarbonate acts as a respiratory stimulant.

Remember, our respiratory drive doesn’t come from the need for oxygen, it comes from the desire to eliminate CO2.

Due to the excretion of bicarbonate and sodium, we also see an overall diuresis.

Additionally, a pleotropic effect of acetazolamide, is that it leads to dilation of the pulmonary vasculature, decreasing permeability and capillary leak.

Due to these pharmacologic effects, acetazolamide has been used for years as a preventative measure for mountain climbers, to stimulate their respiratory drive and improve gas exchange despite high altitudes and low FiO2.

Remember, we are seeing early reports of striking similarities between the ARDS presentations of patients with altitude sickness and those with Covid.

Now let’s put this all together. Theoretically, in a COVID patient who is alkalotic and hypoxic, acetazolamide could decrease capillary leak and edema, improve gas exchange and stimulate the respiratory drive.

Adding those pharmacologic effects to the proven efficacy of proning and oxygen therapy, may be able to correct hypoxia and stave off the need to intubate a patient. Which is especially important when the mortality rate of a ventilated covid patient is so incredibly high.

So now you hopefully see why i see acetazolamide as a possibly helpful medicine in the treatment of covid patients but you’re probably wondering, didn’t he also mention nifedipine?

Yes, yes I did. Let’s talk about why.

Not every covid patient is alkalotic, and using acetazolamide in those non alkalotic patients could further complicate things and lead to acidosis.

Nifedipine on the other hand, dilates the pulmonary vasculature which again, can decrease capillary leak and pulmonary edema, this all occurs without the same impact on pH. In a nonalkalotic patient, one whose BP could tolerate it, this may present a better option.

Ultimately, this explanation and these medicines are unproven but with the striking similarities we are seeing between HAPE and COVID19, this pathophysiology and these therapies are worth consideration as potential adjunct treatments to reduce the likelihood of intubation.