COVID-19: Neurological Hypoventilation

It has been noted that lung damage may not fully account for some deaths induced by COVID-19. People seem to  experience hypoventilation even before the lungs are compromised and experience hypoxia without hyperventilating to compensate, instead they appear normal. Is it possible that the mechanism is neurological rather than purely based on physical damage to the lungs? It may be a combination of both.

Here is from the linked MedScape article:

“Some patients have high pyrexias, are hypoxic and have high metabolic demands and so are breathing hard. It’s the ones that are hypoxic but look reasonably well that are a dilemma. We need to decide how hard their lungs are working and how much damage they’re doing to them by generating high swings in pressure. Natural breathing distributes the oxygen around the lung, but on positive pressure ventilation, the non-dependent part of the lung over-stretches and the dependent slowly collapses. Proning helps to reverse this abnormal stretch and can reduce mortality.

Dr Stevenson: We’re seeing a lot of microvascular thrombi in the lungs, which affects oxygenation, and this is very different to ARDS. There’s a lot that is different with COVID-19.

Prof Mills: There could be something else going on in COVID-19 lungs in that we suspect microthrombi, which affects the way blood flows through the lungs. Knowing how to manage this is the next problem. Rather than giving our normal dalteparin dose we are deciding on doubling it in patients with high d-dimers. Most don’t seem to have pulmonary emboli but there is more general clotting.”

Cytokine storms and particularly IL-6 had been correlated to the incidence of death by COVID-19. IL-6 has mechanisms involved in respiratory depression. Specifically, this cytokine, as well as many others, are linked to mu opioid receptor (MOR) mechanisms. Opioids can even operate as cytokines themselves.

Taken from the paper: Regulation of mu-opioid receptors by cytokines

“There is reason to believe that the regulation of mu-opioid receptors by IL-6 is important for the regulation of inflammatory pain. Up-regulation of mu-opioid receptors in neuronal cells in response to IL-6 was indirectly suggested in a model of peripheral inflammation. It was shown that injection of IL-6 increased antinociceptive mechanisms, which was blocked by a muopioid receptor-specific antagonist (38). The experiments indicate that either endogenous mu-opioid receptor ligands, or mu-opioid receptors, or both are up-regulated by the cytokine at the site of inflammation. Up-regulation of muopioid receptors in neuronal cells in response to IL-6 was also suggested in experiments with mice lacking the IL-6 gene. These mice show weaker analgesic responses, as well as a weaker mu-opioid receptor density in the midbrain (39). In the neuroblastoma cell line SH SY5Y upregulation of mu-opioid receptor mRNA and protein by IL6 was demonstrated directly (40). Furthermore, it was shown that the transcriptional induction is mediated by STAT1, STAT3 or both factors (40; Figure 1).”

Opioid drugs induce respiratory depression/hypoventilation via MOR. Endogenous opioids binding to MOR also play a role in fever.

A paper on sudden infant death syndrome (SIDS) noted that cytokines can cause respiratory depression, especially in vulnerable people such as infants.

A paper on obesity-induced hypoventilation mentions IL-6 as well as other cytokines in the genesis of the condition.

“As highlighted earlier, obesity puts an extra mechanical load on the respiratory system, leading to its restriction and subsequent respiratory failure; however, it seems to be more complicated than this. Recent studies have shown that levels of inflammatory and pro-inflammatory markers like interleukin-6 (IL-6), tumor necrosis factor alpha (TNF alpha), interleukin-1 (IL-1), interleukin-18 (IL-18), prostaglandin E2 (PGE2) and C-reactive protein (CRP), amongst others, are elevated in obese individuals. Moreover, there is a positive correlation between IL-6 or TNF alpha plasma levels and the BMI.[35–39] There is cumulative data suggesting that obesity is characterized by chronic activation of inflammatory pathways in peripheral tissues leading to a state of insulin resistance and hypofunctioning hypothalamic C releasing hormone, which results in sleep-disordered breathing.[40,41]”

Another study notes that obesity-induced hypoventilation patients had 34x more IL-6 than controls, who were also obese (original study). One may wonder if MOR activity is also 34x more intense in that case. Even a fraction of this could be expected to have very significant effects.

High altitude also increases IL-6 in relation to hypoxia, from a paper on high altitude pulmonary edema (HAPE). This is significant because the MedScape article noted that COVID-19 seemed to be like HAPE:

“At issue is the standard use of ventilators for a virus whose presentation has not followed the standard for ARDS, but is looking more like high-altitude pulmonary edema (HAPE) in some patients.

Yet, COVID-19 pneumonia, despite falling in most of the circumstances under the Berlin definition of ARDS, is a specific disease, whose distinctive features are severe hypoxemia often associated with near normal respiratory system compliance,” Dr. Gattinoni and colleagues wrote, noting that this was true for more than half of the 150 patients he and his colleagues had assessed, and that several other colleagues in Northern Italy reported similar findings. “This remarkable combination is almost never seen in severe ARDS.”

If cytokines and MOR mechanisms were involved in the hypoventilation seen in COVID-19, this could present an unexpected mechanism for sudden deaths observed in the disease. It is strange because the hypoventilation of MOR activity is related to the brainstem and neurological alterations of one’s urge to breathe. This leads to one lacking a sense that they are losing air, thus a failure to compensate with hyperventilation during hypoxia. This sounds like the COVID-19 patients who are hypoxic but yet seem to be breathing normally as if they are fine, mentioned in the MedScape quote at the beginning of this post.

Furthermore, in the midst of writing this post, I found this: COVID-19 Neurotoxicity, Acute Severe Respiratory Distress Syndrome. Acquired Central Hypoventilation Syndrome (ACHS).

From the paper:

“The most characteristic symptom of patients with COVID‐19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. [3]

Severe disease onset might result in death due to massive alveolar damage and progressive respiratory failure [3]. But not only. Toxic damage of brainstem possible mechanism of acute disorder of cardiorespiratory center.

Two different syndromes could lead to high mortality:

Acute Severe Respiratory Distress Syndrome – massive alveolar damage and progressive alveolar damage.

Acquired Toxic Central Hypoventilation syndrome of COVID 19 (ACHS) – neurotoxicity of cardio- and breathing centers of brainstem.

However, in many cases main Acquired Toxic Central Hypoventilation syndrome of COVID 19 (ACHS) which is a respiratory disorder that causes ineffective breathing, apnea, or respiratory arrest during wakefulness as a part of acute toxicity and brainstem damage.

In many cases, episodes of apnea occur in sleep, but in a few patients, at the most severe end of the spectrum, apnea also occurs while awake.”

Recently I wrote about the neurological consequences of viruses such as the COVID-19 coronavirus. This noted that the mechanisms likely involve cytokines, glutamate, and dynorphin.

Just a short clip to recap:

Let’s start with a possible mechanism for both brain damage and neuroprotection. Dynorphin is an endogenous dissociative anesthetic (situationally) that blocks NMDA receptors (and reduces AMPAr too). In a sense, dynorphin increases during states of disease, danger, stress, pain, injury, and excitotoxicity (seizure) in order to shut down brain function to protect it. In relevance to viral infection, it may be that dynorphin plays a role once CNS injury occurs through increased glutamate activity that occurs due to inflammatory cytokines that are part of the immune reaction (including COVID-19). This is supported by the fact that NMDA receptor antagonists prevent neural degeneration induced by viruses. There are cases of viral-induced seizures, which are thought to occur when dynorphin activity is too low.

While cytokines might be involved in damaging the brainstem through excitotoxicity, the hypoventilation seen in COVID-19 may be transient and induced by cytokine-MOR based mechanisms. This is something that could potentially be prevented if found to be true. The cytokine storm produced by COVID-19 may induce something similar to the respiratory depression of heroin-overdose, but instead of an opioid drug, it is inflammation overdose. This may be true in the case of obesity as well.

Naltrexone and other MOR antagonists can rescue people who have reached hypoventilation states from overdose on opioid drugs. This drug also suppresses IL-6 activity, which could be situationally useful if IL-6 is part of the mechanism involved with death for reasons other than induced hypoventilation. For example, naltrexone has been shown to reduce mortality from septic shock (involves IL-6 and TNF-α) in animal studies. Even more interesting, naltrexone improves blood gas exchange patterns in breathing problems of obesity-induced sleep apnea. Naltrexone has been used as a respiratory stimulant in COPD, but upon cessation the patients experienced respiratory failure.

This suggests that caution should be taken in the case of using respiratory stimulants due to possible rebound effects. Conversely, the use of normally respiratory depressing drugs may provide protection against this effect due to tolerance, in a similar way that frequent users of opioids are able to tolerate higher doses of opioid drugs without experiencing respiratory failure. This is backed by the very strange protective effect that nicotine might have with COVID-19, despite previous concerns that it would be linked to worse outcomes. This is significant because the respiratory depressive and death-inducing effects of nicotine involve opioid mechanisms. Smoking tobacco (nicotine) has shown a protective effect against altitude sickness as well, which fits in with the comparison of COVID-19 to altitude sickness that was mentioned in the Medscape article. Further supporting this, although a bit more loosely, hypoxic preconditioning is shown to have protective effects against ischemic brain injury. In a sense, nicotine and opioid drugs may be a kind of ‘hypoxic preconditioning’ and provide protective effects during real hypoxic events.

This research, along with the study on naltrexone and COPD, reveals a nuanced and complicated problem with applying respiratory stimulators and depressors and should be cautiously approached in regards to COVID-19. This would suggest that the use of naltrexone should not cease until after the disease has run it’s course, or at least until most of the severe problems have halted. It also seems likely that the head rush that new users of nicotine experience may be partly due to neurological hypoventilation and the subsequent hypoxia that occurs. 

Update: A new study has just come out about nicotine and COVID-19 published on April 21.

It is being dubbed A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications.

Some interesting points made in the study:

On COVID-19 invading the brainstem:

Therefore, the latency period may be adequate for the virus to enter the nervous system, invade the brain stem and affect the medullary neurons of the respiratory centers. However, variability of the neurological signs was observed with patients having anosmia, showing in general a mild evolution without pulmonary attack, in contrast with those without anosmia suggesting a diversity in the mode of proliferation and /or progression of the virus.

On the obesity link:

Of note, our hypothesis could explain the high prevalence of obesity and diabetes mellitus observed in severe forms of Covid19. The diminished vagus nerve activity previously described in these two illnesses could be potentiated by the Covid-19 elicited nicotinic receptor dysregulation, leading to a hyperinflammatory state often reported in obese patients [29].

On cytokine (including IL-6) blockers:

Although selective cytokine blockers (eg, IL1-receptor antagonist anakinra or anti-IL6 tocilizumab) have been proposed for the control of Covid-19 cytokine storm, their efficacy is still to be explored. Interestingly, 𝛼7 agonists, including nicotine, have proven to be effective in reducing macrophage cytokine production and inflammation in animal models of pancreatitis [32] and peritonitis [33].

There are also non-opioid interventions that may prove useful. The authors note that potassium channel blockers acting at carotid bodies, AMPAkines, and serotonin agonists acting on the brainstem may reverse hypoventilation induced by opioids.

Anti-IL-6 drugs are being considered for COVID-19.

Psychedelic serotonin agonists are interesting as immunomodulators as they are found to suppress IL-6. Although, the study exploring non-opioid interventions mentioned that serotonin agonists didn’t work for opioid-induced respiratory depression in humans, only in animal studies. It is possible that this differs depending on the mechanism directing the hypoventilation effects. Whether it is MOR or IL-6 predominantly may change the outcome. Drugs that suppress IL-6 might recover ventilation in theory. While their mechanisms may be intertwined, MOR activity and cytokines may be able to induce the same pathways of effects independently from each other. This means naltrexone could fail to work, while IL-6 suppressing drugs may work and vice versa.

DMT, an endogenous serotonergic agonist and psychedelic, is found to be protective against hypoxia. In rats, DMT releases during cardiac arrest, possibly as a hypoxia protective mechanism. DMT’s suppressant effects on inflammatory cytokines, including IL-6, might explain some of this protective effect against hypoxia. Cytokines have been found to reduce monoamines, including serotonin, which may include DMT as well. Perhaps this would aggravate the potential for hypoventilation. Sudden infant death syndrome has also been associated to serotonin deficiency in the brainstem, possibly explaining the incease of IL-6 mentioned before.

In regards to altitude, this we have covered in the past in Getting High. Monoamine oxidase (MAO) is an enzyme that breaks down monoamines and DMT in the presence of oxygen.

From that post:

I’ve recently discovered there is a link between hypoxia and upregulated MAO. Of course, I should have suspected a deep running link of MAO and oxygen due to the obvious hint in the name of the molecule: ‘oxidase’. MAO functions largely to metabolize monoamines by catalyzing the oxidization of them. Since oxygen is involved in the process of deamination of the monoamines, it makes sense that chronic hypoxia (low oxygen levels) would lead to a failure of deamination and a subsequent abundance of MAO. This study shows decreased activity of MAO in hypoxia, further supporting this idea.

In hypoxic high altitude environments the increased MAO may result in neurodegenerative effects. High altitude may also produce effects that are linked to increased MAO activity such as depression.

The accumulation of MAO may become problematic and promote critical moments when oxygen is received, theoretically. An acceleration of monoamine metabolism may occur which could result in pro-hypoxic effects which start a repeating cycle that involves neurodegenerative effects that involve cytokines. The authors of the paper suggest that the cycle leads to decreasing serotonin synthesis, instead promoting the KYNA pathway. Since MAO metabolizes DMT, the accumulated MAO may breakdown more DMT which means that the brain is unprotected by DMT’s neuroprotective effects during hypoxic states.

There have been cases where serotonin agonists have facilitated viral replication and infection, which is worth noting. 5HT2ar agonists have been shown to facilitate the infection of various viruses such as JC virus, HIV, while on the other hand, serotonin agonists have prevented reovirus infection. Serotonin antagonists have been explored for prior coronaviruses, although I could not access the chapter to read the full context here.

Opioid antagonists, DMT-like compounds, serotonergics, and various respiratory stimulants might prove useful in the pandemic. The immunological impacts of opioid antagonists and serotonergics might complicate the picture and this is beyond what I can assess. Those with more background in immunology might have input or feedback on this topic, which seems worth exploring.

If you found this interesting you may also enjoy the last COVID-19 post: Infectious Loss Of Sense. This one explored the neurodegeneration that may occur with the coronavirus infection, suggesting that the virus enters the brain through the olfactory system, as many viruses have before, including influenzas. 

I’d like to shout out to Emma Stravropoulos and Melissa Bradley for helping me to collect research on this topic. Special thanks to the two patrons, Abhishaike Mahajan and Charles Wright! Abhi is also the artist who created the cover image for Most Relevant. Please support him on instagram, he is an amazing artist! I’d also like to thank Annie Vu, Chris Byrd, and Kettner Griswold for making these projects and the podcast possible.

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