Tuesday, April 14, 2020

ARDS isoprostanes and isofurans

This study from 2012 uses a model and it's based on mice. No one, ever, develops ARDS by inhaling reagent grade lipopolysaccharide following an intra tracheal injection of said LPS. So some caution.

Low levels of tissue factor lead to alveolar hemorrhage, potentiating murine acute lung injury and oxidative stress

I was interested, not because of the tissue factor knockout, but in the control group because I wanted quantification of how much haemorrhage occurred in to the alveoli during the progression of ARDS. I was modestly interested in the concept that pulmonary haemorrhage might reduce systemic haemoglobin value, elevate bilirubin, elevate ferritin and induce oxidative stress due to free haemoglobin or its derivatives. It can do some of these things but what caught my eye was the section on inflammatory markers within the small "human" arm of the study.  This is what they found in real people with real ARDS:

"Patients with diffuse alveolar hemorrhage had progressively increasing BAL isoprostanes and isofurans as their sequential BAL aliquots become more bloody. These findings suggest that liberation of free hemoglobin into the airspace and intraalveolar lipid peroxidation may be important mechanisms of clinical acute lung injury".

I would just comment that while both isoprostanes and isofurans measured in the study are arachidonic acid non-enzymic derived peroxidation products I can see no reason why the toxic derivatives of linoleic acid peroxidation would not also be formed, though these weren't measured in the study.

This would fit well with the likelihood of who is most likely to develop ARDS being predicted by the proportion of polyunsaturated fatty acids in their plasma free fatty acid pool on admission to the ITU.

The role in ARDS of pulmonary haemorrhage, intra-alveolar red cell lysis, free haemoglobin and severe oxidative stress in the airspaces is fascinating and is likely to be a routine feature of all types of ARDS. I got here by trying to decide whether the widely discussed concept that SARS-CoV-2 might be doing something special based on viral protein modelling suggesting the displacement of the Fe atoms from haemoglobin could be causal of whole body damage via systemic hypoxia. Looking at the clinical data coming out of Wuhan and what we have known about ARDS for decades makes me doubtful that we need the "iron hypothesis". I'd not say that it is incorrect, just that an awful lot of the clinical data fit with a severe viral infection induced ARDS including pulmonary haemorrhage in patients loaded with polyunsaturated fatty acids.

Peter



I wrote this post some time ago and felt it wasn't really interesting enough to put up, but the iron/haemoglobin idea keeps resurfacing. Loss of Fe from Hb will undoubtedly impair oxygen delivery but it would not cause arterial oxygen desaturation without concomitant lung dysfunction. With normal lung function whatever undamaged haemoglobin remains would saturate perfectly well. A pulse oximeter would still render a reading of 100% saturated even if little functional haemoglobin remained and tissue oxygen delivery was very low, assuming the colour of the haemoglobin derivatives did not interfere with pulse oximeter function. This is the situation in "normal" profound anaemia. In one of the Wuhan reports clinical anaemia on presentation was undoubtedly associated with decreased survival (though this was not related to mean haemoglobin levels) but equally so were decreased platelet count and decreased albumin levels. These would be compatible with serious problems from multiple tissue haemorrhage, lungs included, as part of the advanced stages of SIRS (systemic inflammatory response syndrome) where DIC (disseminated intravascular coagulation, better known as Death Is Coming) becomes one of the terminal features.

The discussion of mechanical ventilation techniques in causing/avoiding pressure injury to the lungs is almost as old as the eternal discussion of colloid vs crystalloid for volume resuscitation. Personally I prefer crystalloids and would favour IPPV techniques which avoid barotrauma to the lungs if at all possible. But that's just me.

19 comments:

altavista said...

https://doi.org/10.1101/2020.04.08.20057794

Peter said...

Yep

Peter

Jonathan said...

I think I'm missing the point. If you suspect it isn't necessarily iron that's causing the rise in peroxidation of arachidonic acid (and maybe linoleic acid), then what is causing the rise in peroxidation?

I'm reminded of the reperfusion injuries that follow heart attacks. If I understand right (amateur alert, I may well not understand right), the cell death that occurs during a temporary blockage of blood flow causes iron to be released; then when blood flow is reintroduced (reperfusion), the real damage occurs as oxygen hits the freed iron and together they go on an oxidative killing spree. I am curious whether the severity of reperfusion injury is greatly enhanced by the presence of PUFA at the site.

Unknown said...

Kids showing microthrombi. https://twitter.com/DWahezi/status/1248804396470804481?s=19.

Peter said...

Jonathan, on going failure to clear the virus should be adequate to maintain the macrophage driven ROS. Iron itself is a good source of ROS. RBC breakdown and removal will be through macrophages and might easily generate enough ROS. Increased inspired oxygen will do the same. A difficult situation when hypoxia is a core problem. These are not easy to manage. ARDS has a significant death rate.

Unknown, if you go through the feline coronavirus literature, especially at the wet FIP end of the spectrum, you should find it quite frightening. This is certainly the most worrying thing I've see in the reports from humans, especially as the images are NOT from DIC but healthy survivors (assuming they behave as most children do). This looks much more like a vasculitis. In feline cases the formation of wet FIP (a serosal surface intractable vasculitis) was always fatal. There is a morass of argument about the use of an experimental antiviral drug which anecdotally works. Steroid don't. I'm out of clinical work nowadays so I'm not up to date on the feline antiviral (off license from China) but a little googling should bring it up. I wouldn't be surprised if it wasn't being trialed in humans (just looked, it is as Remdesivir). The commonest trigger from feline symptomatic carrier to full wet FIP appears to be psychosocial stress, neutering, air transport etc. Or perhaps making a doctor work in an overwhelmed ITU in an overwhelmed medical service...

Peter

Passthecream said...

Thanks Peter. It's good to hear the voice of clinical experience. I saw some pics of lung tissue slices yesterday showing healthy vs cv post mortem. What a mess. There is a preprint abroad about ivermectin use in cv patients claiming very good results. Ymmv.

Cristian, interesting about asparagine involvement in ace2r.



( idiotic speculation alert) --- perhaps yet another good reason not to consume artificial sweeteners? (asparagine is derived from aspartate.)

Wikiquote

"Upon ingestion, aspartame breaks down into residual components, including aspartic acid, phenylalanine, methanol, and furtherbreakdown products including formaldehyde and formic acid. Human studies show that formic acid is excreted faster than it is formed after ingestion of aspartame."


If you needed a reason.

Passthecream said...

Peter, I think when Gilead announced an rct of remesdevir vs cv in China about a month back it didn't do their share price any harm. They are very tight-lipped about any results so far. There are so many trials going on of all sorts of things that at one point they were running out of volunteers.

LA_Bob said...

This story references this paper, which reminds me somewhat of this post.

Peter said...

Bob, nice one! I wonder how many coronavirus patients are getting dextrose or dextrose saline as their IV? We have a saying in fluid therapy that Hartmann's solution is not a maintenance therapy. But I don't view IV glucose/glucose-saline as maintenance fluids either. I'd plump for Hartmann's and get the calories in orally if at all possible.

Pass, there are undoubtedly some antivirals that do work and the multiple anecdotes of cure from wet FIP in cats using Remdesiver (which carries 100% death rate without, pax the Italian vet protocol) are fascinating and encouraging. But there is a lot going on with the current coronavirus pandemic in addition to meeting the virus...

Christian, no chance to view the protocol but the anecdotes around Remdesivir in cats suggest there is a lot to compete with.

Peter

Dr. Rob said...

Peter, you are right - it is stress and the body’s response to stress that is causing the problem.. And, at a cellular level oxidative stress ROS and RNS have the potential to cause chaos putting great strain on the cell’s defensive mechanisms to maintain order. Lysosomes play a key role in this homeostasis.

https://www.cmghjournal.org/article/S2352-345X(19)30045-1/pdf

lysosomal and mitochondrial dysfunction associated with metabolic syndrome causes a complete intracellular energetic mess and underlies the onset of chronic diseases.

Working in general practice we are seeing lots of extreme lethargy, headaches and GI symptoms with no respiratory symptoms, many of whom have reduced oxygen sats- suggesting this is not predominantly a respiratory infection in many cases.

At a cellular level ROS/RNS ➖ HIF-1➖NRF2 ➖HO-1 ➖iron and CO would explain what is going on.

Frunobulax said...

I found this interesting:
https://www.bccourier.com/a-swiss-researcher-gives-hope-in-the-fight-against-the-pandemic/

Pulmonary embolism suspected as cause of death with COVID-19. This would be the connection to glucose management and atherosclerosis, wouldn't it?

Anonymous said...

https://www.cnn.com/2020/04/19/entertainment/nick-cordero-coronavirus-leg-amputation-trnd/index.html

LA_Bob said...

Hi, Frunobulax,

Regading your bcc link, am I wrong to think this is a very big deal? Someone posted this from The Lancet in a comment on Dr Kendrick's site.

https://marlin-prod.literatumonline.com/pb-assets/Lancet/pdfs/S0140673620309375.pdf

"This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins."

Do you think the anticoagulant prophylactic approach Dr Kucher wants to try might be effective?

Also (and I'm asking as a layman here), does the widespread infection of vascular endothelial cells imply a major failure of the immune system early in the infection to contain the viral spread? Seems like the obvious answer would be, Yes, and it seems like the metabolic disorder that is the co-morbidity would contribute to that failure.

Richard B said...

Frunobulax, would this suggest taking a daily dose of aspirin might provide at least some protection? I am not a fan of this in general, but during the outbreak it could be worthwhile?

Peter said...

Dr Bob, yes, but I would expect these to be common in "normal" SIRS in the ITU... Maybe there will be some benefit from this pandemic if it leads to better SIRS management.

Richard, no, don't do this unless you want to bleed out in to your GI tract.

Bob and Frunobulax, hypercoagulation is a normal part of death through SIRS. Anticoagulation is certainly being mentioned as management in the ITU in the UK and is thought to be helpful. This is based around the problems of DIC, disseminated intravascular coagulation. Excessive activation of the clotting system in SIRS depletes clotting factors leading to generalised bleeding as a precursor to death. Anticoagulation helps as it preserves some clotting factors and limits pathological thrombosis of end arteries. The trade of is therapy induced bleeding where you don't want it. Overall anticoagulation can be of benefit but DIC still carries a remarkably high death rate. But that's ITU work for you...

Peter

Frunobulax said...

@Richard: Aspirin would provide no protection against infection. Anticoagulants could reduce the rate of death and severe complications, if taken *after* the infection is diagnosed. In general I'm not a fan of aspirin, it causes significant damage to our microbiome (->leaky gut), and we know that aspirin does not help against atherosclerosis at all (https://doi.org/10.1016/S0140-6736(18)31924-X).

@Bob: I'm just an amateur :) But the amount of atherosclerotic plaque depends on systemic inflammation and (lack of) glucose control,. It seems logical that additional inflammation caused by Corona could push people already at risk over the edge. As for drugs, I don't know enough about this to have an opinion. But I would advise against "preemptive" drugs, especially statins, that have all kinds of side effects. The best prevention would be strict glucose control, if (!) that theory is correct.

Richard B said...

Frunobulax, Peter. Thanks. I will continue not to take aspirin then.

Passthecream said...

Nothing to see here.

https://www.reuters.com/article/us-health-conoravirus-blood-pressure-ins/blood-pressure-drugs-are-in-the-crosshairs-of-covid-19-research-idUSKCN2251GQ

Scientists at work. Move along.

Justin said...
This comment has been removed by the author.