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.