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Archived Comments for: High mixed venous oxygen saturation levels do not exclude fluid responsiveness in critically ill septic patients

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  1. What were the hemoglobin levels?

    David Whitlock, Nitriceutic LLC

    8 November 2011

    This is very interesting. I appreciate that the conventional wisdom is that O2 levels are all important, but what is also important is the balance of O2 vs NO. It is NO that tonally inhibits mitochondrial reduction of O2 to water by blocking cytochrome c oxidase from binding O2. It is not O2 consumption that is necessary for cells to survive, it is sufficient ATP levels. In sepsis, ATP levels are actually higher than during non-sepsis (for those who survive).[1]

    In the vasculature, hemoglobin is the source of O2, but also the sink of NO. In sepsis, it is the very high NO levels which cause systemic vasodilatation. I hypothesize that the immune system generates such high NO levels during sepsis (via iNOS) to prevent the formation of bacterial biofilms. As bad as bacteria floating around in the blood stream are, biofilms on vessel walls are orders of magnitude worse. Because bacteria grow exponentially with a doubling time of ~20 minutes, effective suppression of biofilm, in the wild, must be very rapid.

    The level of NO needed at the vessel wall to prevent bacterial adhesion comes from the balance between generation by immune cells, mostly in the extravascular space where the infection is, and its destruction by HbO2 in blood. The reaction of NO and HbO2 is first order with respect to both. The NO destruction rate depends on the product of the two concentrations. The NO level at the vessel wall is probably around 10 nM/L because sGC is producing lots of cGMP and so lots of vasodilatation. The NO generation rate to support a certain biofilm inhibiting concentration depends ~linearly on the hemoglobin level.

    Isovolemic dilution of 50% (from 140 to 60 g/L) does not cause much drop in O2 levels in blood, SvO2 (77% to 73%) because there is compensatory vasodilatation, compensatory tachycardia and compensatory hyperdynamic circulation.[2] This compensatory vasodilatation occurs because the NO concentration goes up so the destruction rate matches the production rate. It is the produce of Hb concentration and NO concentration that stays constant. It needs to be appreciated that the important O2 level in blood is the chemical potential of O2, as measured by the partial pressure, not the ¿O2 content¿ in mL/L. O2 can only diffuse down a chemical potential gradient. If venous blood has a ¿normal¿ SvO2, then O2 delivery by the arterial blood is ¿normal¿. There is no deficit in O2 delivery, there may be a deficit in O2 consumption if NO levels are too high. This deficit cannot be corrected by supplying more O2. It needs to be corrected by reducing NO destruction and allowing normal regulation of extravascular NO to a lower level to occur, while maintaining biofilm inhibition at the vessel wall.

    What controls how much O2 tissues take up is the NO levels in those tissues and how much that NO is blocking cytochrome c oxidase. High NO means high cytochrome c blockage and low O2 reduction and low ATP production by oxidative phosphorylation and so a requirement for high glycolytic ATP production.

    Greater hemodilution means a lower NO level is needed in the extravascular space so the level at the vessel wall will be enough to inhibit biofilm formation, so mitochondria in the extravascular space see a lower NO level and so can generate more ATP via oxidative phosphorylation and so cells need less glucose to generate ATP via glycolysis (the reason for cachexia in sepsis). A molecule of glucose generates 19 times more ATP via oxidative phosphorylation than it does via glycolysis. Switching 5% of ATP production from oxidation to glycolysis requires delivery of twice as much glucose. If physiology can't do that, then ATP levels fall, mitochondria turn on, and self-destruct in the high NO environment.

    My hypothesis is that the reduction of HbO2 mediated NO destruction is why hemodilution during sepsis has benefits in experimental animals.[3] The reduced destruction of NO, allows for a compensatory reduction in NO concentrations in the extravascular space and so there is less inhibition of cytochrome c oxidase in mitochondria and so there is more ATP generation by oxidative phosphorylation. This spares glucose for glycolytic ATP production which is necessary to maintain ATP concentrations above normal basal levels. Under this hypothesis, what causes multiple organ failure is the inability to maintain ATP levels via glycolysis, which causes ATP levels to fall, which causes mitochondria to turn-on, which in a high NO environment causes irreversible turn-off via nitration of MnSOD. [I discuss this in detail in 4]. When mitochondria try to operate in an NO environment that is too high, the mitochondria die, the cell dies, the organ dies and the organism dies.

    A degree of hemodilution with fluids may actually be beneficial, even when SvO2 is high.

    1. Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002 Jul 20;360(9328):219-23.

    2. Weiskopf RB, Viele MK, Feiner J, Kelley S, Lieberman J, Noorani M, Leung JM, Fisher DM, Murray WR, Toy P, Moore MA. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA. 1998 Jan 21;279(3):217-21. Erratum in: JAMA 1998 Oct 28;280(16):1404. [see Figure 4]

    3. Creteur J, Sun Q, Abid O, De Backer D, Van Der Linden P, Vincent JL. Normovolemic hemodilution improves oxygen extraction capabilities in endotoxic shock. J Appl Physiol. 2001 Oct;91(4):1701-7.

    4. http://daedalus2u.blogspot.com/2008/06/mechanism-for-mitochondria-failure.html (accessed 06/28/2008).

    Competing interests

    Commercializing use of commensal ammonia oxidizing bacteria on the skin surface to raise NO and nitrite levels via oxidation of ammonia into nitrite (hypothesized to be physiologically relevant mechanism in the "wild")

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