Microcirculatory dysfunction

Patients with ALF, as with other forms of critical illness, frequently demonstrate a covert tissue oxygen debt despite apparently adequate blood pressure and arterial oxygen saturation. Failure to maintain an adequate oxygen uptake to cells appears to be related to a combination of factors resulting in an inability to regulate delivery and extraction of oxygen at a cellular level. The basis of this microcirculatory dysfunction is poorly understood, but evidence is accumulating to suggest the importance of interactions between the endothelium, exogenous factors such as bacterial toxins, and cytokines, specifically tumor necrosis factor and interleukins 1 and 6. Endotoxin and other bacterial toxins stimulate the production of cytokines by activated macrophages which may be maintained in the circulation because of impaired Kupffer cell function. Activation and consumption of platelets with formation of microthrombi within various organs may lead to endothelial damage and release of further vasoactive compounds. This series of events, together with increased adhesion of activated leukocytes to endothelial cells, causes microcirculatory plugging with blood being shunted through non-nutritive arteriovenous channels. Nitric oxide and epoprostenol are important endothelial-derived factors whose role in the control of microcirculatory flow is being increasingly recognized. Patients with ALF have been demonstrated to have elevated levels of the end-products of nitric oxide (nitrite and nitrate) and of cGMP and citrulline, suggesting activation of the nitric oxide pathway. The ability of the endothelium to release prostaglandin I 2 or nitric oxide has an important bearing on the evolution of tissue hypoxia as endothelial interactions may limit release of these factors, thus further potentiating tissue hypoxia and end-organ damage.

In healthy individuals, physiological supply dependency of oxygen only occurs when Do2 falls below a level of 330 ml/min/m2. Any additional fall in delivery below this critical level will result in a fall in tissue oxygen uptake Vo2, with the subsequent development of tissue hypoxia, anaerobic metabolism, and accumulation of lactate. Normal oxygen delivery is around 525 to 675 ml/min/m2; at deliveries between 300 and 525 ml/min/m2 oxygen consumption is maintained at normal levels by increasing extraction ratio in the periphery. In patients with ALF, as well as in those with severe sepsis and multiple trauma, 'pathological supply dependency' for oxygen is observed (Fig 2). Oxygen consumption is then dependent upon delivery over a far greater range such that an increase in Do2 will frequently result in an increase in Vo2. An appropriate level for Vo2 is difficult to estimate in patients with critical illness, but it is likely to be higher than that seen in the resting healthy state owing to the presence of fever, sepsis, inflammatory foci, and increased levels of circulating catecholamines.

Fig. 2 Pathological supply dependency for oxygen.

The presence of pathological supply dependency for oxygen in ALF was first shown by Bihari et al. (1986) who noted that, following infusion of the microcirculatory vasodilator epoprostenol, there was a fall in systemic vascular resistance resulting in an increase in oxygen delivery and a significant increase in oxygen consumption. The patients who failed to survive had both a lower baseline Vo2, indicative of a large oxygen debt, and greater increases in Vo2 following infusion of epoprostenol. In addition, the mixed venous lactate level (a measure of anaerobic metabolism) correlated inversely with systemic vascular resistance index, mean arterial pressure, and oxygen extraction ratio.

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