Reports suggest that muscles lack oxygen and skin oxygenation is impaired in Complex Regional Pain Syndrome (CRPS). While CRPS might be related to tissue ischemia-reperfusion, the affected limb is often hyperperfused, suggesting that oxygen extraction is severely impaired instead. In a recent paper in Pain, we speculate that capillary flow disturbances may explain this peculiarity, and could contribute to the development and maintenance of CRPS.
The perceived one-to-one correspondence between tissue blood flow and oxygenation requires all tissue capillaries to be equally perfused. However, even in normal tissue, there is considerable variability in the transit time of blood through capillaries (capillary transit time heterogeneity; CTH), and some capillaries may be perfused at flow rates that are too high to permit oxygen to be extracted by tissue. Tissue oxygenation can therefore be limited by high flow rates and if a situation arises where capillary flow patterns are not controlled an ‘oxygen shunt’ may result – so-called capillary dysfunction. We propose that acute tissue injury causes capillary dysfunction because high interstitial pressure compresses capillaries, byproducts of blood breakdown cause pericyte constriction, and inflammatory mediators enhance blood cell adhesion to the endothelium.
A critical consequence of capillary dysfunction is that blood flow and CTH combined can become so high that vasodilation fails as a means of maintaining tissue oxygenation. In this case, normal flow, and flow responses, must be suppressed in order to allow more efficient extraction of oxygen across all capillaries. We propose that the finding of hyperemic, yet hypoxic, tissue in CRPS represents the failure to suppress normal vasodilatory responses to tissue hypoxia. The suppression of blood flow to maintain tissue oxygenation in capillary dysfunction comes at a high cost: It appears to be mediated by reactive oxygen species (ROS) release, which attenuates vasodilation, but also causes long-term damage to tissue microvessels, including capillaries.
According to this hypothesis, in order to avoid prolonged oxidative stress and the development of permanent capillary damage, tissue swelling must be reduced as soon as possible after injury. We speculate that the use of corticosteroids and Vitamin C (a ROS scavenger) may reduce the risk of developing CRPS by targeting these disease mechanisms. Further, if permanent capillary damage does develop, we predict that improved capillary flows would alleviate pain and improve tissue function. One option for this would be the use of phosphodiesterase (PDE) inhibitors, which reduce platelet aggregation, decrease blood viscosity, and increase the flexibility of erythrocytes. Indeed, the PDE inhibitor tadalafil may improve muscle force, possibly by improving muscle oxygenation, and reduce pain in some CRPS patients by addressing these mechanisms – even without altering blood flow and limb temperature.
About Leif Østergaard
Leif Østergaard is a consultant at the Department of Neuroradiology at Aarhus University Hospital and professor of neuroradiology at Aarhus University (AU). He directs the Center of Functionally Integrative Neuroscience (CFIN), and the cross disciplinary neuroscience and cognition network MINDLab at AU. He is interested in how the microcirculation limits the delivery of nutrients to tissue, and whether capillary dysfunction plays a role in aging and disease. He now works with researchers from the Danish Pain Research Center to understand the mechanisms of neuropathy and pain
Reference
Ostergaard L, Terkelsen AJ, Finnerup NB, Knudsen L, Drasbek KR, Jespersen SN, Svensson P, Sørensen JC, & Jensen TS (2014). Capillary dysfunction and impaired tissue oxygenation in complex regional pain syndrome: a hypothesis. Pain, 155 (10), 1922-6 PMID: 24946228