Markers of tissue ischaemia in lower limb arterial insufficiency : an experimental and clinical study

Abstract

Lower limb ischaemic rest pain, ulcers or gangrene are late consequences of advanced peripheral arterial disease, one of the facets of systemic atherosclerosis. The majority of patients will meet current criteria for critical limb ischaemia (CLI). Life expectancy in these patients is severely limited mainly due to coexisting coronary heart disease. Once believed to unavoidably end in amputation unless treated, CLI was long considered to imply imperative vascular reconstruction. However, as extensive bypass surgery with significant morbidity is often needed and a spontaneous one-year limb salvage rate of 50 % can be expected, the question has been raised if not some of these patients would fare better with other treatment strategies. To date no methods have been presented that with any certainty predict the fate of the limb of an individual patient with severe limb ischaemia. Identification of metabolic alterations preceding tissue necrosis in chronically ischaemic limbs could be a means to improve patient selection for reconstructive surgery. Lactate is a sensitive marker of tissue ischaemia and could possibly be used for this purpose.

Lactate levels were determined with the microdialysis technique, first in 9 healthy subjects performing onelegged knee extension exercise under a variable degree of skeletal muscle ischaemia in a pressure chamber to validate its capacity to grade ischaemia. There was a good correlation between microdialysate lactate levels and the degree of ischaemia. Microdialysis lactate determinations were then used in 10 patients with CLI. Foot and lower leg subcutaneous adipose tissue and anterior tibial muscle were studied. Patients with CLI showed a heterogeneous metabolic response to apparent severe ischaemia but there seemed to be a connection between ischaemic pain and lactate levels. There was no clear correlation between lactate levels and the degree of ischaemia using ankle or toe pressure or transcutaneous oxygen tension. As lactate determination even with the minimally invasive microdialysis technique was not considered ideal in a larger patient cohort we sought an experimental model of long-lasting ischaemia to allow validations of other methods.

A rat model of unilateral resting limb ischaemia was modified and evaluated. Perfusion measured by laser Doppler imaging was significantly decreased for the full eight-week follow up. Decreased femoral artery volume blood flow and histological signs of ischaemia were seen for up to four weeks. During the early phase, resting lactate levels were increased. Magnetic resonance (MR) T2 characteristics of the tissue are determined by body water content and the composition of tissue fluid. A link betweenMR T2, tissue fluid composition and lactate concentration has been described, suggesting the possibility of using T2 relaxation time as an indirect marker of tissue lactate concentration. In the rat model, T2 levels showed a strong correlation to clinically observed ischaemia score at one day and intramuscular lactate concentrations at one day and one week. T2 levels gradually returned to baseline levels over a period of two months.

Exploring new methods to potentially improve the definition of CLI to safer select patients to treatment has been the overriding aim of this thesis. Both lactate and MR T2 changes appear to correlate to symptoms and degree of ischaemia in patients and under experimental conditions. Further studies are needed to elucidate to what degree such findings are related to prognosis in CLI.