Purpose: Exaggerated leucocyte activity is a crucial step in the pathophysiology of skeletal muscle ischemia-reperfusion injury (IRI). We tested the hypothesis that insulin, via its’ anti-leukocyte activity, attenuates skeletal muscle IRI in humans. Materials and Methods: This randomized, blinded, placebo-controlled trial was conducted in patients with skeletal muscle ischemia who required revascularization. Treatment protocols were similar among them except for the insulin group, which received an infusion of insulin at 2.5 U/h. The degree of endothelial adhesiveness; leukocyte activity and pro-inflammatory status via P-selectin, tumor necrosis factor (TNF)-alpha, and myeloperoxidase (MPO) levels in the venous effluent; and clinical outcomes were measured. Results: Twenty-four consenting patients were randomized to the insulin or control group. There were no significant differences between the two groups except for the median serum insulin level, which was higher in the insulin group (P<0.01). No serious intervention-related adverse events were observed. P-selectin (55.04-99.86 pg/mL; P<0.001), MPO (110.8-160.6 pg/mL; P<0.001), and TNF-alpha (12.16-36.01 pg/mL; P<0.001) levels demonstrated a significant increase post-reperfusion in the ‘control’ group, reaching a peak value at 2 hours post-reperfusion. The increase in all three markers from baseline was significantly diminished in the insulin group at the two-hour (P-selectin, P=0.001; MPO, P=0.001; TNF-alpha, P=0.005) and four-hour (P-selectin, P=0.003; MPO, P=0.002; TNF-alpha, P=0.01) intervals. The differences in clinical outcomes between the insulin and control groups were not statistically significant. Conclusion In clinical practice, insulin has the potential to attenuate the severity of skeletal muscle IRI inhibiting P-selectin, MPO, and TNF-alpha levels.

INTRODUCTIONReperfusion of acutely ischaemic tissue may, paradoxically, lead to systemic complications. This phenomenon is believed to be initiated by humoral factors that have accumulated in the ischaemic tissue. The ancient art of venesection may reduce the load of these mediators at the point of reperfusion. The aim of this study is to test if selective venesection, by removing the initial venous return from the ischaemic tissue, can attenuate the systemic effects of the ischaemic-reperfusion injury using a porcine model of acute limb ischaemia.

MATERIALS AND METHODSThe right femoral arteries of anaesthetised female pigs were clamped. Twelve pigs were divided into 2 groups (n = 6 per group). In the treatment group, 5% of blood volume was venesected from the ipsilateral femoral vein upon reperfusion; the other arm served as control. The animals were sacrifi ced after 4 days for histological examination. A pathologist, blinded to the experimental groups, graded the degree of microscopic injury.

RESULTSFor the control group, the kidneys showed glomeruli and tubular damage. The livers demonstrated architectural distortion with cellular oedema. There was pulmonary oedema as well as extensive capillary congestion and neutrophil infiltration. Such findings were absent or reduced in the venesected animals. Consequently, the injury scores for the kidney, lung, liver and heart were significantly less for the venesected animals.

CONCLUSIONSelective venesection reduces the remote organ injuries of the ischaemic-reperfusion phenomenon.

Animals ; Disease Models, Animal ; Female ; Hindlimb ; injuries ; Multiple Organ Failure ; etiology ; pathology ; prevention & control ; Phlebotomy ; Pulmonary Edema ; etiology ; pathology ; prevention & control ; Reperfusion Injury ; complications ; therapy ; Sus scrofa