A model analysis of lactate accumulation during muscle ischemia.
OBJECTIVE
The mechanistic basis of the relationship between tissue [O2] and tissue or blood lactate (LA) concentration during tissue hypoxia are not fully understood. However, blood and tissue lactate accumulation are still used as indicators of tissue hypoxia in critically ill patients. To investigate this relationship, we applied a previously developed mathematical model of human bioenergetics to simulate the integrated responses (cellular, tissue, and whole body) to moderate (10% to 45%) and severe (50% to 80%) reductions in muscle blood flow.


METHODS
Model simulations of muscle ischemia predicted metabolite concentration changes in muscle, splanchnic bed, and other tissues, and were compared with experimental data in humans for model validation.


RESULTS
In general, simulations closely predicted the pattern of change in substrates and control metabolites to that observed experimentally. Specifically, simulations showed that most of the increase in muscle LA production during moderate ischemia was due to an increase in pyruvate (PY) and notto the change in redox state induced by a small decrease in O2 consumption. However, during severe ischemia, changes in [LA]/[PY] ratio in venous blood corresponded very closely to changes in tissue redox state. Because both blood [LA] and [LA]/[PY] tracked changes in tissue redox state very well, these can be used reliably as indices of tissue hypoxia during severe muscle ischemia.


CONCLUSIONS
Based on the simulations, the commonly used threshold value for venous [LA]/[PY] = 14 as evidence of tissue hypoxia seems appropriate during severe ischemia.
Cabrera
M E
ME
Department of Biomedical Engineering, Case Western Reserve University, Rainbow Babies and Childrens Hospital, Cleveland, OH, USA.
Saidel
G M
GM
Kalhan
S C
SC
D003198:Computer Simulation; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D007511:Ischemia / Q000503:physiopathology*; D019344:Lactic Acid / Q000378:metabolism*; D008954:Models, Biological; D009132:Muscles / Q000098:blood supply* / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D019289:Pyruvic Acid / Q000097:blood; D012039:Regional Blood Flow; D013997:Time Factors
D019344:Lactic Acid; D019289:Pyruvic Acid; D010100:Oxygen