Respiratory muscle O2 consumption, lactate production, and endogenous substrate utilization during endotoxic shock were assessed in two groups of anesthetized spontaneously breathing dogs. In the endotoxin group (Escherichia coli endotoxin 10 mg/kg iv) and the sham group (saline iv), we sampled diaphragm, external intercostal, and gastrocnemius muscle tissue for glycogen and lactate concentrations before and after 3 h of the experimental period. Only in the endotoxin group did blood pressure and cardiac output decline significantly. Arterial O2 content did not change significantly during shock, whereas mixed venous, phrenic venous, and femoral venous O2 contents dropped to 8.0 +/- 1.1, 5.8 +/- 0.8, and 3.6 +/- 0.6 ml/dl at 60 min of shock, respectively, with little change thereafter. At 30 min of shock, femoral venous lactate rose higher than arterial values, whereas at 90 min of shock, onward, phrenic venous lactate was significantly higher than arterial concentrations. All muscle tissues showed significant lactate production and glycogen depletion after shock. In a second set of experiments we measured respiratory muscle blood flow during shock with radioactive microspheres. At 60 min of shock, diaphragmatic and intercostal blood flow rose by six- and twofold, respectively, whereas gastrocnemius blood flow declined significantly. We conclude that during endotoxin shock 1) the increased demands of the respiratory muscles are met by increasing blood flow and O2 extraction; 2) anaerobic metabolism and respiratory muscle substrate depletion, or both, may contribute to the observed fatigue.