I thank Dr Manthous for his interest in the recently published Point/Counterpoint Editorials.1,2 A large portion of his letter addresses concepts and critiques of the trial by Rivers et al,3 which I will leave to Dr Rivers to address. Dr Manthous does, however, raise the point that lactic acidosis is not a marker of tissue-level hypoxia. As stated in my Point Editorial,1 elevated lactate levels reflect the total picture of energy metabolism in the acutely stressed patient with sepsis. Both anaerobic and aerobic processes contribute to lactate production in sepsis. Thus, as opposed to central venous oxygen saturation, which is a rudimentary indicator of only the balance between oxygen supply and demand, lactate clearance biologically reflects more of the general homeostasis of the host and provides more meaningful data about the overall adequacy of the resuscitative processes. I take issue with Dr Manthous’s assertion that treating the macrocirculation using lactic acidosis as a marker of success is ill founded. Human and controlled animal studies alike have consistently shown that impaired oxygen transfer at any point from the lungs to the nicotinamide adenine dinucleotide oxidase enzyme will cause lactic acidosis, and clearing lactate levels almost always signifies improvement in host oxygen use. As such, lactate clearance as a choice of a resuscitative end point in sepsis is supported by high-quality human and animal data and can assist clinicians in their bedside care of this disease.