We agree with Dr Manthous that factors other than global Do2 dependency likely contribute to lactic acidosis (Table 1), making it an insensitive real-time indicator of tissue perfusion. It is important to note, however, that global estimates, such as Scvo2 or mixed venous oxygen saturation, may be insensitive to regional imbalances at the microcirculatory level. Nonetheless, the macrocirculation and microcirculation are connected. Early reversible and correctable causes of global tissue hypoxia, such as arterial hypoxia, anemia, myocardial dysfunction, and increased oxygen demands, should be eliminated as early as possible. This physiologic and rational approach has been described for decades. Perhaps the dramatic outcome benefit in the Rivers et al7 trial, acknowledged by Dr Manthous, was at least partially due to this approach leading to recruitment of compromised microcirculatory beds by macrocirculatory resuscitation. In the United States, patients with sepsis wait an average of 5 h in the ED, which is similar to the Early Goal-Directed Therapy study.8 The origin of these patients is the ED for 52.4% (mortality of 27.6%), ICU for 12.8% (mortality of 41.3%), and hospital wards for 34.8% (mortality of 46.8%).9 These data indicate that sepsis is a hospital-wide disease. The mortality rates for acute myocardial infarction, stroke, and trauma were significantly reduced when the “golden hours” were applied. After 1 decade, a similar approach to sepsis, called early-goal directed therapy, has been robustly replicated in >50 publications and thousands of patients. We agree that although pathogenic questions remain, they should not stand in the way of providing today’s best evidence-based care.