Optimization of preload (CVP) and afterload (mean arterial pressure) were addressed by Jones et al6; however, the remaining components of EGDT, including optimizing Do2 (oxygen carrying capacity [supplemental oxygen and hemoglobin], cardiac output) and decreasing o2 (mechanical ventilation and sedation) to prevent delayed cardiopulmonary complications, were not elicited or examined.14 Over the past decade, numerous studies have validated the clinical utility of Scvo2 in recognizing supply dependency, need for a transfusion, detection of myocardial dysfunction, response to oxygen and mechanical ventilation, early cardiopulmonary complications, and overall influence on mortality. To establish noninferiority, lactate clearance has to be appropriately examined in these scenarios in order to be generalizable to all hemodynamic phases of sepsis and these facets of care.7 The discrepancy between Scvo2-triggered interventions in the Rivers et al1 study vs the 30 interventions (10% of patients) guided by lactate clearance reflects significant differences in hemodynamic phases, patient populations, and frequency and timing of interventions (Fig 2). This undermines the conclusion of equivalency from a noninferiority research design.7 Patients more likely to require inotropes (congestive heart failure or coronary artery disease) or patients with reduced lactate clearance (liver failure) were not described by Jones et al6 (Table 2). This lower number of interventions reflects a lower illness severity compared with other studies,2 the possibility of poor compliance to the protocol, or a study design that is not equivalent to EGDT. The threefold greater use of vasopressors by Jones et al6 may have resulted in higher lactate levels (catecholamines), CVP (increased afterload and venous tone), and Scvo2 (decreased OER). As a result, triggers for more fluid administration, RBC transfusion, inotropes, and mechanical ventilation may have been obscured by catecholamines. In this vasodilatory phase of sepsis, one would expect a higher use of corticosteroids3; however, they were only used in 37% and 35% of eligible patients in the lactate clearance and Scvo2 groups, respectively.