Despite tolerating some EN, the average delivery in most patients fails to reach goal or target feeding rates, as calculated from estimated or measured protein and calorie requirements. Subsequently, some practitioners have adopted the practice of supplementing whatever the patient can tolerate enterally with PN to achieve delivery of full estimated caloric and protein requirements. A meta-analysis of five studies comparing EN alone with combined EN and PN found no difference in any clinical outcome, including mortality, infectious complications, time on the ventilator, or hospital or ICU lengths of stay. There was considerable heterogeneity among the studies, and none of the studies was done using tight glucose control. Differences in interpretation of these studies led to a divergence in consensus guidelines, with one recommending for and one against adding PN to patients who were unable to tolerate full nutrition enterally.15,18 A phase 2, open-label, single-center randomized trial of 130 patients who were mechanically ventilated that were expected to stay in the ICU at least 3 days found that using serial metabolic cart measurements to guide the supplementation of EN with PN resulted in a trend toward lower hospital mortality (32.3% vs 47.7%, P = .058) compared with a strict target delivery of 25 kcal/kg/d of EN.19 However, overall lengths of time on ventilation and ICU stay were longer in the intervention group. A subsequent very large, open-label, randomized, multicenter trial investigated the role of supplementing EN with PN in critically ill adults at moderate nutritional risk.20 Of the 4,640 patients enrolled, 2,312 were randomized to receive only EN as tolerated for up to 7 days before initiating PN (late initiation group) compared with 2,328 patients randomized to receive supplemental parenteral calories in addition to whatever EN they could tolerate during the first 7 days (early initiation group). All patients in this study were managed with a tight glucose control (ie, 80-110 mg/dL) strategy. The study, Impact of Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC), found that early supplementation of EN with PN resulted in lower rates of early, alive discharge from the ICU (hazard ratio, 1.06; P = .04) and hospital (hazard ratio, 1.06; P = .04) than EN alone. In addition, patients in the late-initiation group had lower rates of ICU infections (22.8% vs 26.2%, P = .008). Interpretation of the EPaNIC study results have varied. At the end of January of 2013, the Surviving Sepsis Campaign (SSC) issued updated guidelines regarding the care of patients with severe sepsis. In this third edition of the SSC, the committee recommends avoiding the use of PN alone or as a supplement to hypocaloric enteral feeding.21 Others criticize the EPaNIC study for what was interpreted to be a detrimental effect from IV glucose given in the early supplemental PN. In addition, critics worry that the patients enrolled were only moderately critically ill overall and, therefore, not representative of most patients considered candidates for PN at other institutions. They cite a smaller study by Heidegger and colleagues,22 which showed some improvement in nosocomial infection late in ICU admission with use of supplemental PN started after 72 h in patients receiving < 60% of goal enteral feedings. Subsequently, a post hoc reanalysis of the EPaNIC data showed that the detrimental effect in the early PN group was not due to glucose but instead to the early receipt of parenteral protein.23 By examining quartiles of the APACHE (Acute Physiology and Chronic Health Evaluation) II score, it was evident that greater degrees of critical illness were associated with a worsening adverse effect from early PN regarding mortality and nosocomial infection. Furthermore, in a complicated post hoc analysis, Casaer and colleagues23 showed that the more feeding a patient received through either day three or seven, the lower the likelihood of being discharged alive from the ICU. The effect, however, appeared to be driven by the early receipt of PN, as the receipt of enteral nutrients was similar between the groups throughout the first week. Although the nutrition community might have interpreted the findings that EN and PN are not equal and that early PN is bad in the ICU, Casaer and colleagues23 and Schetz and colleagues24 interpreted results to suggest that all early nutrition was bad and should be withheld or minimized in the first week following ICU admission. They hypothesize that early nutrition, regardless of route of administration, exerts its detrimental effects by suppressing autophagy, or the natural recycling of intracellular nutrients to maintain energy homeostasis during starvation. Autophagy may be important for recovery of organ dysfunction through both the immune response and the removal of toxic intracellular proteins and damaged organelles.24 However, given other contradictory data suggesting benefit to early EN25 and similar outcomes with trophic and full enteral feeding,26,27 this hypothesis needs further testing in a prospective study.