Consensus guidelines recommend enteral over parenteral nutrition in patients with acute respiratory failure who are unable to eat conventionally (13
). Although the same guidelines recommend advancing enteral nutrition to full-energy rates over the first 48-72 hours, they acknowledge the data supporting this latter recommendation are weak (14
). The results of this randomized trial demonstrate that providing trophic enteral nutrition for the first 6 days of ventilation resulted in similar clinical outcomes as a strategy of advancing enteral nutrition to full-energy rates as quickly as possible. Initial trophic feeds did result in fewer episodes of gastrointestinal intolerance over the first 6 days, with fewer elevated GRV and a trend toward less diarrhea. Unlike previous data (19
), this study did not find an increased risk of infection with either feeding strategy.
Enteral nutrition supports the structural and functional integrity of the intestine, helping to prevent increased gut permeability and associated bacterial translocation (5
). Specifically, enteral nutrition stimulates epithelial cell growth and proliferation, maintains mucosal mass and microvilli height (22
), preserves tight junctions between epithelial cells, and promotes blood flow (24
). The intestine responds to intraluminal contents by producing and secreting a variety of endogenous agents which have a trophic effect on the intestinal epithelium (25
Although the benefits of enteral nutrition are well documented (5
), the amount needed to confer these benefits, especially in humans, remains unknown. In animal studies, continuous enteral nutrition of very small volumes, commonly termed trophic feedings for the nourishing effect that they have on the intestinal mucosal, preserve the intestinal microvilli and maintain enteric function (23
). However, data concerning the effect of different volumes of enteral nutrition on outcomes in humans are conflicting. Although confounded by better feeding tolerance in less sick patients, some observational studies have found that higher volumes of enteral nutrition are associated with reduced mortality (30
) and lower rates of bloodstream infections (19
). Additional studies demonstrated that increasing enteral nutrition adequacy by implementing a nutrition protocol shortened the duration of mechanical ventilation (31
) and hospital length of stay with a trend toward lower mortality (32
). By contrast, other observational data found patients who received 33-65% of goal calories had higher rates of survival and being liberated from the ventilator, with a lower likelihood of developing sepsis (20
). A separate cluster randomized trial demonstrated no improvement in clinical outcomes despite use of a protocol resulting in greater nutritional delivery (33
). A prospective controlled trial in 150 medical ICU patients fed either low volume or goal calorie bolus enteral nutrition for the first 4 days of ventilation found similar hospital mortality. However, the patients assigned low volume enteral nutrition experienced significantly less ventilator associated pneumonia and shorter ICU and hospital lengths of stay (21
Our study is the first randomized study comparing different volumes of enteral nutrition by continuous infusion in mechanically ventilated patients. Similar to the findings in animals (28
), these data demonstrate that initial trophic feeds, providing about 15% of goal calories daily, result in similar clinical outcomes as initial full-energy enteral nutrition. Although designed similarly to Ibrahim's study, important differences beyond the results should be noted. This study used concealed randomization to allocate patients and continuous enteral nutrition, as opposed to bolus feedings which may increase the risk of aspiration (34
). Furthermore, our study achieved excellent separation of treatment arms with the full-energy group in our study receiving 70-75% of goal calories daily compared to only 20% in Ibrahim's study.
All patients in this study were at least initially fed via tubes terminating in the stomach. This likely resulted in higher GRV than seen with post-pyloric feeding. In addition, pro-kinetic agents were utilized in only about one of every six patients, less frequently than reported in observational studies of regular practice (4
). Despite this, 94% of patients in the full-energy group still reached goal rates in a little over half a day, as fast or faster than previously reported (4
). Our decision to utilize higher than historic GRV thresholds for holding enteral nutrition likely helped facilitate rapid advancement. However, more recent findings and recommendations suggest that utilizing higher thresholds is both safe and promotes delivery of enteral nutrition (14
). Despite the higher threshold, this study had very little vomiting, regurgitation, or aspiration, although this rapid advancement to goal feeds may have contributed to the higher incidence of diarrhea in the full-energy group (40
). More frequent checking of GRVs while enteral feeds were being advanced to goal rates (q6h vs. q12h) may have contributed to more episodes of elevated GRV in the full-energy group.
This study has some limitations. It is a single center study largely conducted in a medical ICU. However, the sample size, which represents one of the largest published among human enteral nutrition studies, was adequate to detect a clinically significant difference in VFDs of 3 days. However, the study is underpowered to detect smaller differences in VFDs or to determine whether small differences in mortality or other clinical outcomes between the two groups are significant. Furthermore, the study enrolled a heterogeneous medical population with good representation of acute lung injury, pneumonia, sepsis, and overdose. Patients with GI hemorrhage were underrepresented due to clinicians' reluctance to enterally feed these patients early in their ICU course. However, patients with resuscitated shock, who constituted almost 40% of the study population, tolerated enteral nutrition with no documented episodes of intestinal ischemia or infarction.
Although sometimes used, indirect calorimetry was not undertaken to determine energy requirements. Consistent with guideline recommendations (13
) and standard practice in our ICU, energy requirements were instead calculated using a target of 25-30 kcal/kg/d. Furthermore, no patients received added protein or micronutrients, such as anti-oxidants or vitamins, beyond that provided in the enteral nutrition formulation. Protein supplementation has become popular in clinical practice since standard enteral formulas tend to have a low nitrogen to non-protein calorie ratio (14
). Despite receiving five times as much protein (54 vs. 11 grams/day) for the first 6 days, the full-energy group had similar outcomes as the trophic group. However, neither group received the goal of 1.5 g / kg of daily protein. Parenteral nutrition or supplemental intravenous dextrose was not initiated in any study patient, including those unable to tolerate 100% of goal calories after 7-10 days (14
This study also has a number of strengths. The feeding protocol delivered average daily amounts comparable to the best data from other protocolized enteral nutrition strategies (4
), rendering the full-energy group a representative control. Randomization was done via concealed envelopes with complete follow-up of all patients. Similar clinical outcomes with initial trophic compared to full-energy enteral nutrition were found in both subgroups analyzed. Observational data have suggested that increased intakes of energy are associated with improved outcomes in patients with BMI < 25 or ≥ 35 (42
). Since underweight and malnourished patients were excluded from our study, the number of patients with BMI < 25 was too small for subgroup analysis. However, full-energy nutrition did not result in significantly more ventilator-free or ICU-free days nor lower mortality in the subgroup of patients with BMI ≥ 35.
Guidelines recommend initiating enteral nutrition within 24 to 48 hours of intubation (13
) and a recent meta-analysis suggests improved survival in critically ill patients when enteral nutrition is initiated within 24 hours of injury or admission (12
). This study does not address the question of whether early administration of enteral nutrition improves outcomes, nor does it address the question of what is the optimal composition. Although advancement to full-energy rates was later in the trophic group, all patients received some enteral nutrition within 48 hours of ventilation. In fact, enteral nutrition was initiated on average about 24 hours after intubation in all study patients which is considerably earlier than reported in routine clinical practice (4