Lower versus higher dose of enteral caloric intake in adult critically ill patients: a systematic review and meta-analysis

In this systematic review and meta-analysis of RCTs of critically ill patients in which there was a significant difference in the caloric intake via EN, we found that lower versus higher dose of caloric intake was not associated with mortality. However, patients in the lower caloric intake group had lower risk of blood stream infections and incident renal replacement therapy. The associations between lower compared with higher caloric intake and all studied outcomes were not different between caloric restriction and non-caloric restriction trials, except for the hospital LOS. Our certainty in the meta-analytic estimates is reduced due to the moderate risk of bias.

The optimal EN dose during critical illness is unknown. Malnourishment is generally associated with poor outcomes leading to the notion that replacement of full energy needs is intuitively needed. However, in critically ill patients, multiple metabolic changes may occur and differ from one patient to another. The metabolic rate is highly variable, being increased in about 50 % of patients but low in others [70]. Glycolysis is increased as the energy source is altered from predominantly fat to glucose oxidation [71]. Proteolysis is accelerated especially as prolonged starvation is associated with dysregulated metabolism, such that major stimulation of both ketogenesis and concomitant gluconeogenesis do not occur [72]. The normal suppression of lipolysis and proteolysis by the exogenous supply of fat or carbohydrates is blunted [71]. Additionally, excess caloric provision might be detrimental, particularly to the mitochondria by increasing oxygen radical production [73], and full EN may lead to gastrointestinal intolerance, which may increase infection risk. On the other hand, caloric restriction may enhance autophagy, which might be protective [74, 75]. These changes have led to the premise that lower caloric intake may have a protective effect.

The available studies on this topic produced mixed results. In this meta-analysis of RCTs in which critically ill patients received significantly different caloric intake, we found no difference in the primary outcome of hospital mortality. The results were similar in caloric restriction and non-caloric restriction trials and when studies were stratified based on age, severity of illness, amount of calories in the lower calorie group and the difference in calories between the intervention groups. Moreover, there was no clear dose–effect relationship as observed in the meta-regression. Marik and Hooper have recently published a systematic review and meta-analysis of six trials that assessed the outcomes of ICU patients randomized to either normocaloric or hypocaloric feeding and also found no difference in mortality and infectious complications [76]. However, our study differed in its inclusion and exclusion criteria and thus included 21 trials, which evaluated various interventions that resulted in different caloric intake. We also analyzed multiple subgroups and performed meta-regression.

We note that in one of the included trials, the TICACOS trial [63], the difference in energy intake was largely provoked by greater administration of PN rather than EN. However, we included the study because it met our a priori inclusion criterion; the mean enterally delivered energy in the study group was 1515 ± 756 kcal/day compared with 1316 ± 456 kcal/day in the control group (p = 0.09), which is more than 10 % [63]. We also note that in the included INTACT trial [67], the number of days between hospital admission and enrollment were 8.8 ± 8.7 and 6.4 ± 6.6 days in the intensive medical and standard nutrition groups, respectively (Table 1) and the caloric target was 30 kcal/kg in the intensive medical group. These issues raised concerns about the occurrence of refeeding syndrome, which was not studied in the trial, and of overfeeding in the intensive medical group which may have led to early ICU deaths [67, 77‐79].

The relationship between nutrition and infection risk has been evaluated in different settings. A meta-analysis found that EN versus PN was associated with a significant decrease in infectious complications in critically ill patients (relative risk 0.64, 95 % CI 0.47–0.87; p = 0.004) [80]. Another meta-analysis found that EN within 24 hours after elective gastrointestinal surgery compared with nil-by-mouth management reduced any infection risk (relative risk 0.72, 95 % CI 0.54–0.98; p = 0.04) [81]. However, the impact of EN dose in critically ill patients is not well-studied. In the current study, we have observed that lower caloric intake was associated with lower nosocomial blood stream infection risk. However, there was no effect on total infections or pneumonia. This could be related to the heterogeneity of studies and publication bias.

Caloric restriction has been shown to be reno-protective in animal models of acute kidney injury [82‐84]. However, a secondary analysis in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy trial found that the increased caloric intake was associated with lower 90-day mortality on multivariable logistic regression analysis (odds ratio per 100 kcal increment 0.95, 95 % CI 0.91–1.00; p = 0.06) on multivariable logistic regression analysis [85]. This was more pronounced after excluding patients who died within 96 hours of ICU admission [85]. However, the mean caloric intake during treatment was low (approximately 11 ± 9 kcal/kg/day). Our meta-analysis identified lower incident renal replacement therapy rates in the lower calorie group, but this finding is limited by the small number of studies (n = 5) that reported on this outcome. Other possible mechanisms for the difference in renal replacement therapy, which may include differences in protein intake or fluid balance between the two groups, could not be examined in our meta-analysis. Further studies are needed to clarify this association.

Multiple observational and interventional studies have identified variable associations between EN dose and ICU and hospital LOS and mechanical ventilation duration [9, 12, 86‐88]. Our meta-analysis did not identify differences in mechanical ventilation duration or ICU LOS. Lower caloric intake was associated with longer hospital LOS in the subgroup of studies that compared caloric restriction with standard feeding.

This study needs to be interpreted in the light of its strengths and limitations. Potential confounders were controlled for because of the randomized design of the included trials. For example, age and severity of illness were similar in the two arms in the included trials (Table 1). A further strength is that rather than being selective and possibly biased in selecting trials, we included all studies in which a difference in enteral intake was provoked by the intervention. As such we included not only studies on caloric restriction but also studies evaluating other interventions that affect caloric intake, such as gastric residual volume management or small bowel feeding. Such relatively wide inclusion criteria allowed the inclusion of more trials. However, this strength may have provoked a possible weakness. Studies were pooled despite different design, some of them not even focused on improving outcome by reaching feeding goals or by nutrient restriction. We have addressed this limitation by our subgroup analyses and by the meta-regression. Our study focused on EN and did not include studies that had PN as the primary intervention. Hence, the study by Heidegger et al., in which ICU patients who received <60 % of their calorimetry-calculated caloric target from EN were randomized to either EN or EN plus supplemental PN [89], was not included. Although several studies showed similar outcomes with the two routes [80, 90], we chose not to include PN trials as this may further contribute to the heterogeneity. In addition, permissive underfeeding in PN has been studied in earlier systematic reviews [8, 91].

Another limitation is related to the quality of the included studies, most of which had one or more form of bias. Furthermore, the caloric intake in all included studies in the higher feeding group was generally less than the estimated caloric requirement. This is a reflection of the difficulty in achieving full targets in cohorts of ICU patients (although it certainly is achievable in many individual patients). However, this resembles what has been shown in many observational studies and in real-world practice. Given that the full enteral intake was reached in a few studies only, the benefit of this strategy remains unclear. While some studies calculated the calories from sources other than EN and PN, such as intravenous dextrose (including medications) and propofol [14, 55, 63, 66‐68], this was not a consistent approach among all trials. Most included studies have used predictive equations rather than indirect calorimetry to estimate caloric intake. However, this is consistent with usual practice in most ICUs, given the limited evidence supporting either approach. Energy requirements were estimated using different predictive formulae in all but one study, which used indirect calorimetry [63]. This method has been shown to poorly correlate with indirect calorimetry [92], which is considered to be the standard. Based on recent evidence, calorimetry-guided nutrition might be superior to predictive formula-based feeding in improving patient-centered outcomes [63, 89].

The caloric dose and target varied among the included studies and what was lower caloric intake in one study was high in another. However, the meta-regression analysis suggested that the differences in calories between groups and the amount of calories in the lower caloric intake group did not influence hospital mortality. Moreover, not all studies reported on all the outcomes, thus reducing the sample size used and the ability to find small but potentially clinically significant effects. Given the reported data in the individual studies, further analysis of the impact of protein intake could not be performed. Our systemic review highlights the limited data on this important issue and calls for further studies on the impact of protein intake on the outcomes of critically ill patients. Our meta-analysis was not an individual-patient meta-analysis and did not include economic or long-term endpoints.