Comparisons between intragastric and small intestinal delivery of enteral nutrition in the critically ill: a systematic review and meta-analysis

In the critically ill, nutritional therapy is a component of standard care. Delivery into the gastrointestinal tract is the preferred route of nutrient administration, via a tube into either the stomach or small intestine [1]. However, whether these feeding tubes should be preferentially placed into the stomach or small intestine remains contentious. Several clinical practice guidelines have recommended that enteral nutrition should be commenced using an intragastric tube [1, 2], whereas other guidelines advise that when small bowel feeding is feasible that this route is preferable [3].

The advantages of commencing with intragastric feeding include that naso- or oro-gastric tubes are relatively easy to insert, so that once a decision is made to feed, delivery of nutrient can promptly commence. However, disadvantages of the intragastric approach include delayed gastric emptying, which occurs frequently in the critically ill [4, 5], and predisposes to inadequate nutrient administration. Indeed, observational studies, in which most patients receive intragastric feeding, have shown that the proportion of calories and protein delivered to critically ill patients are about 50 to 70% of targeted calorie and protein loads [6‐8].

Small intestinal feeding tubes are more difficult to insert, often requiring specific expertise and equipment. Their potential advantages include bypassing the stomach, which should theoretically 'guarantee' delivery of nutrients, as the major gastrointestinal motility disorders in the critically ill appear to occur in the antral-pyloro region of the stomach [9]. Not only does increasing administration of nutrients have the potential to reduce mortality and length of stay, particularly in those patients at risk of critical illness malnutrition and its consequences [10], but delivery of nutrients into the small intestine has been reported to reduce the incidence of hospital-acquired pneumonia, possibly because episodes of gastro-oesophageal regurgitation occur less frequently [11, 12]. Intuitively, a reduction in pneumonia should shorten intensive care unit (ICU) and hospital length of stay and may reduce mortality [13].

Systematic reviews and meta-analysis have been published that evaluated small bowel and gastric feeding in the critically ill [14‐17]. An update incorporating important recent studies [18‐20] was published by Jiyong and colleagues [17]. However, a limitation of the latter review is that the authors included a study in which patients received care on the general hospital ward rather than a critical care environment. In addition, Jiyong and colleagues included studies of both adult and paediatric subjects. Finally, data from the ENTERIC study were not included, and we believe that this study is the pivotal study in the area [21]. For these reasons we sought to update previous reviews to determine whether small bowel, when compared to intragastric delivery of nutrition, is associated with improved outcomes in the critically ill.

The objectives of this study were to determine the effects of small bowel and gastric tube delivery of liquid nutrients on hospital-acquired pneumonia, duration of mechanical ventilation, length of ICU and hospital stay, mortality and nutritional intake in adult critically ill patients.

The meta-analysis was performed in line with the recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [22].

The literature search resulted in 22 RCTs. After reviewing these studies, four were excluded because they were systematic reviews [14‐17], one had < 50% of enrolled patients admitted to an ICU [28], one did not report clinical outcomes [11] and one [29] was an analysis of data already included.

We conducted a systematic review and meta-analysis of all RCTs of gastric vs. small bowel feeding in the ICU setting, including the recently published ENTERIC study [21]. The main observations are that delivery of nutrients directly into the small intestine may be associated with a reduction in the incidence of ICU-acquired pneumonia when compared to intragastric delivery, but despite this, days of ventilation, ICU and hospital length of stay and mortality appear unaffected. In addition, while there were relatively few, and substantial heterogeneity between, studies that evaluated nutritional efficiency, there was a signal that feeding into the small intestine increased nutrient intake.

It is possible that our meta-analysis over-estimated any reduction in pneumonia caused by small intestinal feeding. In several studies the diagnosis of pneumonia was made while investigators were aware of treatment allocation. Moreover, nearly all studies were conducted at a single ICU and the number of subjects was relatively small. Biases, including publication and selection biases, are well known to occur in studies involving fewer subjects, thereby affecting point estimates calculated in meta-analyses [38]. To limit bias we also analysed studies that used quantitative microbiological assessment. When this was performed, the interpretation remained similar supporting the original observation. Nevertheless, a reduction in pneumonia was not apparent in the largest cohort studied (ENTERIC). Given that discrepancies between meta-analyses and the 'truth' occur frequently [39, 40], circumspect interpretation of these aggregate data related to the incidence of pneumonia is recommended.

While we report a reduction in ICU-acquired pneumonia, the number of days of ventilation, length of ICU and hospital stay, as well as mortality, were unaffected by the route of feeding. While the lack of effect on the latter outcomes may reflect an inadequate sample size or, as described, that our meta-analysis overestimated the effect of route of feeding on the risk of pneumonia, there are plausible mechanisms that may explain these seemingly discrepant findings. In several of the studies artificial nutrition was administered for only a short period and so-called 'early-onset' ventilator-associated pneumonia is often caused by susceptible organisms and responds rapidly to antibiotic therapy [41]. Accordingly, attributed outcomes, such as length of ventilation and mortality, may actually be unaffected by 'early-onset' hospital-acquired pneumonia. Indeed, other factors, such as depth of sedation [42], may be greater determinants of length of ventilation and ICU stay than development of pneumonia.

There was a signal for increased nutritional intake when using small intestinal feeding tubes. There was, however, substantial statistical heterogeneity indicating that this observation should be interpreted with caution. The heterogeneity may reflect that placement of small intestinal tube can be technically difficult, requiring expertise and sophisticated methodologies [25]. Somewhat surprisingly, time-to-placement and placement success was not consistently reported. We suggest that the improvement in nutritional intake will only be generalisable to institutions that have the capacity to rapidly insert feeding tubes into the small intestine.

There were also inconsistencies between studies as to reporting concurrent gastrokinetic drug administration. This is likely to be important when trying to interpret the nutritional data, as gastrokinetic drugs can have potent effects on gastric emptying, but the response varies markedly between drug classes and regimens [4, 43, 44]. It should, therefore, be emphasised that data relating to nutritional intake do not extend to a comparison between small intestinal feeding and intragastric feeding with concurrent gastrokinetic drug administration.

While nutrient intake may have been 'improved', as discussed, mortality was unaffected. However, the optimal amount of calories and protein that should be administered to the critically ill is uncertain. Moreover, the benefits of nutrient administration may vary according to a number of factors specific to the individual patients. Those likely to benefit more from artificial nutrition compared to other ICU patients are those with a body mass index at either extreme [6], increased NUTRIC score [45], and anticipated prolonged length of stay in the ICU [10]. It should be emphasised that in some studies the period of nutrition required was relatively brief [18]. Hence, the power to detect any benefit from improved nutritional efficiency is markedly diminished [45]. It should also be noted that administration of more nutrient might have effects that are important to patients, but are not measured using data such as length of stay and mortality. Rice and colleagues reported that patients who received fewer calories were less likely to return to independent living on discharge [46]. Unfortunately, only one study reported longer-term function (neurological outcomes in this case) [24] and none measured muscle strength after ICU discharge. These functional outcomes may be very important to patients, and future studies of nutritional interventions would benefit from measuring such outcomes.

A further consideration is that the delivery of nutrients into the small intestine does not guarantee absorption, and it is absorption, rather than delivery of nutrients, which will improve patient outcomes, as undigested nutrients entering into the large intestine will lead to gas formation and abdominal distension, as well as diarrhoea [47]. Whether nutrients are administered proximal or distal to the pylorus does not, however, appear to affect absorption [48].

Although our search strategy was relatively comprehensive, and our methodology robust, there are several limitations to our findings. Statistical heterogeneity was modest and clinical heterogeneity was substantial. Some studies attempted to identify a cohort that was likely to have delayed gastric emptying [21], whereas others evaluated all patients requiring enteral nutrition at the beginning of their ICU stay [18]. There are no studies that include only patients with persistent feed-intolerance and/or those at the greatest risk of ICU-acquired pneumonia. This is important because while delayed gastric emptying occurs frequently in the critically ill [4, 5], the prevalence is probably no greater than 30% of all ICU patients that receive enteral nutrition. We suggest that patients with relatively 'normal' gastric emptying and oesophago-gastric motility are unlikely to benefit from small intestinal feeding. For this reason, we recommend against extrapolating this systematic review to patients with documented enteral feed-intolerance (as a marker of delayed gastric emptying) [49], particularly when feed-intolerance occurs during gastrokinetic drug use, and/or those at the greatest risk of ICU-acquired pneumonia - as these groups of patients may well benefit from small intestinal feeding.

Future studies should therefore target patients who develop feed-intolerance while receiving gastrokinetic drugs. In particular, targeting patients who are most likely to benefit from augmented nutritional delivery and who will require nutritional support for a substantial period of time will be a priority. In addition, these studies would also benefit from using a technique that affords rapidly and repeatedly successful placement of small intestinal feeding tubes as well as measuring longer-term functional outcomes.

Small bowel feeding may be associated with a reduction in ICU-acquired pneumonia and increases in nutrient delivery, but days of ventilation, ICU and hospital stay, and mortality were unaffected. Until further data are available, decisions as to whether to preferentially feed patients into the small intestine will need to be at an institutional level, incorporating the feasibility, safety and delays in obtaining access, while identifying patients most likely to benefit from this route of feeding.