A middle aged woman presented with an acute abdomen. At laparotomy she was found to have generalised peritonitis secondary to small bowel perforation due to adhesional obstruction. She remained ventilated and on noradrenaline support for several days post-op. Trophic enteral feeds were introduced at 24hrs post-op, but NG aspirates remained high for a further 48 hours despite prokinetics. The decision was made to institute parenteral nutrition if no improvement at day 5 post-op, but was never commenced as NG aspirates improved and enteral nutrition was gradually increased.
What is the evidence for enteral versus parenteral feed as a source of nutrition in critical ill patients?
Sam Clark
Evidence of a close association between malnutrition, negative nitrogen and calorific balance and poor outcomes including the inevitability of death if continued unabated has led it to be standard practice to provide nutrition support to critical ill patients. It has been shown that there is an association between length of stay in ICU and its concomitant risks (1).
Essentially, there are two main routes for feeding patients: enteral and parenteral. Enteral feeding can either be oral, gastric or jejunal and the latter two can be either oral or nasal tubes or via percutaneous methods. The advantages of enteral feeding have been suggested to include reduced hyperglycaemia, improved immune function of the GI tract, reduced risk of stress ulcers, cheaper, and potential reduced risk of infections (2). Its disadvantages include sepsis secondary to gut bacteria translocation and regurgitation leading to increased risk of ventilator-associated pneumonia. These coupled with decreased GI motility both as a consequence of the underlying acute phase reaction and many drugs used in ICUs means that the parenteral route is occasionally the only alternative either for complete nutritional support or partial supplementation of enteral feed. Parenteral feed has the advantages that it can be started early, simple with no delay in caloric intake, it does not rely of gastric/intestinal function and therefore less need for interruptions, however catheter related sepsis, hyperglycaemia, hypercholesterolaemia, refeeding syndrome and abnormalities in LFTs are significant complications.
To that effect, there have been a number of guidelines published to help clinicians: in Europe, there has been ESPEN, and ASPEN in United States guidelines (3,4). ESPEN (European Society of Parenteral and Enteral Nutrition) advocates “…All patients who are not expected to be on normal nutrition within 3 days should receive parenteral nutrition (PN) within 24 to 48 h if enteral nutrition (EN) is contraindicated or if they cannot tolerate EN…” (3). They also suggest that any patient that has not attained the target set for enteral feed within 48 hours of admission should be considered for parenteral supplementation. In contrast, ASPEN guidelines (from the American Society of Parenteral and Enteral Nutrition) though also advocating early enteral nutrition, they recommended that no nutritional support is preferable to early initiation of parenteral nutrition in the first seven days after hospitalization. Unfortunately, these guidelines are based mainly on observational studies and meta-analyses of small poorly conducted trials (5). The Canadian guidelines, which adhere to a similar view that early enteral nutrition should be instituted, but that parenteral nutrition should delayed for 7 days were utilised in the ACCEPT trial that demonstrated across 462 patients divided into a control group and an intervention group that used the aforementioned guidelines to drive their nutritional decision making (6). ACCEPT found that use of the guidelines led to a significant increase in days of enteral feed, as well as 10 day reduction in mean hospital day and trend towards a reduction in mortality, which suggested that though despite their thin evidence base, these guidelines had clinical merit.
Most recently, however, there have been a number of larger well-conducted randomized control trials that looked at various issues influencing the balance between enteral and parenteral routes. The Tight Calorie Control Study (TICACOS), a single centered prospective RCT that compared 130 mechanically ventilated patients with a control group that were fed with a calculated energy target (25kCal/kg/24hr) to an intervention group, whose energy requirements were individualized by indirect calorimeter. The results were contradictory with a trend towards reduced mortality offset (21/65 patients vs. 31/65 patients, p = 0.058) by a significant increase in infections and ICU length of stay (7). The EDEN trial is a well-conducted RCT established to compare trophic versus full enteral feed (8). They enrolled 1118 relatively young and well-nourished medical ICU patients with acute lung injury and randomly assigned them to either trophic feed for the first week or full enteral feed for the first week of their ICU admission. The results showed that as expected the full feed group received more calories in the first six days (1,300kcal/d vs. 400 kcal/d, p<0.001), but there were no significant differences in ventilator-free days, 60-day mortality or infectious complications. The patients in the full feed group suffered more vomiting (2.2% vs. 1.7%, p<0.05), elevated gastric residual volumes 4.9% vs. 2.2%) and constipation (3.1% vs. 2.1%, p=0.03). EDEN questioned the necessity of large volume feeds in previously well-nourished medical patients, but it is debatable that such an interpretation could be extended other ICU patient groups e.g. Surgical patients.
Two further trials looked at a mixture of medical and surgical patients either at nutritional risk or with relative contraindication to enteral nutrition (9,10). The largest randomized control trial to date was the EPaNIC trial (Impact of Early Parenteral Nutrition in Adult Critically Ill Patients). It studied 4640 patients (out of over 8,000 patients assessed for eligibility), who were considered at risk of nutritional insufficiency. Both groups were trialed on enteral feed in short order after admission to ICU. The intervention group was initially started on 20% glucose for the first 48 hours and then early initiation of parenteral nutrition to supplement any enteral feed. The control group was given delayed parenteral nutrition (from day 8 onwards if nutritional targets were not yet met), for the first week they were given 5% glucose to match the volume of fluid of the intervention groups. The results demonstrated that the control group i.e. late initiation of PN, was associated with an increase in likelihood of being discharged both from ICU and hospital alive earlier (p<0.04 for both) and reduced complications (22.8% vs. 26.2%, P = 0.008) (9). The Early Parenteral Nutrition trial examined patients were a relative contraindication to early enteral feed. 1,372 patients in 31 ICUs were randomized to either standard therapy (at treating the physician’s discretion) or early parenteral nutrition within 24 hours after admission (10). Of 686 patients in the standard group, 29% commenced early EN, 27% had early PN and 40% remained unfed. There was no significant difference in 60-day mortality (22.8 vs. 21.5%), ICU length of stay and hospital stay. The early PN route showed shorter time on mechanical ventilation (7.73 vs. 7.26 days per ten patients ICU days, p=0.01), however though significant statically, the effect size is small.
Most recently, the CALORIES trial was published, which examined a self-styled pragmatic approach to the question of the most effective route for early nutrition (11). They assigned 2,400 patients to be fed either by early parenteral nutrition or early enteral nutrition, both started within 36 hours of admission. Their primary outcome was 30-day mortality. There were no significant differences in: 30-day mortality (33.1% for PN vs. 34.2% for EN, p=0.57), 90-day mortality (37.3% for PN vs. 39.1% for EN), or infections (0.22 for PN vs. 0.21 for EN). They did find differences in rates of vomiting and hypoglycaemia. It is interesting to note that both groups of patients were unable to meet their calorie goals in most cases. They concluded that there was neither benefit nor harm from parenteral over enteral routes for early nutrition.
Conclusion:
Overall, the evidence from the generally well-conducted RCTs have been inconclusive. EPaNIC and EDEN suggest that in certain circumstances attempting to achieve full feed during early stages of ICU admission may be harmful, while in contrast EDEN and CALORIES suggest that the perceived increased risk of infections with parenteral nutrition are not bourne out. Though it is noticeable that the patients in the CALORIES trial did not often reach full feed. One approach is to establish low level enteral feeding during the acute phase of critical illness, moving to more substantial feeding after the first seven days unless well tolerated earlier in patients who were previously well-nourished, but in patients with an absolute contraindication to enteral feed or are previously malnourished, serious consideration should be given to the initiation of early parenteral nutrition. However, there a number of questions remain unanswered: benefits of enteral versus none in the acute phase; the benefits of macro versus micronutrients on the catabolic process; potential scoring systems to stratify those at risk from not receiving nutrition.
References:
1. Alberda C, Gramlich L, Jones N, et al. The relationship between nutritional in- take and clinical outcomes in critically ill patients: results of an international multi- center observational study. Intensive Care Med 2009;35:1728-37.
2. Macdonald K., Page K., Brown L. & Bryden D. Parenteral nutrition in critical care. CEACCP, 2013;13:1-5.
3. Martindale RG, McClave SA, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Soci- ety of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition: executive summary. Crit Care Med 2009;37:1757-61.
4. Singer P, Berger MM, Van den Berghe G, et al. ESPEN guidelines on parenteral nutrition: intensive care. Clin Nutr 2009; 28:387-400.
5. Casaer M. & Van den Berghe G. Nutrition in the acute phase of critical illness. NEJM. 2014; 370;13: 1227-1236.
6. Martin CM, Doig GS, Heyland DK, Morrison T, Sibbald WJ. Multicentre, cluster-randomized clinical trial of algo- rithms for critical-care enteral and paren- teral therapy (ACCEPT). CMAJ 2004;170: 197-204.
7. Singer P, Anbar R, Cohen J, et al. The Tight Calorie Control Study (TICACOS): a prospective, randomized, controlled pilot study of nutritional support in critically ill patients. Intensive Care Med 2011;37: 601-9.
8. The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syn- drome (ARDS) Clinical Trials Network. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 2012;307:795- 803
9. Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011; 365:506-17.
10. Doig GS, Simpson F, Sweetman EA, et al. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA 2013; 309:2130-8.
11. Harvey SE, Parrott F, Harrison DA, et al. Trial of the route of early nutritional support in critically ill adults. N Engl J Med 2014;371:1673-1684
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