Prospective Randomized Clinical Trials

Rationale of the study

The difference in patients’ outcome cannot be very clear when eternal nutrition (EN) of two types i.e. conventional oral diet and tube feeding with standard care or the intravenous dextrose is compared with parenteral nutrition (PN). This study tried to systematically review and statistically aggregated the results of PRCTs (prospective randomized clinical trials) in examining the relations amongst the mortality rates, complications, and nutrition interventions. The rationale for this meta analysis has been the provision of an interim guide to make decision till the large trials results with marginal gastrointestinal function conducted in populations have the availability. A literature’s comprehensive search has been conducted using clinically relevant criteria for assessed outcomes and study selection.


The evolving of the artificial nutritional support to primary therapeutic intervention in preventing the lean body mass’ loss and metabolic deterioration have been with the aim of improving the critically ill patients’ outcomes. Alongside the initiation timing and macronutrients of targeted amount, the delivery route is viewed as a key determinant of the nutritional intervention’s effect. The use of enteral route is considered as more physiologic that provides various non-nutritional and nutritional benefits which include maintaining the functional and structural gut integrity and preservation of intestinal microbial diversity (Casaer et al., 2011). The enteral nutrition’s (EN) disadvantages have been in relation to the potentially lower nutritional adequacy, especially in the phase of acute disease and in the gastrointestinal dysfunction’s presence. Contrastingly, parenteral nutrition (PN) can secure better the intake of intended nutrition although it has association with more infectious complications, mainly because of hyperglycemia and hyperalimentation, as indicated consistently in the earlier meta-analyses (Fan et al., 2016).


These clinical data resulted in wide ranging consensus amongst the current guidelines pertaining to recommendations and expert opinions related to the preference of enteral route in the patients with no contraindication to EN.

The researchers and clinicians believe that timing, route and nutritional amount do support the effect of critical illness outcome. The nutritional supports’ major international guidelines for ill patients recommend EN that must be preferred over PN, as there is acceptance that EN considerably reduces infections (Harvey et al., 2014). Nonetheless, the most recent multicenter clinical trial of large scale, the CAORIES trial conducted in UK and having the randomization of 2,400 critically ill patients being the recipient of early PN or early EN having found to be without a difference in infectious complications (Berger et al., 2011). It is interesting to note that despite the CALORIES that did not start PN or EN while there was active shock in the patients systolic blood pressure


The National Library of Medicine, Bethesda, MD, MEDLINE has been under search for PRCTs evaluating the PN effects comparing with standard care or tube feeding conducted between 2009 and 2018. The PRCTs having done the evaluation of the PN effects administering at or above the estimated needs of the energy in comparison to the ones of standard care or tube feeding with clinical significance (mortality and morbidity) that have been reviewed. The studies evaluating the nutritional outcomes only (e.g. serum protein and nitrogen balance) that have not been in inclusion as these were under the consideration of surrogate endpoints. The studies are having the limitation to those that have the involvement of English speaking adult patients. The finding of the Reference list from the studies has been by the search which has been subject to review for the additional reports. Also, Ronald Koretz has extended the provision of all studies’ list published about the support of nutrition which has been complied for > 10 years. In manual search, some of them are found for literature completed for the Cochrane Collaboration publishing The Cochrane Library’s (Oxford, United Kingdom) COCHRANE DATABASE OF SYSTEMATIC REVIEWS.

There are differences in the design and study populations causing variation in results. For heterogeneity, 4 sources have been defined as a priori: (a) year of the publication of the study; (b) score of the study quality; (c) patients’ nutritional status; and (d) percentage of ill patients. In each study, the used method have been subject to evaluation for these characteristics’ quality: well defined outcomes, well described protocols of treatment, endpoints (whether blinded to staff), baselines, and analysis by intent of treatment. For each of these traits, one point was given ranging from 0 to 6 and has been calculated for each investigation. The categorization of the studies into the ones with low score of study quality (< 4 points) and the ones with high score of study quality (>= 4 points) and analyses of separate subgroup for each category were performed.

In hospitalized patients, PEM have had the association with high rates of mortality and morbidity (Abrishami et al., 2010). In addressing this possible heterogeneity score, the patients’ nutritional status at the enrollment time has been examination. The PEM definition of each investigator has been used when possible. When not stated specifically, a loss of unplanned body weight >= 15 percent of normal body weight was usable as PEM classification’s cutoff. The studies have been subject to categorization into 2 groups based on PEM participants’ percentage (%PEM) those with high (>=50%) and those with


The primary objective of this study is determining whether PRCTs aggregated results supported the tube feeding use instead of PN. Additionally, another objective was determining whether the risk of nutrition support complications, infections, alternative complications, and mortality have been greater with PN or standard care. It has been found that both standard care and tube feeding have had the association with infections of lower risks compared to the PN, and this lower risk has not been an artifact or whether there is inclusion of catheter sepsis in the analysis. There is remaining of this lower risk for tube feeding irrespective of study quality score, year of publication of study, nutritional status, and presence of illness.

There has been report that in animals EN does more so PN lowering the infection risk with the preservation of the integrity of gastrointestinal tract and the enhancement of its ability in providing to endogenous gut bacteria with an immunocompetent barrier and thereby preventing the bacterial translocation occurrence (Taylor et al., 2016). However, the EN’s role is played to prevent the human’s bacterial translocation is something which is still debated (Harvey et al., 2014). It cannot be suggested that the findings of this study support the hypothesis of the aggressive EN’s protective role (tube feeding) to prevent bacterial translocation as there has been a number of aspects of this study’s meta-analysis design prohibiting this. To be specific, no study that are included in the discussion does investigation of the bacterial translocation as a primary hypothesis, and all infection types have been subject to groupings within the infection category, furthering the limitation of the interpretation.

Also, it cannot be determined from the results whether aggressive EN can do reduction to the infection risk or whether PN led to greater infection risk. The findings of this study show less infection having association with both standard care and tube feeding compared to the PN in normally nourished populations that is suggestive that EN results in lowering the infection risk and PN results in higher infection risk.

The infection’s higher risk having association with PN may be explained partially by larger number of hyperglycemia patients in this population. The elevated concentrations of glucose can do reduction of phagocytosis and neutrophil chemotaxis and have been found to be an independent risk factor in patients for short term infection that undergoes the coronary artery surgery (Reignier et al., 2018). There have been 20 trials comparing PN with tube feeding and out of the 20 trials, 16 included infection data (Tian et al., 2015) and 7 reported on hyperglycemia data, 6 of which reported data on both hyperglycemia and infection.

The occurrence of hyperglycemia, in all of these investigations, has been more frequent in patients that are recipient of PN compared to the ones that were tube fed. However, the nature of the presentation of data made it impossibility in discerning whether patients with infection are the ones with hyperglycemia. In this meta analysis, what will be included is the feeding protocols for PN as well as tube feeding which needs provision of energy at or above the estimated needs. However, the patients that are tube fed are frequent recipients of less than the prescribed amount as there is interruptions and feeding intolerance. In determining whether the reported hyperglycemia was the cause of greater infusion of energy that PN receives compared to the tube feeding, the 5 investigations reporting both hyperglycemia and infection were reviewed. There is random assignment of patients in receiving the PN who were the recipients of less energy than had been the case with tube fed patients in one investigation, and in 4 investigations, there has been equal amounts and in one investigation, greater amounts. Therefore, the causation of hyperglycemia has been by the difference in the energy amounts that have been subject to dispensation. Standard PN solution is contained with energy to the tune of 60-75% as dextrose, where solutions of standard tube feeding contain energy to the tune of 40-55% as dextrose. The metabolic altercations accompanying the stress response has resulted in the production of more endogenous glucose and the capacity of oxidizing plasma glucose is reduced directly (Altintas et al., 2011). The hyperglycemia’s higher incidences that excessive glucose loads have caused are on the stress response, superimposed in PN leading to an impaired immune response contributing to the infection’s higher observed risk.

Overall, a significant higher risk has been found in nutrition support complications with association with tube feeding compared to the PN, although the heterogeneity has been significant (P = 0.04). When separable into priori categories, there is remaining of the results, and there is no significance in the heterogeneity in the studies that are relatively recent or the ones with higher study quality score. There are several complications (e.g. abdominal distention and diarrhea) having association with tube feeding occurring frequently although having the consideration of being clinically less severe compared to the ones having association with PN. In addressing this, the complications of less severe nature of tube feeding, such as ileus, vomiting, and diarrhea have the limitation to the instances having the requirement of feedings or medication that is stoppable for >= 24 hours. Therefore, despite 8 of the 20 studies comparing the PN with tube feeding have reported diarrhea, there has been restrictions of our definitions as the complication is supported by nutrition to only 3 studies. There have been no instances of ileus or vomiting using the modified criteria. The involvement of the technical risks with maintaining and inserting feeding tubes can have significance and are frequently underrated. Six of the 20 trials comparing PN with tube feeding have had the report of problems of feeding tube maintenance and placement and accounting 14% (9 of 66) of the support complications of the reported nutrition. The catheter sepsis, which is a complication of severe nature having the association with PN, has had the categorization of an infection instead of the complication of nutrition support. When there is categorization of catheter sepsis as the nutrition support complication, the difference in the complications of nutrition support risk has been between PN and tube feeding has been eliminated (CI: 0.79, 1.4, RR: 1.05; 95%).


The patients in broad spectrum having gastrointestinal function compromised with tube feeding having fewer infections in the patients that are tube fed compared to the ones that are recipient of PN. These findings have similarity, albeit not as strong, compared to the PN with standard care in patients that are normally nourished. It has also been found that nutrition support complications’ higher risk with tube feeding compared to the PN. In a collective way, these results are suggestive that to wait 7-10 days in initiating any aggressive nutrition intervention form may have the prudence for normally nourished population with gastrointestinal function that is compromised. The studies comparing tube feeding outcomes with the ones of standard care in both malnourished and normally nourished populations are needed. Lastly, the studies that compared the associated costs with the provision of either tube feeding or PN with the ones with standard care needed in guiding third party payers, hospital administrators, and clinicians in their decision making.

Relevance to diabetic practice

This study has shown that PN has resulted in certain tertiary outcomes’ improvements (hypoglycaemia, acute colonic pseudo-obstruction, bowel obstruction, diarrhea, and vomiting). However, the differences like these failed translating to improvements in outcomes that are clinically important such as mortality, ICU stay, mechanical ventilation duration, pneumonia. Moreover, tertiary outcomes like some of these were relatively rare. For instance, there are 85 patients requiring treatment with early PN in preventing a bowel ischemia case. In 2012, the total cost to deliver to an ICU patient for one day of EN has been estimated at $US52.50. On the other hand, the total cost to deliver PN to an ICU patient for one day has been estimated to be around $US229.66 (Doig et al., 2013).

Major systematic reviews and clinical trials have recommended that initial permissive hypocaloric EN has the association with gastrointestinal intolerance of lower risk (Doig and Simpson, 2013). The starting of EN should have the 20 to 25 kcals/kg/day full target dose rate. There has not been any awareness of any major clinical guidelines recommending EN at full-target dose rates. Thus, question can be asked as to whether hypocaloric EN has more appropriateness in the critically ill patients requiring the continuation of vasoactive support following resuscitation from active shock. With regards to the economic considerations, there is no reason to believe that there is sufficient evidence in recommending PN instead of EN. The patients having absolute contraindication to EN has the provision of added convincing evidence that PN has viability in clinical option. Infections are not increased by PN; neither do harmful effects are led by it and in comparison to withhold the support of nutrition. In fact costs are actually reduced by it (Arabi et al., 2015).

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  • Abrishami, R., Ahmadi, A., Abdollahi, M., et al. (2010) ‘Comparison the inflammatory effects of early supplemental parenteral nutrition plus enteral nutrition versus enteral nutrition alone in critically ill patients’, Daru, 18(2):103‐6.
  • Altintas, N.D., Aydin, K., Türkoğlu, M. A., et al. (2011) ‘Effect of enteral versus parenteral nutrition on outcome of medical patients requiring mechanical ventilation’, Nutr Clin Pract., 6:322-9.
  • Arabi, Y. M., Aldawood, A. S., Haddad, S. H., et al. (2015) ‘Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults’, N Engl J Med, 372:2398-408.
  • Berger, M., Brancato, V., Graf, S., Heidegger, C., Darmon, P. and Pichard, C. (2011) ‘SPN study: supplemental parenteral nutrition (PN) to reach energy target does not compromise glucose control’, Clinical Nutrition, Suppl 6 (1):11‐12.
  • Casaer, M. P. and Van den, B. G. (2014) ‘Nutrition in the acute phase of critical illness’, N Engl J Med., 370: 2450-2451.
  • Casaer, M. P., Hermans, G., Wilmer, A. and Berghe, G. (2011) ‘Impact of early parenteral nutrition completing enteral nutrition in adult critically ill patients (EPaNIC trial): a study protocol and statistical analysis plan for a randomized controlled trial’, Trials, 12:21.
  • Doig, G. S. and Simpson, F. (2013) ‘Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a full economic analysis of a multicenter randomized controlled trial based on US costs’, Clinicoecon Outcomes Res, 5:369-79.
  • Doig, G. S., Chevrou-Severac, H. and Simpson, F. (2013) ‘Early enteral nutrition in critical illness: a full economic analysis using US costs’, Clinicoecon Outcomes Res, 5:429-36.
  • Fan, M. C., Wang, Q. L., Fang, W., et al. (2016) ‘Early enteral combined with parenteral nutrition treatment for severe traumatic brain injury: effects on immune function, nutritional status and outcomes’, Chinese Medical Science Journal, 31(4):213‐20.
  • Harvey, S. E., Parrott, F., Harrison, D. A., et al. (2014) ‘Trial of the route of early nutritional support in critically ill adults’, N Engl J Med, 371:1673-84.
  • Harvey, S. E., Parrott, F., Harrison, D. A., et al. (2014) ‘Trial of the route of early nutritional support in critically ill adults’, New England Journal of Medicine, 371(18):1673‐84.
  • Reignier, J., Boisramé-Helms, J., Brisard, L. et al. (2018) ‘Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2)’, Lancet, 391:133-43.
  • Taylor, B. E., McClave, S. A., Martindale, R. G., et al. (2016) ‘Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.)’, Crit Care Med, 44:390-438.
  • Tian, F., Wang, X., Gao, X., et al. (2015) ‘Effect of initial calorie intake via enteral nutrition in critical illness: a meta-analysis of randomized controlled trials’, Crit Care, 19:180.

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