O’Keefe, Stephen J.D.
Department of Medicine, Division of Gastroenterology, University of Pittsburgh, Pennsylvania, USA
Correspondence to Stephen J.D. O’Keefe, MD, MSc, FRCP, Professor of Medicine, Division of Gastroenterology, University of Pittsburgh, Lab 570 Scaife Hall, Presby Campus, Pennsylvania, USA. E-mail: firstname.lastname@example.org
For this year's Nutrition section of Current Opinion in Gastroenterology, I selected topics which have attracted most interest over the past year and are likely to have the greatest impact on clinical nutrition, namely the urgency and timing for nutritional support in hospitalized patients (Todd Rice), the value of nutritional supplementation in patients with liver disease (Ron Koretz), the development of gut peptide analogues to ‘superadapt’ the residual bowel in patients with massive intestinal loss (Palle Jeppeson), and finally the role of the human microbiota and its metabolites in human disease (Erwin Zoetendal and James Kinross).
It has always been assumed that nutritional support will help the recovery of any hospitalized patient who is unable to eat. Prior to the 1970s, critically ill patients lost weight progressively until they either died, or recovered and were able to eat again. Then came the development of intravenous feeding, termed at the time ‘hyperalimentation’ or ‘total parenteral nutrition’ (TPN). For the first time, this meant that full nutritional support could be given to any patient, no matter how sick, and it was embraced as part of the routine care of any sick patient who was unable to eat. Over the following decade of experience, clinicians became increasingly concerned about the complications that accompanied TPN, namely catheter-related sepsis, hyperglycaemia, and central vein thrombosis. This finally prompted the conduct of randomized controlled trials (RCTs) to assess benefit. The most significant of these was the VA Cooperative study of perioperative TPN which showed quite clearly that the conventional use of perioperative followed by postoperative intravenous feeding was not only expensive but also increased infectious complications . Post-hoc analysis, however, suggested that there might have been some benefit if patients were initially malnourished.
It was assumed that the complications of TPN were outweighing the benefits of nutritional support, and so great effort was then expended in the development of interventional enteral (tube) feeding techniques that restored gut function. It was shown that most of the feeding problems in the critically ill were related to upper gastrointestinal dysfunction, in particular, poor gastric emptying, such that if a feeding tube was placed below the pylorus, enteral feeding could provide full nutritional requirements, obviating the need for TPN. Comparative studies showed clearly that enteral feeding was superior to parenteral nutrition with regard to infectious complications and cost, leading to a swing to enteral feeding. Studies then emerged that showed the problem with enteral feeding was that it was difficult to ramp the rates up to ‘goal’ within the first week, leading to the development of an ‘energy gap’. Uncontrolled studies found that the magnitude of the energy gap was related to long-term mortality, leading to the practice of bi-modal nutritional support where early enteral feeding was ‘topped up’ with parenteral nutrition until goal enteral feeding rates were achieved .
For many years now, Koretz  has been like a voice crying in the wilderness for the conduct of adequately powered and properly designed RCTs to prove that nutritional support is better than no support at all – bearing in mind that both parenteral and enteral feeding are interventional procedures and have their own set of complications. Many ignored his call, stating that it was obvious that forced feeding would improve the rate of recovery and hospital outcome, as healing requires a profuse supply of nutrients, and claimed that failure to feed a starving patient was unethical.
For the first time, two such large, well designed RCT feeding studies were recently conducted and the results were published. Rice has reviewed these in his accompanying article. The first was a randomized multi-centre clinical trial on 4640 ICU patients, which examined the question of ‘topping up’ early enteral feeding with parenteral nutrition during the first week, which is the current guideline of the European Society of Enteral and Parenteral Nutrition, versus waiting a week and then only ‘topping up’ if enteral nutrition has not met its goals. Contrary to expectation, the late parenteral nutrition group did better. The second study was conducted by the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, and published with Rice as first author. In this, the consortium randomized 1000 ICU patients with respiratory failure to early ‘trophic feeding’ (i.e. 10 ml/h within 48 h) for the first week followed by an advance to goal rates thereafter, versus early ‘full’ enteral feeding (25 ml/h with an increase every 6 h until full caloric needs were met). Again, the more aggressive form of feeding offered no survival benefit and was associated with more gastrointestinal complications. Rice concludes from these studies that early enteral feeding should be recommended for ventilated patients, and parenteral nutrition should not be used to prevent the energy gap in the first week. Whilst this conclusion may well prove to be correct, given that early ‘trophic’ feeding preserves gut function and reduces inflammatory responses [4,5], we still do not know whether early trophic feeding in the first week is better than no feeding, particularly given the fact that most hospitalized patients in the US today are overweight and have more than adequate body stores of energy and protein that would last them for weeks.
The liver is often considered the ‘heart of metabolism’. Consequently, it is reasonable to expect that patients with liver disease will more rapidly develop nutritional problems, and that nutritional support or supplementation would improve recovery. Indeed, the high incidence of malnutrition in patients with liver disease was recently highlighted by a review by Cheung et al., which included recommendations on how it could be treated or prevented. However, as Koretz notes in his review, ‘it cannot be emphasized too strongly that association does not infer causation, so it cannot be assumed that improving nutritional status improves clinical outcome’. To test this concern, Koretz et al. have recently published a meta-analysis in Cochrane Reviews where they identified 37 eligible RCTs comparing enteral, parenteral, or oral supplemental feeding to no feeding in patients with a variety of liver diseases, ranging from chronic liver disease to liver transplantation. In his current review, he has identified three more eligible studies, which have not substantially changed his conclusions that ‘the data do not compellingly justify the routine use of parenteral nutrition, enteral nutrition, or oral nutritional supplements in patients with liver disease’.
For nutritionists, this is all very depressing, but it should not be. What our bodies are trying to tell us is that they only need support when stores begin to run out. We have evolved over millions of years to survive acute injury without nutrition support; we have body stores that cover these events. No one can doubt that a critically ill patient will need supplementation with fluids and electrolytes within 48 h as part of initial resuscitation, but protein and energy (fat) stores can last weeks. Thus Koretz’ conclusion should probably be modified to include ‘in the absence of documented nutrient deficiency’. This raises another problem, how do we measure nutrient deficiency? With fluid, electrolytes and minerals we can measure blood levels, but we still do not know how low body protein and energy stores have to drop before they affect vital organ function and wound healing. Studies we have performed detected abnormalities in digestive function in a group of patients with an average BMI of 13.5 kg/m2, which is well below the lower limit of normal range of 18.5, leading us to suggest that in the absence of oedema, any patient with a BMI less than 17 deserves nutritional support. The bottom line is that we must first prove there is a deficiency before using an intervention that has inherent complications, as outcome can only be worsened.
One field where nutritional support is life-saving is the intestinal failure that accompanies massive intestinal loss. Here, RCTs are not needed to show survival benefit as we know that in the days before TPN these patients became progressively more malnourished and died. However, home parenteral nutrition (HPN) on which these patients depend is associated with all the complications of parenteral nutrition mentioned above, and the inconveniences of nightly cycles of intravenous infusions of fluid, electrolytes, protein, energy, vitamins and trace elements, and high stomal excretions and often uncontrollable diarrhoea, resulting in difficulties in social interactions and poor quality of life . Small bowel transplantation is the only therapy that predictably removes the need for HPN and restores normal eating, digestion and absorption – but at a price in terms of operative and immunosuppression-associated morbidity and mortality. Jeppesen in his accompanying article reviews the latest developments in new forms of pharmacological treatment, including the use of gut peptide derivatives that may increase absorption by the remaining intestine, termed ‘superadaptation’. Teduglutide is a protease-resistant analogue of the ileal brake peptide glucagon-like peptide 2, which has been shown to have remarkable effects on villus growth and absorption in experimental and now human studies, with significant reductions in the need for parenteral nutrition supplementation shown by two multi-centre multinational RCTs discussed in detail by Jeppesen. On the basis of these results, the US Food and Drug Administration has recently approved teduglutide's use for the management of intestinal failure due to massive intestinal loss. However, the drug only allows a small proportion of these patients to come off HPN completely, and follow-up studies are now needed to see whether the reductions in parenteral nutrition requirements translate into improved quality of life.
Perhaps the hottest topic in nutrition and gastroenterology today is the previously unrecognized importance of the human microbiota in bodily health. The two reviews – one by Zoetendal on the microbiota, and the other by Kinross on its metabolome – provide state-of-art summaries on the key role played by the microbiota in a widening variety of diseases, which include the ‘westernized diseases’, obesity, the metabolic syndrome, atherosclerosis, diabetes and colon cancer – whose emergence has been considered the most serious threat to public health in the US today. The size and the metabolic activity of the microbiota justify the claim that it should be considered one of our own organs with its own intrinsic metabolic needs and functions which are essential to those of the rest of the body. On the basis of the accumulating evidence from human studies that diet has a powerful influence on the microbiota to produce a vast array of bioactive molecules within the body, Kinross argues that ‘dietary modification of the microbiota may challenge the notion that our genetic make-up is the most important explanation for heterogeneous metabolic response to a homogenous diet’. To date, very little attention has been paid to examining the role of the microbiota, let alone its nutritional requirements, in sickness. In a normal diet, dietary fibre provides most of its nutritional needs and current recommendations suggest that a healthy diet should contain at least 35 g/day. Early studies showed that the composition of conventional enteral feeds is lacking in sufficient dietary residue to support a healthy microbiota, with 0–5 g fibre/l, and that the combined use of proton pump inhibitors (PPIs) and antibiotics with these diets was associated with gross suppression of the microbiota and dysbiosis . Suppression of the microbiota deprives the colon of its preferred ‘food’ supply and epithelial proliferative regulator, butyrate, a short-chain fatty acid that is produced by microbiota fermentation of dietary fibre. Dysbiosis also places patients at high risk of developing overgrowth with Clostridium difficile organisms and subsequent development of colitis, a condition with high morbidity in the infirm and critically ill that is difficult to treat and tends to recur . Whereas specific antibiotics such as vancomycin and fidaxomicin are effective treatments , they worsen dysbiosis, increasing the risk of recurrence. Clearly, the goal with any treatment should be to remove the initiating factor, but it is often difficult to remove antibiotics and PPIs from critically ill patients. An alternative is to restore the microbiota with a ‘transplant’ from a healthy donor. This has proved remarkably successful as discussed by Zoetendal, whose group recently published the results of the first RCT on the subject . C. difficile clearance at 10 weeks was significantly higher (81%) in the faecal-transplant group compared to either of the control groups (21–33%) at the interim analysis, and so the study was terminated. However, it is important to note that the group of patients with the highest mortality associated with C. difficile, unstable ICU patients and those needing antibiotics , were excluded, and so further studies are needed to determine whether transplants can endure and thus reduce hospital morbidity and mortality.
Conflicts of interest
Research support was obtained from NPS Pharmaceuticals.
1. Perioperative total parenteral nutrition in surgical patients. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group. N Engl J Med 1991; 325:525–532.
2. Wischmeyer PE, Heyland DK. The future of critical care nutrition therapy. Crit Care Clin 2010; 26:433–441.vii.
3. Koretz RL. What supports nutritional support? Dig Dis Sci 1984; 29:577–588.
4. Fukatsu K, Kudsk KA. Nutrition and gut immunity. Surg Clin North Am 2011; 91:755–770.vii.
5. Fong YM, Marano MA, Barber A, et al. Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in humans. Ann Surg 1989; 210:456–457.[discussion 449–456].
6. Cheung K, Lee SS, Raman M. Prevalence and mechanisms of malnutrition in patients with advanced liver disease, and nutrition management strategies. Clin Gastroenterol Hepatol 2012; 10:117–125.
7. Koretz RL, Avenell A, Lipman TO. Nutritional support for liver disease. Cochrane Database Syst Rev 2012; 5:CD008344.
8. Winter TA, Lemmer ER, O’Keefe SJ, Ogden JM. The effect of severe undernutrition, and subsequent refeeding on digestive function in human patients. Eur J Gastroenterol Hepatol 2000; 12:191–196.
9. O’Keefe SJ, Emerling M, Koritsky D, et al. Nutrition and quality of life following small intestinal transplantation. Am J Gastroenterol 2007; 102:1093–1100.
10. O’Keefe SJ, Ou J, Delany JP, et al. Effect of fiber supplementation on the microbiota in critically ill patients. World J Gastrointest Pathophysiol 2011; 2:138–145.
11. Kenneally C, Rosini JM, Skrupky LP, et al. Analysis of 30-day mortality for clostridium difficile-associated disease in the ICU setting. Chest 2007; 132:418–424.
12. Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, noninferiority, randomised controlled trial. Lancet Infect Dis 2012; 12:281–289.
13. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013; 368:407–415.