|Year : 2021 | Volume
| Issue : 1 | Page : 2
Peptide-Based Enteral Nutrition for Critically Ill Patients
Ke Wang, Zhidan Zhang
Department of Infectious Disease, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
|Date of Submission||02-Feb-2021|
|Date of Acceptance||07-Jun-2021|
|Date of Web Publication||23-Aug-2021|
Dr. Zhidan Zhang
Department of Infectious Disease, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province
Source of Support: None, Conflict of Interest: None
This review discusses the clinical beneficial effects of peptide-based enteral nutrition (EN) for critically ill patients, especially those with gastrointestinal (GI) dysfunction. The GI dysfunction is very common in critically ill patients and always leads to intolerance of enteral feeding. Experimental and clinical studies suggest that peptide-based EN can be easily digested and absorbed by the GI tract which improving the feeding intolerance and provide better nutritional effects for critically ill patients. In addition, peptide-based EN may also have anti-inflammation, anti-oxidation, and immune-modulation effects and can facilitate muscle protein synthesis to improve muscle weakness which is commonly seen in critically ill patients. Peptide-based EN may have both nutritional and nonnutritional beneficial effects for critically ill patients. Further, large prospective randomized clinical trials should to be done to make the definite results.
Keywords: Critically ill, gastrointestinal dysfunction, peptide-based enteral nutrition, whey protein
|How to cite this article:|
Wang K, Zhang Z. Peptide-Based Enteral Nutrition for Critically Ill Patients. J Transl Crit Care Med 2021;3:2
| Introduction|| |
Critical illness is a hyperinflammatory and hypercatabolic state. The prevalence of malnutrition in the critical ill patients ranges from 38% to 78% and is independently associated with poor outcomes. Timely and adequate nutrition support may optimize the host response and thereby minimize nutritionally related complications while improving overall outcome. Early administration of enteral nutrition (EN) has been shown to reduce infectious complications and decrease length of intensive care units (ICUs) stay so that decrease mortality in critical care patients when compared with parenteral nutrition. Peptide-based EN formulas (PEF) or semi-elemental formulas contain peptides of varying chain length and can be better absorbed and tolerated in patients with malabsorptive conditions. However, its use in critically ill patients is still controversial. Although the guidelines of nutritional support for critically ill patients do not suggest the routine use of PEF,, there are still many experimental and clinical studies which suggest the better efficacy of peptide-based EN versus standard EN.,, The purpose of this review is to comprehensively summarize the experimental and clinical evidence of peptide-based EN for critically ill patients and explore the current status and further researches for clinical usage of peptide-based EN.
| The Dysfunctional Gut and the Demand for Enteral Nutrition Formula|| |
The gastrointestinal (GI) system is considered critical to the development of sepsis and multiple organ dysfunction syndrome (MODS). The GI dysfunction in critically ill patients are common and the severity of GI dysfunction is significantly associated with the risk of mortality. Regarding EN, the main clinical manifestations of GI dysfunction include the motility disturbances and the digestive and absorptive disorders for enteral nutrients which result in feeding intolerance (FI). 1953 critically ill patients were enrolled, and the proportions of participants starting EN within 72 h after ICU entry were <40%, whereas the proportions of participants receiving >80% estimated energy target within 72 h after ICU entry were <20%. The acute GI dysfunction associated with the critical illness was the main impediment of the suboptimal EN in Chinese ICUs.
GI motility disturbances are common in critical illness. Up to 60% of critically ill patients have been reported to experience GI dysmotility of some form necessitating therapeutic intervention. GI dysmotility has significant clinical consequences, being associated with FI and malnutrition, gastroesophageal reflux, bacterial overgrowth, and translocation. Delayed gastric emptying (GE) is the most common GI dysmotility pattern in critically ill patients. Chapman et al. found that the prevalence of delayed GE was very high in critically ill patients with mechanical ventilation. Rauch et al. used a novel wireless motility capsule to evaluate the GE and small bowel transit times in eight critically ill trauma patients and found both GE and small bowel transit were significantly delayed. Therefore, the optimal EN formula for critically ill patients should has faster GE to reduce gastric retention and alleviate FI. Dalziel et al. evaluated the different GI transit for whey, casein and their hydrolysates in elderly rats. The investigators found that the whey protein and their hydrolysate had faster GE and slower small intestine transit than casein protein, which facilitated them to pass through the stomach rapidly and increased time for nutrient absorption to occur in the intestine. These would be helpful for improved nutrition support in the elderly. Meanwhile, the whey protein hydrolysate (WPH) had increased fecal output which further suggested their benefit for GI dysfunction. These results ultimately indicated that incorporation of whey hydrolysate peptide into nutritional formulations would be beneficial in treating GI dysfunction involving gastric retention and constipation, particularly for the aged and critically ill patients.
Besides the impaired absorption of glucose induced by delayed GE found by Chapman et al., Ali Abdelhamid et al. also found that the both absorption for glucose and lipid by the small intestinal were diminished during critical illness. On the other hand, the pancreatic enzymes are essential for the digestion of macronutrients and inadequate release of pancreatic enzymes may lead to maldigestion and malabsorption of fat, as well as, to a lesser extent, proteins and carbohydrates. Wang et al. recruited 563 adult patients with critical illnesses in a prospective cross-sectional study and found that >50% of critically ill adult patients without primary pancreatic diseases had exocrine pancreatic insufficiency (EPI) and nearly one-fifth of them had severe EPI. The risk factors for EPI included shock, sepsis, diabetes, cardiac arrest, hyperlactacidemia, invasive mechanical ventilation, and hemodialysis. The status of EPI could reduce luminal absorption of enteral nutrients and leads to invalid EN thus aggravate the malnutrition of the critically ill patients. Therefore, the predigestive or the PEF is optimal for critically ill patients theoretically, especially for those with GI dysfunction and EPI. The ingestion of a protein peptide hydrolysate, as opposed to its intact protein, had been proposed to facilitate protein digestion and absorption and increased plasma amino acid (AA) availability in elderly patients,, which further suggested that the peptide-based EN could really be easily absorbed than the whole-protein diet and provided better nutritional support for the critically ill patients with GI dysfunction.
| The Effects of Peptide-Based Enteral Nutrition for Critically Ill Patients|| |
Nutritional effect of peptide-based enteral nutrition
The peptide-based EN was well tolerated in critically ill patients. In 1990, Hamaoui et al. first evaluated the GI tolerance and nutritional effect of small peptide-based EN in major abdominal surgery patients compared with total parenteral nutrition (TPN). The GI tolerance to peptide-based EN was excellent during the postoperative period especially the first 3 days. Although the overall mean daily calorie and nitrogen intakes were lower for the EN group than those for the TPN group, the EN group was nevertheless in positive caloric and nitrogen balance and maintained similar serum albumin, prealbumin, and plasma transferrin levels. The average daily cost of EN group was much lower than TPN group. Therefore, the peptide-based EN was well tolerated and cost-effective in the immediate postoperative period of major abdominal surgery patients.
Heimburger et al. recruited 50 critically ill patients and randomized them to treatment with a small peptide-based enteral diet or an isoenergetic, isonitrogenous whole-protein diets for 10 days. During 10 days feeding, the peptide-based diet produced greater increases in serum rapid-synthesis proteins such as prealbumin and fibronectin than did the whole-protein diet. The frequency of diarrhea was similar in both groups. The study further suggested that the peptide-based enteral diet was well tolerated in critically ill patients and may have better nutritional effects than standard EN. Liu et al. further evaluated the tolerance and nutritional outcomes of PEF and whole-protein EN formula (WPF) for abdominal surgery patients treated in the ICU. They found that the mean serum albumin level on postoperative day (POD)-10, prealbumin levels on POD-5 and POD-10, and total lymphocyte count on POD-5 were significantly higher in the PEF group as compared to those in the WPF group. The average maximum gastric residual volume (GRV) of the PEF patients during their ICU stays was significantly lower than that for WPF patients. There were no significant differences between the two groups in terms of the prevalence of diarrhea and pneumonia. The average length of stay (LOS) in the ICU for the PEF group was significantly shorter than that for the WPF group.
The peptide-based EN was cost-effective in critically ill patients. Seres et al. performed a prospective, randomized clinical comparison pilot study to assess the safety, tolerance, and effectiveness of PEF in critically ill patients from medical, surgical, and cardiothoracic ICUs. They reported a 30% relative risk reduction of abdominal distension in the peptide-based EN group versus the high protein polymeric formula group and a 40% reduction in the number of days with undesired GI events. Recently, Curry et al. developed a US-based cost-consequence model to compare the total ICU costs for patients with and without GI intolerance who were receiving EN in the ICU and to quantify the economic impact of early utilization of a PEF instead of a standard formula. The results of the analysis indicated that out of 100 patients receiving EN, 31 had GI intolerance requiring a median ICU stay of 14.4 days versus 11.3 days for each patient without GI intolerance. This prolongation of LOS in ICU increased the total cost of critically ill patients. It was assumed that the early utilization of PEF would contribute to shorten the LOS in ICU due to prevention of GI intolerance. The model finally calculated that PEF was cost saving versus standard formula when just only three cases of GI intolerance were prevented per 100 patients (7% of GI intolerance cases avoided). It is difficult to predict upfront which critically ill patient would develop digestion and absorption problems and FI before EN initiation. While Gungabissoon et al. reported that approximately one-third of critically ill patients developed GI intolerance which was associated with more frequent interruptions in enteral feedings. Thus, due to the large proportion of GI intolerance, the initial utilization of PEF instead of standard EN formula for critically ill patients would result in cost savings through the avoidance of GI intolerance and the reduction of LOS in ICU.
In conclusion, patient populations those have difficulty in digesting or absorbing standard diets, or those who are unable to attain adequate nutrition support, may be able to achieve improved health outcomes and nutritional goals through the use of peptide-based EN formula.
Other nonnutritional effects of peptide-based enteral nutrition
Currently, most PEF s mainly contain WPHs. The components of whey protein include beta-lactoglobulin, alpha-lactalbumin, bovine serum albumin, lactoferrin, immunoglobulins, lactoperoxidase enzymes, glyco-macropeptides, lactose, and minerals. Whey protein has been recognized as a dietary protein supplement that can provide many other effects except nutrition support such as anti-inflammation, anti-oxidation, immunemodulation, improving muscle strength and organ protection which may provide additional beneficial effects for critically ill patients.
Oz et al. examined a whey-peptide-based diet high in cysteine, EPA-DHA, and prebiotic FOS (CYSPUFA) against systemic inflammatory syndrome compared with standard EN formula in LPS-induced septic rats. The investigators found that the septic rats in CYSPUFA group lost considerably less weight than those in the standard group. Concentration of liver enzyme and pathology of LPS-induced liver injury were improved in rats receiving CYSPUFA. These results suggested that the whey-peptide-based diet had the ability to protect against LPS-induced systemic inflammatory responses. Tsutsumi et al. found whey-peptide-based diets could suppress the release of inflammatory cytokine (tumor necrosis factor-α, interleukin-6, interferon-gamma) and alleviate the oxidative stress damage in septic rats. These anti-inflammatory and anti-oxidative effects of PEF could result in decreased liver injury and intestinal damage and play a role in organ protection. Nakamura et al. adopted an immune-modulating EN formula enriched with whey peptides and fermented milk in diet-induced acute pancreatitis mice to examine its nonnutritional effects. Compared with standard EN formula, the newly PEF significantly improved splenomegaly, hepatomegaly, and the elevation of hepatic enzymes induced by acute pancreatitis which further suggested that the PEF could protect the remote organ injury induced by systemic inflammation. In addition, many other studies also indicated that the whey PEF could ameliorate the hepatic and gut ischemia/reperfusion injury,, attenuate elastase-induced emphysema through the suppression of inflammation in the lung, and was associated with the lower incidence of bacteremia after liver transplantation.
Moriya et al. examined the influences of various dietary formulations on gut immunity and found that the whey peptide-based diet could maintain the intestinal Peyer's patch lymphocyte numbers and gut morphology. At the same time, the gut IgA levels were preserved more effectively in whey peptide-based EN diets than did standard diets. This study provided us a new insight into the usefulness and advantages of PEF for preserving the intestinal immunologic defenses in critically ill patients. Tsutsumi et al. also demonstrated that whey PEF could promote protective microbiota within the intestine and decrease the intestinal permeability thus improving the intestinal barrier dysfunction. These immune modulation effects of whey PEF would augment the beneficial effects of peptide-based EN for critically ill patients. However, the related clinical studies should to be done in the further research.
As we all know, there is a high prevalence of ICU acquired weakness (ICU-AW) in critically ill patients which can delay the recovery of dysfunctional organs and deteriorate the quality of life out of ICU. A bundle of therapies should be adopted to prevent and improve ICU-AW, which including awake and breathing coordination, choose light sedation, delirium monitoring and management, early mobility and exercise, feeding and adequate protein, gain function, and muscle growth. The optimal nutrition therapy to provide adequate calories and proteins is very essential for the patients with ICU-AW. While the whey proteins contain all the essential AAs in higher concentrations than vegetable protein sources and also have a high concentration of branched-chain AAs – leucine, isoleucine, and valine – important factors in tissue repair and muscle protein synthesis. Koopman et al. found that ingestion of a WPH not only accelerated protein digestion and absorption from the intestine and increased the plasma AAs level but also tended to increase the incorporation the dietary AAs into mixed muscle protein synthesis in elderly men. These results suggested the potential effect of peptide-based EN for muscle protein synthesis and enhancement of muscle strength which may be beneficial for the critically ill patients with ICU-AW. Further clinical research should still be done to make definite results.
| The Contrary Opinions for Peptide-Based Enteral Nutrition in Critically Ill Patients|| |
Although there are many experimental and clinical studies suggesting the beneficial effects of peptide-based EN for the critically ill patients which including well toleration, better nutritional outcomes as well as anti-inflammation, anti-oxidation, immune modulation, and enhancement of muscle strength, there are still some contrary opinions for its clinical usage. First, the most results are from animal experiments or small-sample, nonrandomized clinical trials. The large multicenter prospective randomized clinical trials are scarce and should be done in the future to confirm the beneficial effects of peptide-based EN in critically ill patients. Second, most PEF used in those clinical trials mainly contain WPHs. Whether the protein hydrolysates from casein or soy protein still have those beneficial effects like whey protein should be further confirmed. Third, the whey PEF used in recent clinical trials always contain some other nutrients with immune-modulating effects, such as w-3 fatty acid, EPA, DHA, and fermented milk, which may interfere the anti-inflammation and immune-modulation effects of peptide-based EN. Last, the critically ill patients enrolled in those clinical trials have higher heterogeneity. The most suitable patients for peptide-based EN should be those with digestion and absorption disorders who may present FI. However early evaluation of the digestion and absorption function of the GI tract and prediction the possibility of FI in critically ill patients are very important but difficult for clinical usage of peptide-based EN precisely. New biomarkers representing GI function and new methods to evaluate the motility, digestion and absorption of GI tract need to be further inspected.
To conclude, in theory, peptide-based EN may be more easily digested and absorbed in critically ill patients, especially those with GI dysfunction and FI. In addition, peptide-based EN may also have anti-inflammation, anti-oxidation, immune-modulation effects and can facilitate muscle protein synthesis to prevent and improve muscle weakness in critically ill patients. Although the nutritional guidelines for critically ill patients do not suggest the routine utilization of peptide-based EN, there is still an important value for its usage in some specified patient population. Large multicenter prospective randomized clinical trials should be done to further confirm the efficacy of peptide-based EN for critically ill patients.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Sharma K, Mogensen KM, Robinson MK. Pathophysiology of critical illness and role of nutrition. Nutr Clin Pract 2019;34:12-22.
Reintam Blaser A, Starkopf J, Alhazzani W, Berger MM, Casaer MP, Deane AM, et al.
Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines. Intensive Care Med 2017;43:380-98.
Alexander DD, Bylsma LC, Elkayam L, Nguyen DL. Nutritional and health benefits of semi-elemental diets: A comprehensive summary of the literature. World J Gastrointest Pharmacol Ther 2016;7:306-19.
Mehta NM, Skillman HE, Irving SY, Coss-Bu JA, Vermilyea S, Farrington EA, et al.
Guidelines for the provision and assessment of nutrition support therapy in the pediatric critically ill patient: Society of critical care medicine and American Society for Parenteral and Enteral Nutrition. JPEN J Parenter Enteral Nutr 2017;41:706-42.
Singer P, Blaser AR, Berger MM, Alhazzani W, Calder PC, Casaer MP, et al.
ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr 2019;38:48-79.
Zhang J, Yu WQ, Wei T, Zhang C, Wen L, Chen Q, et al
. Effects of Short-Peptide-Based Enteral Nutrition on the Intestinal Microcirculation and Mucosal Barrier in Mice with Severe Acute Pancreatitis. Mol Nutr Food Res 2020;64:e1901191.
Seres DS, Ippolito PR. Pilot study evaluating the efficacy, tolerance and safety of a peptide-based enteral formula versus a high protein enteral formula in multiple ICU settings (medical, surgical, cardiothoracic). Clin Nutr 2017;36:706-9.
Green B, Sorensen K, Phillips M, Green L, Watson R, McCallum A, et al
. Complex Enterally Tube-Fed Community Patients Display Stable Tolerance, Improved Compliance and Better Achieve Energy and Protein Targets with a High-Energy, High-Protein Peptide-Based Enteral Tube Feed: Results from a Multi-Centre Pilot Study. Nutrients 2020;12:3538.
Reintam A, Parm P, Kitus R, Starkopf J, Kern H. Gastrointestinal failure score in critically ill patients: A prospective observational study. Crit Care 2008;12:R90.
Hu B, Sun R, Wu A, Ni Y, Liu J, Guo F, et al.
Severity of acute gastrointestinal injury grade is a predictor of all-cause mortality in critically ill patients: A multicenter, prospective, observational study. Crit Care 2017;21:188.
Ladopoulos T, Giannaki M, Alexopoulou C, Proklou A, Pediaditis E, Kondili E. Gastrointestinal dysmotility in critically ill patients. Ann Gastroenterol 2018;31:273-81.
Chapman MJ, Fraser RJ, Matthews G, Russo A, Bellon M, Besanko LK, et al.
Glucose absorption and gastric emptying in critical illness. Crit Care 2009;13:R140.
Rauch S, Krueger K, Turan A, You J, Roewer N, Sessler DI. Use of wireless motility capsule to determine gastric emptying and small intestinal transit times in critically ill trauma patients. J Crit Care 2012;27: 12.e7-12.
Escuro AA, Hummell AC. Enteral formulas in nutrition support practice: Is there a better choice for your patient? Nutr Clin Pract 2016;31:709-22.
Dalziel JE, Young W, McKenzie CM, Haggarty NW, Roy NC. Gastric emptying and gastrointestinal transit compared among native and hydrolyzed whey and casein milk proteins in an aged rat model. Nutrients 2017;9:1351.
Ali Abdelhamid Y, Cousins CE, Sim JA, Bellon MS, Nguyen NQ, Horowitz M, et al.
Effect of critical illness on triglyceride absorption. JPEN J Parenter Enteral Nutr 2015;39:966-72.
Wang S, Ma L, Zhuang Y, Jiang B, Zhang X. Screening and risk factors of exocrine pancreatic insufficiency in critically ill adult patients receiving enteral nutrition. Crit Care 2013;17:R171.
Calbet JA, Holst JJ. Gastric emptying, gastric secretion and enterogastrone response after administration of milk proteins or their peptide hydrolysates in humans. Eur J Nutr 2004;43:127-39.
Koopman R, Crombach N, Gijsen AP, Walrand S, Fauquant J, Kies AK, et al.
Ingestion of a protein hydrolysate is accompanied by an accelerated in vivo
digestion and absorption rate when compared with its intact protein. Am J Clin Nutr 2009;90:106-15.
Hamaoui E, Lefkowitz R, Olender L, Krasnopolsky-Levine E, Favale M, Webb H, et al.
Enteral nutrition in the early postoperative period: A new semi-elemental formula versus total parenteral nutrition. JPEN J Parenter Enteral Nutr 1990;14:501-7.
Heimburger DC, Geels VJ, Bilbrey J, Redden DT, Keeney C. Effects of small-peptide and whole-protein enteral feedings on serum proteins and diarrhea in critically ill patients: A randomized trial. JPEN J Parenter Enteral Nutr 1997;21:162-7.
Liu MY, Tang HC, Hu SH, Chang SJ. Peptide-based enteral formula improves tolerance and clinical outcomes in abdominal surgery patients relative to a whole protein enteral formula. World J Gastrointest Surg 2016;8:700-5.
Seres DS, Ippolito PR. Pilot study evaluating the efficacy, tolerance and safety of a peptide-based enteral formula versus a high protein enteral formula in multiple ICU settings (medical, surgical, cardiothoracic). Clin Nutr 2017;36:706-9.
Curry AS, Chadda S, Danel A, Nguyen DL. Early introduction of a semi-elemental formula may be cost saving compared to a polymeric formula among critically ill patients requiring enteral nutrition: A cohort cost-consequence model. Clinicoecon Outcomes Res 2018;10:293-300.
Gungabissoon U, Hacquoil K, Bains C, Irizarry M, Dukes G, Williamson R, et al.
Prevalence, risk factors, clinical consequences, and treatment of enteral feed intolerance during critical illness. JPEN J Parenter Enteral Nutr 2015;39:441-8.
Abrahão V. Nourishing the dysfunctional gut and whey protein. Curr Opin Clin Nutr Metab Care 2012;15:480-4.
Oz HS, Chen TS, Neuman M. Nutrition intervention: A strategy against systemic inflammatory syndrome. JPEN J Parenter Enteral Nutr 2009;33:380-9.
Tsutsumi R, Horikawa YT, Kume K, Tanaka K, Kasai A, Kadota T, et al.
Whey peptide-based formulas with ω -3 fatty acids are protective in LPS-mediated sepsis. JPEN J Parenter Enteral Nutr 2015;39:552-61.
Nakamura K, Fukatsu K, Sasayama A, Yamaji T. An immune-modulating formula comprising whey peptides and fermented milk improves inflammation-related remote organ injuries in diet-induced acute pancreatitis in mice. Biosci Microbiota Food Health 2018;37:1-8.
Hanaoka J, Shimada M, Utsunomiya T, Morine Y, Imura S, Ikemoto T, et al.
Beneficial effects of enteral nutrition containing with hydrolyzed whey peptide on warm ischemia/reperfusion injury in the rat liver. Hepatol Res 2014;44:114-21.
Nakamura K, Ogawa S, Dairiki K, Fukatsu K, Sasaki H, Kaneko T, et al
. A new immune-modulating diet enriched with whey-hydrolyzed peptide, fermented milk, and isomaltulose attenuates gut ischemia-reperfusion injury in mice. Clin Nutr 2011;30:513-6.
Tomoda K, Kubo K, Dairiki K, Yamaji T, Yamamoto Y, Nishii Y, et al.
Whey peptide-based enteral diet attenuated elastase-induced emphysema with increase in short chain fatty acids in mice. BMC Pulm Med 2015;15:64.
Kamo N, Kaido T, Hamaguchi Y, Uozumi R, Okumura S, Kobayashi A, et al.
Impact of enteral nutrition with an immunomodulating diet enriched with hydrolyzed whey peptide on infection after liver transplantation. World J Surg 2018;42:3715-25.
Moriya T, Fukatsu K, Noguchi M, Nishikawa M, Miyazaki H, Saitoh D, et al.
Effects of semielemental diet containing whey peptides on Peyer's patch lymphocyte number, immunoglobulin A levels, and intestinal morphology in mice. J Surg Res 2018;222:153-9.
Wischmeyer PE, San-Millan I. Winning the war against ICU-acquired weakness: New innovations in nutrition and exercise physiology. Crit Care 2015;19 Suppl 3:S6.