Abstract
Diarrhea is one of the most common complications associated with enteral nutrition in hospitalized patients. Oligomeric enteral nutrition has been considered to reduce the incidence of diarrhea. We herein introduced and examined the effects of a specific oligomeric enteral nutrition with the low-molecular-weight whey peptides, Peptino® in critically ill patients with refractory diarrhea or at high risk of mesenteric ischemia. A retrospective study of a consecutive case series was conducted. Patients were divided into two groups: enteral nutrition products were switched to Peptino® (switching group) and Peptino® was the initial enteral nutrition product (first initiation group). Sixty-eight patients were administered Peptino® in the ICU. Diarrhea occurred in 28.3% of patients in the switching group and 13.3% in the first initiation group. EN failure with gastrointestinal intolerance was observed in 6 patients (8.8%). Diarrhea resolved in 29 out of the 35 patients (82.9%) with diarrhea prior to the switch to Peptino®. Diarrhea cessation within 24 h of the initiation of Peptino® was achieved in 11 patients (31.4%) and within 24–48 h in 12 (34.3%). Mesenteric ischemia was not detected in any patients. In conclusion, Peptino® may be effective against diarrhea and gastrointestinal intolerance in critical care nutrition.
Keywords: critical care, peptide, diarrhea, oligomeric formula, enteral nutrition
Introduction
Since enteral nutrition (EN) is a cost-effective treatment beneficial for infectious complications, its early initiation in critical care nutrition is recommended.(1,2) EN may cause complications, such as mesenteric ischemia and vomiting, and one of its most common side effects is diarrhea.(3) The incidence of diarrhea was previously reported to be 15–50% in critically ill patients.(4–6) Since diarrhea is not solely attributed to EN,(3) it does not always necessitate the cessation of EN.(1,2) However, diarrhea and its management are challenging for both patients and medical staff.
It currently remains unclear whether EN products decrease the incidence of diarrhea in patients receiving critical care. Although long-term EN, a high-osmolality, low-fiber formula, bolus feeding, rapid increases to the target, and postpyloric EN were previously identified as risk factors for diarrhea,(7,8) a cause-and-effect relationship has not yet been reported.(3) However, some EN products, particularly oligomeric EN, have been shown to reduce the incidence of diarrhea.(9,10) Although it is not recommended in the ESPEN guidelines,(2) we sometimes change EN products to oligomeric EN in patients with diarrhea not caused by infection or drugs.(3)
The specific oligomeric EN, Peptino® (TERMO Co., Tokyo, Japan) is administered to patients with refractory diarrhea or those at a high risk of mesenteric ischemia due to circulatory shock or multiple organ failure in the intensive care unit (ICU) at Hitachi General Hospital. This EN product consists of low-molecular-weight whey peptides, which are absorbed earlier than amino acids,(11) and no fat or dietary fiber. These features are advantageous for the treatment of diarrhea. Therefore, all the patients who had previously described risks are administered EN with Peptino®. We extracted all patients administered Peptino® in the ICU and retrospectively analyzed their outcomes, focusing on the occurrence of diarrhea in the first 2 days from Peptino® introduction.
Materials and Methods
This was a retrospective study of a consecutive case series at the Hitachi General Hospital Emergency and Critical Care Center. Hitachi General Hospital is one of the largest tertiary medical centers in Japan and has an 8-bed closed mixed ICU for patients from the Emergency Department and in-hospital patients. The present study was approved by the Ethics Committee of our hospital (2017-95).
Peptino® contains 100 kcal, 3.6 g protein, 21.4 g carbohydrate, and 0 g fat per 100 ml, with 1 kcal/ml energy and 500 mOsm/L osmolarity. It is not routinely administered because it is a specific EN without any fat and dietary fiber; however, we introduced it for patients with refractory diarrhea or those at a high risk of mesenteric ischemia because there is currently no alternative EN product for these patients in the ICU. We extracted all patients administered Peptino® in the ICU between January 2020 and March 2021. Because the reasons why Peptino® was introduced might be different, patients were divided into two groups: EN products were switched to Peptino® (switching group) and Peptino® was the initial EN product (first initiation group). Furthermore, a subgroup of patients for whom EN products were switched to Peptino® and with Bristol Stool Form Scale >6(12) diarrhea prior to the initiation of Peptino® was analyzed.
Information on age, sex, body mass index (BMI), sequential organ failure assessment (SOFA) scores on admission, acute physiology and chronic health evaluation (APACHE) II scores on admission, and adjunctive treatments of mechanical ventilation, renal replacement therapy, vasopressive agents, extracorporeal membrane oxygenation (ECMO), and intra-aortic balloon pumping (IABP) as well as on basic diseases, including of sepsis, heart failure, stroke, cardiopulmonary arrest, postoperative complications, respiratory failure, trauma, and endocrine and metabolic disorders was extracted from medical records. The reasons why Peptino® was introduced were extracted from medical records both in the switching group and in the first initiation group. Trajectory of administrated dose of Peptino® (ml/kg) on the first 7 days and previously administered EN products in the switching group were also analyzed.
The occurrence of diarrhea 24 to 48 h after the initiation of Peptino® was the primary outcome. Diarrhea was defined as Bristol Stool Form Scale >6 in medical records. In the subgroup analysis, the cessation of diarrhea within 24, 48, and 72 h was examined. Diarrhea cessation was defined as the absence of diarrhea within that period, and without recurrence during the period of Peptino® administration. In-hospital mortality, the lengths of ICU and hospital stays, the duration of mechanical ventilation, the duration of Peptino® administration, vomiting events, gastric residual volume (GRV), and mesenteric ischemia were analyzed. Mesenteric ischemia was defined as any of the following: evidence of absent blood flow in bowel wall irrespective of main artery occlusion in computed tomography, presence of colonic ischemia in endoscopy according to the Favier classification system, and evidence of bowel ischemia during surgery. The cessation of EN due to vomiting events, diarrhea events, GRV >200 ml, or mesenteric ischemia was defined as EN failure.
Continuous variables were expressed as medians (interquartile ranges) and compared using the Mann–Whitney U test. Regarding categorical variables, the proportions of patients in the respective categories were calculated. Groups were then compared using the chi-squared test. All statistical analyses were conducted using JMPpro14 (SAS Institute, Inc., Tokyo, Japan). P values <0.05 were considered to be significantly different.
Results
Among 651 patients admitted to the ICU between January 2020 and March 2021, 68 were administered Peptino® and included in the analysis (Fig. 1). There were 47 patients in the switching group and 21 in the first initiation group. Thirty-five patients were classified into the subgroup in which EN products were switched to Peptino® and with Bristol Stool Form Scale >6 diarrhea prior to the initiation of Peptino®.
Fig. 1.
Study outline
Table 1 shows the characteristics of patients. Patients with a median age of 70 years, BMI 22, SOFA score of 8 to 9, and APACHE II score of 22 were administered Peptino® in both groups. Diarrhea was already present prior to the administration of Peptino® in 74.5% of patients in the switching group and 19.1% in the first initiation group. In these patients, purpose of diarrhea reduction was the reason why Peptino® was introduced. In the rest population, Peptino® was initiated to reduce the risk of mesenteric ischemia in the condition of unstable circulation. Other condition for the risk of mesenteric ischemia, such as respiratory failure, was not observed. Regarding adjunctive treatments, no significant differences were observed in mechanical ventilation, renal replacement therapy, or vasopressive agents, while the number of patients receiving ECMO and IABP was slightly higher in the first initiation group, which correlated with the risk of mesenteric ischemia by circulatory instability. Sepsis and respiratory failure were more frequent in the switching group, while cardiopulmonary arrest was more frequent in the first initiation group. Previously administered EN products in the switching group were Peptamen Intense®, Peptamen AF®, Glucerna-REX® and Hine E-Gel®, in decreasing order respectively. Administrated Peptino® dose on the first 7 days was shown in Supplemental Fig. 1*.
Table 1.
Patient characteristics
| Group | Switching group (Switched from other EN products) |
First initiation group (Started with Peptino®) |
p value |
|---|---|---|---|
| N | 47 | 21 | |
| Age | 72 (58, 80) | 68 (53, 81) | 0.25 |
| Male, n (%) | 27 (57.4) | 14 (66.7) | 0.48 |
| Body mass index | 21.9 (18.3, 24.4) | 22 (17.9, 25.6) | 0.59 |
| SOFA on admission | 9 (7, 11) | 8 (6, 11) | 0.2 |
| APACHE II on admission | 21 (16.5, 30) | 22 (16, 27) | 0.73 |
| Bristol scale >6 diarrhea before administration of Peptino® | 35 (74.5) | 4 (19.1) | <0.0001 |
| Adjunctive treatments | |||
| Mechanical ventilation, n (%) | 35 (74.5) | 15 (71.4) | 0.83 |
| Renal replacement, n (%) | 23 (48.9) | 10 (47.6) | 0.82 |
| Vasopressive agent, n (%) | 34 (72.3) | 17 (80.1) | 0.44 |
| ECMO, n (%) | 11 (23.4) | 8 (38.1) | 0.25 |
| IABP, n (%) | 1 (2.1) | 7 (33.3) | 0.0017 |
| Basic diseases | |||
| Sepsis, n (%) | 37 (78.7) | 9 (42.9) | 0.004 |
| Heart failure, n (%) | 12 (25.5) | 6 (28.6) | 0.8 |
| Stroke, n (%) | 3 (6.4) | 0 | 0.13 |
| Cardiopulmonary arrest, n (%) | 3 (6.4) | 9 (42.9) | 0.0004 |
| Postoperative complications, n (%) | 12 (25.5) | 4 (19.0) | 0.69 |
| Respiratory failure, n (%) | 36 (76.6) | 7 (33.3) | 0.0007 |
| Trauma, Burn, n (%) | 8 (17.0) | 1 (4.7) | 0.25 |
| Endocrine and metabolic disorders, n (%) | 6 (12.8) | 3 (14.3) | 0.87 |
| Previously administered EN products in switching group | |||
| Peptamen Intense® | 19 (40.4) | ||
| Peptamen AF® | 10 (21.3) | ||
| Glucerna-REX® | 10 (21.3) | ||
| Hine E-Gel® | 8 (17.0) |
EN, enteral nutrition; SOFA, sequential organ failure assessment; APACHE, acute physiology and chronic health evaluation; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pumping.
Table 2 shows the outcomes of both groups. As the primary outcome, diarrhea events 24 to 48 h after the initiation of Peptino® occurred in 28.3% of patients in the switching group and 13.3% in the first initiation group. For the secondary outcomes, in-hospital mortality was as high as 50%, and the median length of the hospital stay was >30 days. The length of the ICU stays, and duration of mechanical ventilation were significantly higher in the switching group. The failure of EN with Peptino® was noted in 4 patients (8.5%) in the switching group and 2 (9.5%) in the first initiation group. The reasons for the discontinuation of EN with Peptino® were diarrhea events, GRV increases, and vomiting events in 2 patients each. Since EN with Peptino® was continued for a median of 5–6 days, the risk of gastrointestinal intolerance was low.
Table 2.
Outcomes
| Group | Switching group (Switched from other EN products) |
First initiation group (Started with Peptino®) |
p value |
|---|---|---|---|
| N | 47 | 21 | |
| Diarrhea event 24–48 h after administration, n (%) | 13 (28.3) | 2 (13.3) | 0.077 |
| In-hospital mortality, n (%) | 26 (55.3) | 9 (42.9) | 0.34 |
| Length of ICU stay, days | 18 (12, 25) | 9 (6, 15) | 0.0011 |
| Length of hospital stay, days | 39 (19, 71) | 34 (18.5, 59.5) | 0.56 |
| Mechanical ventilation, days | 12 (7, 24) | 8 (2.5, 10) | 0.0088 |
| Enteral nutrition failure with Peptino®, n (%) | 4 (8.5) | 2 (9.5) | 0.89 |
| Duration of enteral nutrition with Peptino®, days | 6 (4, 10) | 5 (2, 8.5) | 0.16 |
| Reason for the discontinuation of enteral nutrition with Peptino® | |||
| Vomiting events | 0 | 2 | |
| Diarrhea events (Bristol scale >6) | 2 | 0 | |
| Gastric residual volume >200 ml | 2 | 0 | |
| Mesenteric ischemia | 0 | 0 |
ICU, intensive care unit.
EN-related outcomes in the subgroup are shown in Table 3. The cessation of diarrhea was achieved in 29 patients (82.9%); within 24 h of the initiation of Peptino® in 11 (31.4%) and within 24–48 h in 12 (34.3%). EN failure was noted in 3 patients (8.6%); due to diarrhea in 1 and GRV increases in 2. Mesenteric ischemia necessitating the cessation of Peptino® did not occur in any patient.
Table 3.
Outcomes of patients for whom EN products were switched to Peptino® and with Bristol Stool Form Scale >6 diarrhea prior to the initiation of Peptino®
| Group | Switched from other EN products and Bristol scale >6 diarrhea before Peptino® |
|---|---|
| N | 35 |
| Diarrhea cessation during administration, n (%) | 29 (82.9) |
| Diarrhea cessation within first 24 h of administration, n (%) | 11 (31.4) |
| Diarrhea cessation 24–48 h after administration, n (%) | 12 (34.3) |
| Diarrhea cessation 48–72 h after administration, n (%) | 6 (17.1) |
| Enteral nutrition failure with Peptino®, n (%) | 3 (8.6) |
| Duration of enteral nutrition with Peptino®, days | 6 (3.5, 9.5) |
| Reason for the discontinuation of enteral nutrition with Peptino® | |
| Vomiting events | 0 |
| Diarrhea events (Bristol scale >6) | 1 |
| Gastric residual volume >200 ml | 2 |
| Mesenteric ischemia | 0 |
Discussion
In this case series analysis, EN with Peptino® was effective for diarrhea in the first 2 days from introduction and gastrointestinal intolerance. The switch from other EN products to Peptino® resulted in the cessation of diarrhea in more than 80% of patients.
To the best of our knowledge, this is the first study to investigate the impact of Peptino® on diarrhea in critical care settings. Due to a lack of evidence, the ESPEN guidelines do not recommend changes in EN products for diarrhea.(1,2) However, some EN products reportedly had a lower impact on diarrhea.(13) Since diarrhea is one of the most common complications associated with EN failure, a switch in EN products may allow for the continuation of treatment, at least in patients with refractory diarrhea.
A number of features of Peptino® are effective for diarrhea. Previous studies indicated that oligomeric EN was advantageous for diarrhea.(14,15) Low-molecular-weight whey peptides as the oligomeric formula are one of the components that may attenuate diarrhea symptoms. Some peptides are absorbed easier and earlier in the intestinal tract than amino acids. Peptino® comprises low-molecular-weight peptides that are rapidly absorbed. This product was previously shown to preserve gut immunity and inhibit intestinal mucosal atrophy in an animal model.(11) Moreover, Peptino® contains no fat or dietary fiber. Such EN products have been suggested to not only attenuate diarrhea, but also promote gastric emptying.(16,17) Although its osmolarity is not low, the present results suggest that Peptino® is an effective approach for the cessation of diarrhea in critical care nutrition.
The present study had several limitations. This was a retrospective analysis of a case series of Peptino®. We could not analyze the patients in whom only other EN products were administered during ICU period. Further randomized control trials are needed to validate its effects. However, when diarrhea occurred as a result of EN with other EN products during the study period, we switched to Peptino®. Therefore, the diarrhea cessation rate after switching to Peptino® suggests its efficacy in critical care nutrition. Moreover, since Peptino® has a number of features that contribute to the amelioration of diarrhea, the most effective factor was not identified. Further studies are needed on the therapeutic effects of oligomeric EN for the development of diarrhea countermeasures in critical care nutrition.
Conclusions
Oligomeric EN with low-molecular-weight whey peptides appears to be an effective approach for the cessation of diarrhea and gastrointestinal intolerance in critical care nutrition.
Author Contributions
KN: conception of the study, interpretation, and drafting of the manuscript. HN, MM, DI, HN, MM, YT, HH: conduction of the study. TK: data analysis and contribution to the manuscript. HN, HH: revision of the manuscript. All authors have read and approved the manuscript.
Funding
No funding was given for this study.
Availability of Data and Materials
The datasets generated and/or analyzed during the present study are available from the corresponding author upon reasonable request.
Abbreviations
- APACHE
acute physiology and chronic health evaluation
- EN
enteral nutrition
- ICU
intensive care unit
- SOFA
sequential organ failure assessment
Conflict of Interest
No potential conflicts of interest were disclosed.
Supplementary Material
References
- 1.McClave SA, Taylor BE, Martindale RG, et al. 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.). JPEN J Parenter Enteral Nutr 2016; 40: 159–211. [DOI] [PubMed] [Google Scholar]
- 2.Singer P, Blaser AR, Berger MM, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr 2019; 38: 48–79. [DOI] [PubMed] [Google Scholar]
- 3.Reintam Blaser A, Deane AM, Fruhwald S. Diarrhoea in the critically ill. Curr Opin Crit Care 2015; 21: 142–153. [DOI] [PubMed] [Google Scholar]
- 4.McClave SA, Sexton LK, Spain DA, et al. Enteral tube feeding in the intensive care unit: factors impeding adequate delivery. Crit Care Med 1999; 27: 1252–1256. [DOI] [PubMed] [Google Scholar]
- 5.Montejo JC. Enteral nutrition-related gastrointestinal complications in critically ill patients: a multicenter study. The Nutritional and Metabolic Working Group of the Spanish Society of Intensive Care Medicine and Coronary Units. Crit Care Med 1999; 27: 1447–1453. [DOI] [PubMed] [Google Scholar]
- 6.Reintam Blaser A, Poeze M, Malbrain ML, et al. Gastrointestinal symptoms during the first week of intensive care are associated with poor outcome: a prospective multicentre study. Intensive Care Med 2013; 39: 899–909. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Montejo JC, Grau T, Acosta J, et al. Multicenter, prospective, randomized, single-blind study comparing the efficacy and gastrointestinal complications of early jejunal feeding with early gastric feeding in critically ill patients. Crit Care Med 2002; 30: 796–800. [DOI] [PubMed] [Google Scholar]
- 8.Davies AR, Morrison SS, Bailey MJ, et al. A multicenter, randomized controlled trial comparing early nasojejunal with nasogastric nutrition in critical illness. Crit Care Med 2012; 40: 2342–2348. [DOI] [PubMed] [Google Scholar]
- 9.Sanz-Paris A, Martinez-García M, Martinez-Trufero J, et al. Oligomeric enteral nutrition in undernutrition, due to oncology treatment-related diarrhea. Systematic review and proposal of an algorithm of action. Nutrients 2019; 11: 1888. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.De Luis Román D, Domínguez Medina E, Molina Baena B, et al. Oligomeric formulas in surgery: a delphi and consensus study. Nutrients 2021; 13: 1922. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Moriya T, Fukatsu K, Noguchi M, 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: 153–159. [DOI] [PubMed] [Google Scholar]
- 12.Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997; 32: 920–924. [DOI] [PubMed] [Google Scholar]
- 13.Nakamura K, Inokuchi R, Fukushima K, et al. Pectin-containing liquid enteral nutrition for critical care: a historical control and propensity score matched study. Asia Pac J Clin Nutr 2019; 28: 57–63. [DOI] [PubMed] [Google Scholar]
- 14.Takagi S, Utsunomiya K, Kuriyama S, et al. Effectiveness of an ‘half elemental diet’ as maintenance therapy for Crohn’s disease: a randomized-controlled trial. Aliment Pharmacol Ther 2006; 24: 1333–1340. [DOI] [PubMed] [Google Scholar]
- 15.Sakurai T, Matsui T, Yao T, et al. Short-term efficacy of enteral nutrition in the treatment of active Crohn’s disease: a randomized, controlled trial comparing nutrient formulas. JPEN J Parenter Enteral Nutr 2002; 26: 98–103. [DOI] [PubMed] [Google Scholar]
- 16.Heddle R, Collins PJ, Dent J, et al. Motor mechanisms associated with slowing of the gastric emptying of a solid meal by an intraduodenal lipid infusion. J Gastroenterol Hepatol 1989; 4: 437–447. [DOI] [PubMed] [Google Scholar]
- 17.Chaudhri OB, Salem V, Murphy KG, Bloom SR. Gastrointestinal satiety signals. Annu Rev Physiol 2008; 70: 239–255. [DOI] [PubMed] [Google Scholar]
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Supplementary Materials
Data Availability Statement
The datasets generated and/or analyzed during the present study are available from the corresponding author upon reasonable request.