FMT for Feeding Intolerance Due to Gastrointestinal Dysfunction in Critically Ill Patients

Official title

Fecal Microbiota Transplantation for Feeding Intolerance Due to Gastrointestinal Dysfunction in Critically Ill Patients: A Single-Center, Single-Blind, Randomized Controlled Trial

Overview

Critically ill patients admitted to the intensive care unit (ICU) frequently present with gastrointestinal dysfunction and are at elevated risk of malnutrition. Gastrointestinal dysfunction is correlated with adverse clinical outcomes, including prolonged mechanical ventilation duration, extended ICU length of stay, and increased 90-day mortality. In critically ill ICU patients, severe gut microbiota dysbiosis and intestinal barrier impairment may occur due to the burden of primary critical illnesses, as well as the administration of proton pump inhibitors and antibiotics. This cascade contributes to a high prevalence of gastrointestinal dysfunction, alongside profound gut-derived systemic inflammatory responses and organ damage. Given the pivotal role of gut microbiota in maintaining intestinal homeostasis, fecal microbiota transplantation (FMT) holds promise as a novel therapeutic strategy for enteral feeding intolerance secondary to gastrointestinal dysfunction in critically ill ICU patients. This study intends to deliver FMT via a nasojejunal tube to critically ill patients with gastrointestinal dysfunction admitted to the ICU. Its objectives are to evaluate the intervention's effects on gastrointestinal function recovery and the alleviation of enteral feeding intolerance, while also assessing its impacts on intestinal barrier function, gut microbiota composition and metabolic profiles, serum metabolite signatures, immune-inflammatory responses (including lymphocyte subsets, cytokines, C-reactive protein, and procalcitonin), ICU delirium, ICU sleep quality, and clinical outcomes (encompassing ICU mortality, in-hospital mortality, 28-day all-cause mortality, 90-day all-cause mortality, 90-day readmission rate, and 90-day incidence of secondary infections).

Interventions

• Other Fecal microbiota transplantation (FMT)
  Patients received FMT via a nasojejunal tube in addition to standard ICU care. Specifically, 50-100 mL of intestinal microbiota suspension was administered daily via the nasojejunal tube between 11:00 and 13:00 for three consecutive days.

Primary outcome measures

• Enteral nutrition FI improvement rate [Time frame: 24, 48, 72, 96, and 120 hours after study enrollment]

Secondary outcome measures (12)

• Gut microbiota composition as well as α and β diversity measured from rectal swabs by 16S rRNA gene sequencing [Time frame: 24-0 hours and 120 hours after study enrollment]
• Fecal metabolite profile (by untargeted LC-MS) from rectal swabs [Time frame: 24-0 hours and 120 hours after study enrollment]
• Serum metabolite profile (by untargeted LC-MS) [Time frame: 24-0 hours and 120 hours after study enrollment]
• Serum level of citrulline [Time frame: 0, 24, 48, 72, 96, and 120 hours after study enrollment]
• APACHE II score [Time frame: 0, 24, 48, 72, 96, and 120 hours after study enrollment]
• SOFA score [Time frame: 0, 24, 48, 72, 96, and 120 hours after study enrollment]
• Cumulative intravenous dose of vasopressor agents (including norepinephrine, epinephrine, dobutamine, etc.) [Time frame: 0, 24, 48, 72, 96, and 120 hours after study enrollment]
• Serum level of C-reactive protein [Time frame: 0, 24, 48, 72, 96, and 120 hours after study enrollment]
• Serum level of procalcitonin [Time frame: 0, 24, 48, 72, 96, and 120 hours after study enrollment]
• Peripheral blood level of cytokines (including IL-6, IL-17, TNF-α, IL-10, IL-1β, etc.) [Time frame: 0 and 120 hours after study enrollment]
• Peripheral blood lymphocyte subsets (including CD4+ T, CD8+ T, B lymphocytes, NK cells, etc.) [Time frame: 0, 24, 48, 72, 96, and 120 hours after study enrollment]
• ICU mortality [Time frame: Within 28 days after study enrollment]

Eligibility criteria

Inclusion criteria

• Aged 18 to 70 years inclusive, regardless of ethnicity or gender;
• Female participants are either non-fertile (i.e., physiologically incapable of pregnancy, including women with ≥2 years of menopause) or have no pregnancy plans;
• Have been admitted to the ICU for ≥24 hours;
• Expected ICU stay ≥7 days after study enrollment;
• Screened positive for ≥1 manifestation of gastrointestinal dysfunction (intra-abdominal hypertension \[IAH\], massive gastric retention, diarrhea, lower gastrointestinal paralysis, bowel dilatation); enteral nutrition is then implemented under the guidance of the enteral feeding intolerance (FI) score, and participants with persistent FI after a 3-day trial are formally enrolled;
• Participants can actively cooperate or passively complete relevant examinations and follow-up procedures;
• Have signed a written informed consent form.

Exclusion criteria

• Severe systemic infection in the early resuscitation phase, with hemodynamic instability, insufficient tissue perfusion, or severe fluid-electrolyte and acid-base imbalances;
• Patients assessed by clinicians as having a high risk of death within 5 days, or those with restricted treatment decisions;
• Active gastrointestinal bleeding, perforation, or other conditions with severe intestinal barrier impairment;
• Patients unable to tolerate enteral nutrition meeting 50% of caloric requirements due to severe diarrhea, significant fibrotic intestinal stenosis, massive gastrointestinal bleeding, or high-output enterocutaneous fistula;
• Planned or recent abdominal surgery (within 14 days prior to enrollment);
• Current diagnosis of fulminant colitis or toxic megacolon;
• Neutropenia (neutrophil count < 1500 cells/µL);
• Patients with congenital or acquired immunodeficiency disorders;
• Recent receipt of high-risk immunosuppressive or cytotoxic agents, e.g., rituximab, doxorubicin, or medium-to-high-dose corticosteroids (≥ 20 mg/day prednisone equivalent) for a duration of > 4 weeks;
• Pregnant or lactating women;
• Participation in another clinical trial as a subject at the time of enrollment or within 3 months prior to enrollment;
• Doubtful validity of informed consent: subjects with mental illness, intellectual disability, poor motivation, or other factors that restrict the validity of informed consent for participation in this study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

China · 1 center

• Union Hospital, Tongji Medical College, Huazhong University of Science and Technology — Wuhan

Publications

• Uhde M, Ajamian M, Caio G, De Giorgio R, Indart A, Green PH, Verna EC, Volta U, Alaedini A. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016 Dec;65(12):1930-1937. doi: 10.1136/gutjnl-2016-311964. Epub 2016 Jul 25. PMID 27459152
• Heming N, Carlier R, Prigent H, Mekki A, Jousset C, Lofaso F, Ambrosi X, Bounab R, Maxime V, Mansart A, Crenn P, Moine P, Foltzer F, Cuenoud B, Konz T, Corthesy J, Beaumont M, Hartweg M, Roessle C, Preiser JC, Breuille D, Annane D. Effect of an enteral amino acid blend on muscle and gut functionality in critically ill patients: a proof-of-concept randomized controlled trial. Crit Care. 2022 Nov 17 PMID 36397118
• Piton G, Manzon C, Cypriani B, Carbonnel F, Capellier G. Acute intestinal failure in critically ill patients: is plasma citrulline the right marker? Intensive Care Med. 2011 Jun;37(6):911-7. doi: 10.1007/s00134-011-2172-x. Epub 2011 Mar 12. PMID 21400011
• Yadegar A, Bar-Yoseph H, Monaghan TM, Pakpour S, Severino A, Kuijper EJ, Smits WK, Terveer EM, Neupane S, Nabavi-Rad A, Sadeghi J, Cammarota G, Ianiro G, Nap-Hill E, Leung D, Wong K, Kao D. Fecal microbiota transplantation: current challenges and future landscapes. Clin Microbiol Rev. 2024 Jun 13;37(2):e0006022. doi: 10.1128/cmr.00060-22. Epub 2024 May 8. PMID 38717124
• McClave SA, Patel J, Bhutiani N. Should fecal microbial transplantation be used in the ICU? Curr Opin Crit Care. 2018 Apr;24(2):105-111. doi: 10.1097/MCC.0000000000000489. PMID 29432297
• Beyi AF, Wannemuehler M, Plummer PJ. Impacts of Gut Microbiota on the Immune System and Fecal Microbiota Transplantation as a Re-Emerging Therapy for Autoimmune Diseases. Antibiotics (Basel). 2022 Aug 12;11(8):1093. doi: 10.3390/antibiotics11081093. PMID 36009962
• Schluter J, Peled JU, Taylor BP, Markey KA, Smith M, Taur Y, Niehus R, Staffas A, Dai A, Fontana E, Amoretti LA, Wright RJ, Morjaria S, Fenelus M, Pessin MS, Chao NJ, Lew M, Bohannon L, Bush A, Sung AD, Hohl TM, Perales MA, van den Brink MRM, Xavier JB. The gut microbiota is associated with immune cell dynamics in humans. Nature. 2020 Dec;588(7837):303-307. doi: 10.1038/s41586-020-2971-8. Epub 202 PMID 33239790
• Arunachala Murthy T, Chapple LS, Lange K, Marathe CS, Horowitz M, Peake SL, Chapman MJ. Gastrointestinal dysfunction during enteral nutrition delivery in intensive care unit (ICU) patients: Risk factors, natural history, and clinical implications. A post-hoc analysis of The Augmented versus Routine approach to Giving Energy Trial (TARGET). Am J Clin Nutr. 2022 Aug 4;116(2):589-598. doi: 10.1093/aj PMID 35472097

Identifiers

NCT: NCT07640633 · zjc202402

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗