Metabolic Pathway Analysis in Intensive Care Unit Patients With Refeeding Syndrome

Metabolic Pathway Analysis in Refeeding Syndrome: a Nested Explorative Metabolomics Substudy of the GUTPHOS Multicenter Observational Study (GUTPHOS-Metabolomics)

The overall aim of the study is to improve understanding of refeeding syndrome (RFS) in patients admitted to the intensive care unit (ICU) using metabolomics. Patients are included as part of a prospective multicenter observational study on phosphate disorders in the ICU. Blood samples are collected day 1-7 of ICU stay. Samples from patients who develop refeeding hypophosphatemia and matched controls without hypophosphatemia are analysed for metabolomics and proteomics. Untargeted analyses will be performed to identify the affected metabolic pathways. The investigators will also perform AUROC analyses to identify potential biomarkers for early detection of RFS.

Study Overview

• Status: Completed
• Conditions: Critical Illness; Hypophosphatemia; Refeeding Syndrome
• Intervention / Treatment: Diagnostic test: Metabolomics

Detailed Description

A nested case-control study situated within GUTPHOS Part B: A prospective, multicenter non-interventional cohort study investigating the incidence of abnormal phosphate levels and associated outcomes in adult patients admitted to the ICUs of participating sites. Inclusion/exclusion criteria for GUTPHOS Part B are described in the separate study protocol.

At sites participating in the nested substudy, an additional 2 ml EDTA blood sample is drawn once daily in all patients included in GUTPHOS Part B from ICU admission up to a maximum of calendar day 7 in ICU. The sampling for metabolomics analysis should be performed in close proximity with daily routine blood tests, and always before treatment of hypophosphatemia with phosphate supplementation or restricted nutritional intake. Plasma samples are obtained through centrifugation within 20 minutes and frozen to -80 degrees Celcius within 60 minutes until analysis. The timing and handling of samples according to standard operating procedures will be documented on a separate case report form.

In ICU patients diagnosed with refeeding hypophosphatemia, comprehensive metabolomic profiling is performed in the plasma sample from ICU admission and the sample drawn in conjunction to the blood phosphate measurement diagnostic of RH.

Cases with RH are matched in a 1:1 ratio to ICU patients without RH. Controls are matched according to sex, age, illness severity on admission and energy delivery (kcal/kg adjusted body weight) in the 24 hours preceding the diagnosis of RH.

Refeeding hypophosphatemia is defined as new onset hypophosphatemia (<0.65 mmol/L) within 72 hours from the start of medical nutrition therapy, with a drop of >0.16 mmol/L from any previous Pi value during ICU stay and where no other likely cause of hypophosphatemia is present.

• Study Type: Observational
• Enrollment (Actual): 218

Contacts and Locations

Study Locations

• Czechia
  • Prague, Czechia
    • University Hospital Královské Vinohrady
• Italy
  • Foggia, Italy
    • University Hospital Policlinico of Foggia
• Sweden
  • Stockholm, Sweden
    • Karolinska Universitetssjukhuset Solna
  • Stockholm
    • Huddinge, Stockholm, Sweden, 14186
      • Karolinska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients admitted to the intensive care unit.

Description

Inclusion Criteria:

• Admission to ICU during the study period
• Age ≥18 years

Exclusion Criteria:

• Age <18 years
• Patients with restrictions of care such as "no intubation" or "no renal replacement therapy" on ICU admission and patients admitted for treatment as organ donors
• Continuous chronic home ventilation for neuromuscular disease;
• Declined participation or informed consent (if the local ethics committee requests the latter for this non-interventional study);
• Readmission to ICU during the study period

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Refeeding hypophosphatemia; ICU patients who fulfill diagnostic criteria for refeeding hypophosphatemia.	Diagnostic test: Metabolomics; Analysis of the metabolome in plasma samples.
Controls; ICU patients without refeeding hypophosphatemia. Controls selected to match for sex, age, severity of illness and nutritional delivery prior to refeeding hypophosphatemia.	Diagnostic test: Metabolomics; Analysis of the metabolome in plasma samples.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolomics	The plasma metabolome (>300 metabolites related to cell metabolism) will be characterized by mass spectroscopy from blood samples taken at the onset of refeeding syndrome (RFS) and analyzed for specific alterations in metabolic pathways associated with RFS in an untargeted approach.	Onset of RFS, within the first 7 days in ICU.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolomics	Potential biomarkers in the plasma metabolome (>300 metabolites related to cell metabolism) associated with the development of refeeding syndrome (RFS) will be identified through principal component analysis and ROC curve analysis.	Prior to onset of RFS, within the first 7 days in ICU.

Collaborators and Investigators

• Sponsor: Karolinska University Hospital
• Collaborators: Faculty Hospital Kralovske Vinohrady; Foggia Hospital
• Investigators: Study Chair: Olav Rooyackers, PhD, Karolinska University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2024
• Primary Completion (Actual): June 2, 2024
• Study Completion (Actual): June 2, 2024

Study Registration Dates

• First Submitted: March 7, 2024
• First Submitted That Met QC Criteria: March 27, 2024
• First Posted (Actual): April 3, 2024

Study Record Updates

• Last Update Posted (Actual): April 2, 2025
• Last Update Submitted That Met QC Criteria: March 27, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nutrition Disorders; Disease Attributes; Metabolic Diseases; Disease; Phosphorus Metabolism Disorders; Malnutrition; Syndrome; Critical Illness; Hypophosphatemia; Refeeding Syndrome
• Other Study ID Numbers: K 2023-10247

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No