A Longitudinal Investigation of Energy Expenditure and Substrate Utilization in Critically Ill Patients (EPIC)

A Longitudinal Investigation of Energy Expenditure and Substrate Utilization in Critically Ill Patients: a Prospective Observational Multi-center Study

The metabolic alterations associated with critical illness have significant implications for the nutritional management of ICU patients. Despite this, little is known about these changes in patients requiring prolonged organ support and nutritional therapy.

The overall aim of this study is to describe changes in metabolism over time in a large prospective cohort of patients requiring >10 days of ICU care. Our hypothesis is that there is a significant change in mean energy expenditure and respiratory quotient (RQ) between the early (day 1-3), intermediate (day 4-10) and late (>10 days) phase in ICU.

Study Overview

• Status: Completed
• Conditions: Critical Illness
• Intervention / Treatment: Diagnostic test: Indirect calorimetry

Detailed Description

Background

Critical illness has profound effects on human metabolism. The most prominent feature in the early phase is an upregulation of catabolic pathways, which promotes the production of endogenous energy substrates and net protein breakdown [1].

There is very little published data describing trends of energy expenditure and substrate utilization in patients with a prolonged ICU stay. While this group only constitutes a small fraction of ICU patients, it accounts for a large part of ICU resource allocation, morbidity and mortality [2]. Several studies have been conducted in recent years to better characterize patients with persistent critical illness, focusing on markers of catabolism and inflammation [3, 4]. It is not known if these changes are associated with alterations in energy metabolism and substrate utilization.

Bridging these knowledge gaps will improve our understanding of the nutritional needs and metabolism of patients beyond the early phase in ICU. We therefore plan to conduct a prospective observational multi-center study to address these questions.

Aim and hypothesis

The overall aim of this project is to describe longitudinal changes in energy expenditure and associated clinical characteristics in a large cohort of patients with a prolonged ICU stay. Our hypothesis is that there is a significant change in mean energy expenditure and respiratory quotient (RQ) between the early (day 1-3), intermediate (day 4-10) and late (>10 days) phase in ICU. Correlations between metabolic rate and other clinical characteristics will also be analysed for hypothesis-generating purposes.

Population

All adult ICU patients with at least one measurement of energy expenditure by indirect calorimetry at participating study sites will be included in the study. Study sites are encouraged to routinely perform indirect calorimetry every 3-4 days. Study subjects will be followed until ICU discharge or death, whichever comes first.

Data collection and reporting

Patient data will be reported pseudonymized through a secure online form.

On admission

• Admission date
• Admission diagnosis (ICD-10)
• Surgery prior to admission (YES/NO), elective or emergent
• Outcome prediction score (SAPS 3, APACHE III/IV, MPM, etc.) and risk of death on admission (%)
• ICU source admission (ER/ward/OT/other ICU)
• Days in hospital before ICU admission

Demographic and anthropometric data:

• Sex (male/female)
• Age (years)
• Weight (kg)
• Height (cm)

Chronic comorbidities registered in electronic health records (YES/NO):

• Hypertension
• Ischemic heart disease
• Heart failure
• Diabetes mellitus
• COPD
• Chronic kidney disease
• End-stage renal disease
• Liver cirrhosis
• Active cancer (not in complete remission)
• Haematological malignancy
• Solid organ transplant

On the day of each indirect calorimetry

• REE (kcal/24 h), RQ, VO2 (ml/min), VCO2 (ml/min) and date of investigation
• Invasive mechanical ventilation (YES/NO) or renal replacement therapy (YES/NO)

If YES to invasive mechanical ventilation:

• Fraction of inspired oxygen
• Positive end-expiratory pressure (cmH2O)

Factors that may influence REE:

• Sequential organ failure assessment (SOFA) score
• Fever (≥38.5 ℃) within 2h of measurement (YES/NO/MISSING)
• Richmond Agitation-Sedation Scale score

Results of daily blood tests if available from routine testing:

• P-CRP (mg/L)
• P-albumin (g/L)
• P-urea (mmol/L)
• P-creatinine (μmol/L)
• Haemoglobin (g/L)

Medications, nutrition and other therapies:

• Infusions of vasoactive medications (YES/NO, if YES → name of medication(s))
• Infusions of sedatives or analgesics (YES/NO, if YES → name of medication(s), if propofol → infusion rate at time of measurement)
• Infusions of parenteral and/or enteral nutrition (YES/NO, if YES → brand name, formulation and rate at time of measurement)

On discharge

• Discharge date
• Survival status (ALIVE/DEAD)
• Sepsis during ICU stay (NO/SEPSIS/SEPTIC SHOCK)

Sample size considerations

The goal of this study is to include ≥200 patients with an ICU length of stay of >10 days. Based on data from the Swedish Intensive Care Registry between 2015-2019, these patients accounted for 5% of all ICU admissions [5]. This proportion is comparable to results from a registry study conducted in Australia and New Zealand of over one million ICU admissions [2]. Based on these figures we intend to screen 6000 unique patients for study participation, accounting for the possibility that multiple measurements of indirect calorimetry are not consistently performed. In total we expect to include around 1250 unique subjects with at least one measurement with indirect calorimetry.

Statistics

Descriptive data will be presented as mean +/- standard deviation or median (interquartile range) as appropriate. The primary and secondary outcome measures will be analysed using a generalized linear mixed-effects model. Exploratory outcomes and their association to other clinical variables will be analysed using generalized linear regression models. If values are found to be not missing at random, conditional logistic regression censoring will be used to calculate inverse probability weights for accounting for difference in drop-out probabilities.

• Study Type: Observational
• Enrollment (Actual): 714

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia
    • Royal Melbourne Hospital
  • Melbourne, Australia
    • The Alfred
• Netherlands
  • Ede, Netherlands
    • Gelderse Vallei Hospital
• Sweden
  • Stockholm, Sweden
    • Capio S:t Görans Sjukhus
  • Örebro, Sweden
    • Universitetssjukhuset Orebro
  • Stockholm
    • Huddinge, Stockholm, Sweden, 14186
      • Karolinska University Hospital
• Switzerland
  • Lucerne, Switzerland
    • Lucerne Cantonal Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult intensive care unit patients with ≥1 measurement of energy expenditure by indirect calorimetry.

Description

Inclusion Criteria:

1. >/= 18 years old.
2. Admitted to the ICU of a participating study site.
3. At least one measurement of energy expenditure performed during ICU stay.

Exclusion Criteria:

1. Patients readmitted to the ICU of a participating study site >72 hours after ICU discharge and already included in the study (≥1 measurement of energy expenditure performed during prior admission). If a patient is readmitted within ≤72 hours of ICU discharge this is considered a continuation of the last ICU admission for the purposes of this study.
2. Burns >20% of body surface area.
3. Pregnancy.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in resting energy expenditure over time in patients who stay in ICU for >10 days.	Kcal/kg adjusted body weight/24 hours.	From date of ICU admission to the date of ICU discharge or death, whichever came first, assessed up to 24 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in respiratory quotient over time in patients who stay in ICU for >10 days.	Quotient of carbon dioxide production and oxygen consumption.	From date of ICU admission to the date of ICU discharge or death, whichever came first, assessed up to 24 months.
Change in resting energy expenditure (kcal/kg/day) over time in patients who stay in ICU for ≤10 days.	Kcal/kg adjusted body weight/24 hours.	From date of ICU admission to the date of ICU discharge or death, whichever came first, assessed up to 24 months.
Change in respiratory quotient over time in patients who stay in ICU for ≤10 days.	Quotient of carbon dioxide production and oxygen consumption.	From date of ICU admission to the date of ICU discharge or death, whichever came first, assessed up to 24 months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlations between energy expenditure/respiratory quotient and markers of inflammation, protein catabolism, antecedent characteristics and outcomes.	CRP, albumin, urea/creatinine ratio, age, sex, SOFA, ICU mortality.	From date of ICU admission to the date of ICU discharge or death, whichever came first, assessed up to 24 months.

Collaborators and Investigators

• Sponsor: Karolinska University Hospital
• Collaborators: Karolinska Institutet
• Investigators: Principal Investigator: Martin Sundström Rehal, MD PhD, Karolinska University Hospital; Study Chair: Olav Rooyackers, PhD, Karolinska Institutet

Publications and helpful links

General Publications

• Preiser JC, Ichai C, Orban JC, Groeneveld AB. Metabolic response to the stress of critical illness. Br J Anaesth. 2014 Dec;113(6):945-54. doi: 10.1093/bja/aeu187. Epub 2014 Jun 26.
• Iwashyna TJ, Hodgson CL, Pilcher D, Bailey M, van Lint A, Chavan S, Bellomo R. Timing of onset and burden of persistent critical illness in Australia and New Zealand: a retrospective, population-based, observational study. Lancet Respir Med. 2016 Jul;4(7):566-573. doi: 10.1016/S2213-2600(16)30098-4. Epub 2016 May 4.
• Haines RW, Zolfaghari P, Wan Y, Pearse RM, Puthucheary Z, Prowle JR. Elevated urea-to-creatinine ratio provides a biochemical signature of muscle catabolism and persistent critical illness after major trauma. Intensive Care Med. 2019 Dec;45(12):1718-1731. doi: 10.1007/s00134-019-05760-5. Epub 2019 Sep 17.
• Nakamura K, Ogura K, Nakano H, Naraba H, Takahashi Y, Sonoo T, Hashimoto H, Morimura N. C-reactive protein clustering to clarify persistent inflammation, immunosuppression and catabolism syndrome. Intensive Care Med. 2020 Mar;46(3):437-443. doi: 10.1007/s00134-019-05851-3. Epub 2020 Jan 9.

Helpful Links

• Reporting on length of ICU stay 2015-2019 from the Swedish ICU Registry database.

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2022
• Primary Completion (Actual): July 18, 2024
• Study Completion (Actual): March 21, 2025

Study Registration Dates

• First Submitted: October 25, 2021
• First Submitted That Met QC Criteria: November 15, 2021
• First Posted (Actual): November 18, 2021

Study Record Updates

• Last Update Posted (Actual): April 11, 2025
• Last Update Submitted That Met QC Criteria: April 9, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Energy expenditure; Metabolism; Indirect calorimetry; Prolonged critical illness
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness
• Other Study ID Numbers: K 2021-6909

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