Urea-to-Creatinine Ratio as a Marker of Metabolic Transition in Septic Shock: A Comparison With Indirect Calorimetry

Overview

Urea-to-Creatinine Ratio as a Marker of Metabolic Transition in Septic Shock: A Comparison with Indirect Calorimetry. This study investigates whether the urea-to-creatinine ratio can serve as a simple marker of metabolic state in patients with septic shock. Septic shock is associated with hypermetabolism and severe protein catabolism, which worsen outcomes. Although indirect calorimetry is the gold standard for measuring energy expenditure and metabolic demand in critically ill patients, its availability in ICUs is limited. The authors hypothesize that the urea-to-creatinine ratio reflects protein catabolism and correlates with energy expenditure measured by indirect calorimetry, making it a potential tool to identify the transition from the catabolic to the anabolic phase and to guide nutritional therapy. The primary objective is to assess the correlation between the urea-to-creatinine ratio and energy expenditure in septic shock patients. Secondary objectives include evaluating changes in systemic inflammation over time using C-reactive protein (CRP). This is a prospective observational cohort study of adult patients with septic shock admitted to a medical-surgical ICU who require at least three days of mechanical ventilation and undergo indirect calorimetry. Energy expenditure will be measured at predefined intervals during the ICU stay, while urea, creatinine, and CRP levels will be collected regularly. Patients with severe renal dysfunction, renal replacement therapy, or high oxygen requirements will be excluded. Data will be analyzed across three time periods during mechanical ventilation to examine trends in energy expenditure, urea-to-creatinine ratio, and inflammation. Demographic and clinical variables will also be collected. The study aims to determine whether changes in the urea-to-creatinine ratio mirror metabolic transitions detected by indirect calorimetry, potentially offering a practical alternative for metabolic monitoring in septic shock patients.

Detailed description

Urea-to-Creatinine Ratio as a Marker of Metabolic Transition in Septic Shock: A Comparison with Indirect Calorimetry

INTRODUCTION: Patients with septic shock develop profound metabolic alterations characterized by hypermetabolism and accelerated protein catabolism, leading to loss of lean body mass and worse clinical outcomes. Indirect calorimetry is the gold standard for assessing energy expenditure and metabolic demand in critically ill patients; however, it is not widely available in ICUs.

The urea-to-creatinine ratio has been proposed as a simple and readily available marker of protein catabolism. Nevertheless, its relationship with measured energy expenditure remains unclear.

HYPOTHESIS: The urea/creatinine ratio may be an efficient catabolism marker to guide nutritional therapy in critically ill patients. Evidence to confirm this hypothesis can be obtained by comparing the urea-to-creatinine ratio with indirect calorimetry, which is the gold standard for evaluating energy expenditure and metabolic demands in these patients.

OBJECTIVES: The primary objective of this study is to evaluate the correlation between the urea-to-creatinine ratio and energy expenditure measured by indirect calorimetry in patients with septic shock, in order to identify the transition from the catabolic to the anabolic phase. This transition is expected to be reflected by a reduction in the urea-to-creatinine ratio accompanied by a decrease in measured energy expenditure.

Secondary objectives include the analysis of inflammatory activity over time, as assessed by C-reactive protein (CRP) levels.

METHODS: This is a prospective observational cohort study including adult patients with septic shock, defined according to Sepsis-3 criteria, admitted to a 53-bed medical-surgical intensive care unit between April 2026 and March 2027. Eligible patients will be required to have undergone invasive mechanical ventilation for at least three consecutive days and to have had energy expenditure measured by indirect calorimetry.

Indirect calorimetry assessments will be performed on days 1, 4, 7, 11, 14, 17, and 20 after ICU admission. Patients will be excluded if they had a serum creatinine level greater than 4.0 mg/dL at hospital admission, chronic kidney disease requiring dialysis, initiation of renal replacement therapy during ICU stay, or if they require an inspired oxygen fraction (FiO₂) greater than 70% on the fourth day of mechanical ventilation.

Energy expenditure measurements will be obtained using the E-COVX module integrated into the Carescape B650 monitor (GE Healthcare, Helsinki, Finland). Urea and creatinine levels will be collected daily, and the urea-to-creatinine rati calculated accordingly. CRP levels will also be measured as an indicator of systemic inflammation.

For analysis, energy expenditure, urea-to-creatinine ratio, and CRP values will be grouped into three time periods based on days since initiation of mechanical ventilation: days 1-4, days 7-11, and days 14-20.

Demographic and clinical data to be collected include age, sex, Simplified Acute Physiology Score III (SAPS III), Sequential Organ Failure Assessment (SOFA) score at admission, admission category (medical or surgical), the sepsis focus and relevant comorbidities. Data will be collected prospectively using standardized case report forms.

Written informed consent will be obtained from patients or their legal representatives. The study protocol will be submitted for approval to the Research Ethics Committee of Hospital São Domingos

Primary outcome measures

• Urea-to-creatinine ratio and energy expenditure measured by indirect calorimetry [Time frame: 20 days]

Secondary outcome measures (1)

• C-reactive protein (CRP) [Time frame: 20 days]

Eligibility criteria

Inclusion Criteria: Adult patients with septic shock, defined according to Sepsis-3 criteria, admitted to a 53-bed medical-surgical intensive care unit between April 2026 and March 2027. Eligible patients will be required to have undergone invasive mechanical ventilation for at least three consecutive days -

Exclusion Criteria:Patients will be excluded if they had a serum creatinine level greater than 4.0 mg/dL at hospital admission, chronic kidney disease requiring dialysis, initiation of renal replacement therapy during ICU stay, or if they require an inspired oxygen fraction (FiO₂) greater than 70% on the fourth day of mechanical ventilation.

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

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Center list to be confirmed — check the primary protocol.

Publications

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• Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287. PMID 26903338
• Paulus MC, Melchers M, van Es A, Kouw IWK, van Zanten ARH. The urea-to-creatinine ratio as an emerging biomarker in critical care: a scoping review and meta-analysis. Crit Care. 2025 May 2;29(1):175. doi: 10.1186/s13054-025-05396-6. PMID 40317012
• 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. PMID 31531715
• Niederer LE, Miller H, Haines KL, Molinger J, Whittle J, MacLeod DB, McClave SA, Wischmeyer PE. Prolonged progressive hypermetabolism during COVID-19 hospitalization undetected by common predictive energy equations. Clin Nutr ESPEN. 2021 Oct;45:341-350. doi: 10.1016/j.clnesp.2021.07.021. Epub 2021 Aug 3. PMID 34620338
• Long CL, Schaffel N, Geiger JW, Schiller WR, Blakemore WS. Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorimetry and nitrogen balance. JPEN J Parenter Enteral Nutr. 1979 Nov-Dec;3(6):452-6. doi: 10.1177/014860717900300609. PMID 575168
• Israfilov E, Kir S. Comparison of Energy Expenditure in Mechanically Ventilated Septic Shock Patients in Acute and Recovery Periods via Indirect Calorimetry. JPEN J Parenter Enteral Nutr. 2021 Sep;45(7):1523-1531. doi: 10.1002/jpen.2063. Epub 2021 Feb 16. PMID 33314315

Identifiers

NCT: NCT07412366 · Study 01-2026

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗