Trial reportCritical care (London, England)2013
Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis.
Trial report in Critical care (London, England), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02370030 (Controlled Randomized Multi-centric Clinical Trial on the Effect of Citrulline on the Clinical and Biochemical Evolution of Patients With Sepsis.), which is not on this map. Cited by 37 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Controlled Randomized Multi-centric Clinical Trial on the Effect of Citrulline on the Clinical and Biochemical Evolution of Patients With Sepsis.
Who cites it
37 citing papers in PubMed, 77 citations in OpenAlex.
- Plasma Citrulline as a Biomarker in Critical Illness: A Structured Narrative Review.Diagnostics (Basel, Switzerland) · 2026Review
- Systems Bioengineering of Septic Shock Metabolism: Citrulline, β-Hydroxybutyrate and Plasma Biomarker-Based Phenotyping.Biomolecules · 2026Review
- Recent advances in the biosensing platforms for sepsis diagnosis.RSC advances · 2026Review
- COVID-19: A Systematic Review of Metabolomics Data and Predicting Potential Biomarkers Based on Pathway Analysis.Tanaffos · 2025Review
- Increased Oxidative Stress and Decreased Citrulline in Blood Associated with Severe Novel Coronavirus Pneumonia in Adult Patients.International journal of molecular sciences · 2024Article
- Arginine-NO metabolites are associated with morbidity in single ventricle infants undergoing stage 2 palliation.Pediatric research · 2024Article
- Liraglutide pretreatment attenuates sepsis-induced acute lung injury.American journal of physiology. Lung cellular and molecular physiology · 2023Article
- An untargeted metabolomic approach to investigate antiviral defence mechanisms in memory leukocytes secreting anti-SARS-CoV-2 IgG in vitro.Scientific reports · 2023Article
- Intestinal Fatty Acid Binding Protein (I-FABP) as a Prognostic Marker in Critically Ill COVID-19 Patients.Pathogens (Basel, Switzerland) · 2022Article
- Metabolic differences among newborns born to mothers with a history of leukemia or lymphoma.The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians · 2022Article
- S-nitroso-L-cysteine stereoselectively blunts the adverse effects of morphine on breathing and arterial blood gas chemistry while promoting analgesia.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2022Article
- Plasma microRNA and metabolic changes associated with pediatric acute respiratory distress syndrome: a prospective cohort study.Scientific reports · 2022Article
- Development of Biomarkers for Radiation Biodosimetry and Medical Countermeasures Research: Current Status, Utility, and Regulatory Pathways.Radiation research · 2022Article
- Beneficial effects of citrulline enteral administration on sepsis-induced T cell mitochondrial dysfunction.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Photolytic Measurement of TissueMolecules (Basel, Switzerland) · 2022Article
- PGC-1α activity and mitochondrial dysfunction in preterm infants.Frontiers in physiology · 2022Review
- Association of citrulline concentration at birth with lower respiratory tract infection in infancy: Findings from a multi-site birth cohort study.Frontiers in pediatrics · 2022Article
- Amino Acid Metabolism is Significantly Altered at the Time of Admission in Hospital for Severe COVID-19 Patients: Findings from Longitudinal Targeted Metabolomics Analysis.Microbiology spectrum · 2021Article
- Citrulline, Biomarker of Enterocyte Functional Mass and Dietary Supplement. Metabolism, Transport, and Current Evidence for Clinical Use.Nutrients · 2021Review
- Kynurenic acid may underlie sex-specific immune responses to COVID-19.Science signaling · 2021Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
introductionThe role of nitric oxide synthase (NOS) in the pathophysiology of acute respiratory distress syndrome (ARDS) is not well understood. Inducible NOS is upregulated during physiologic stress; however, if NOS substrate is insufficient then NOS can uncouple and switch from NO generation to production of damaging peroxynitrites. We hypothesized that NOS substrate levels are low in patients with severe sepsis and that low levels of the NOS substrate citrulline would be associated with end organ damage including ARDS in severe sepsis.
methodsPlasma citrulline, arginine and ornithine levels and nitrate/nitrite were measured at baseline in 135 patients with severe sepsis. ARDS was diagnosed by consensus definitions.
resultsPlasma citrulline levels were below normal in all patients (median 9.2 uM, IQR 5.2 - 14.4) and were significantly lower in ARDS compared to the no ARDS group (6.0 (3.3 - 10.4) vs. 10.1 (6.2 - 16.6), P = 0.002). The rate of ARDS was 50% in the lowest citrulline quartile compared to 15% in the highest citrulline quartile (P = 0.002). In multivariable analyses, citrulline levels were associated with ARDS even after adjustment for covariates including severity of illness.
conclusionsIn severe sepsis, levels of the NOS substrate citrulline are low and are associated with ARDS. Low NOS substrate levels have been shown in other disease states to lead to NOS uncoupling and oxidative injury suggesting a potential mechanism for the association between low citrulline and ARDS. Further studies are needed to determine whether citrulline supplementation could prevent the development of ARDS in patients with severe sepsis and to determine its role in NOS coupling and function.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.