Relevance of plasma lipoproteins and small metabolites in assessment of nutritional status among patients with severe injuries

Abstract

Background: This study aimed to identify plasma lipoproteins and small metabolites associated with high risk of malnutrition during intensive care unit (ICU) stay in patients with severe injuries.

Methods: This observational prospective exploratory study was conducted at two level-1 trauma centers in the Netherlands. Adult patients (aged ≥18 years) who were admitted to the ICU for more than 48 h between July 2018 and April 2022 owing to severe injuries (polytrauma, as defined by Injury Severity Scores of ≥16) caused by blunt trauma were eligible for inclusion. Partial least squares discriminant analysis was used to analyze the relationship of 112 lipoprotein-related components and 23 small metabolites with the risk of malnutrition (modified Nutrition Risk in Critically Ill score). Malnutrition was diagnosed based on Subjective Global Assessment scores. The relationship of lipoprotein properties and small metabolite concentrations with malnutrition (during ICU admission) was evaluated using mixed effects logistic regression.

Results: Overall, 51 patients were included. Lower (very) low-density lipoprotein ([V]LDL) (free) cholesterol and phospholipid levels, low particle number, and higher levels of LDL triglycerides were associated with a higher risk of malnutrition (variable importance in projection [VIP] value >1.5). Low levels of most (V)LDL and intermediate-density lipoprotein subfractions and high levels of high-density lipoprotein Apo-A1 were associated with the diagnosis of malnutrition (VIP value >1.5). Increased levels of dimethyl sulfone, trimethylamine N-oxide, creatinine, N, N-dimethylglycine, and pyruvic acid and decreased levels of creatine, methionine, and acetoacetic acid were also indicative of malnutrition (VIP value >1.5). Overall, 14 lipoproteins and 1 small metabolite were significantly associated with a high risk of malnutrition during ICU admission (P <0.05); however, the association did not persist after correcting the false discovery rate (P=0.35 for all).

Conclusion: Increased triglyceride in several lipoprotein subfractions and decreased levels of other lipoprotein subfraction lipids and several small metabolites (involved in the homocysteine cycle, ketone body formation, and muscle metabolism) may be indicative of malnutrition risk. Following validation in larger cohorts, these indicators may guide institution of preventive nutritional measures in patients admitted to the ICU with severe injuries.

Keywords: Lipoproteins; Malnutrition; Metabolites; Nutritional status; Severely injured; Trauma.

Figure 1

Small metabolites analyzed in this study.Associated metabolic cycles and relation with malnutrition (according to available literature). Solid arrows signify single-step reactions and dotted arrows signify multiple steps. γ-GPA: γ-Glutamyl phenylalanine; α-KG: α-ketoglutarate; 3-PG: 3-phosphoglycerate; AcCoA: Acetyl-CoA; Ace: Acetic acid; Ala: Alanine; Arg: Arginine; AS: Argininosuccinate; Bet: Betaine; Car: Carnitine; Cho: Choline; CI: Chiro-inositol; Cit: Citrulline; Citr: Citrate; Cr: Creatine; Creat: Creatinine; CS: Cystathionine; Cys: Cysteine; DMG: N,N-Dimethylglycine; For: Formic acid; Fum: Fumarate; Gla: γ-carboxyglutamic acid; GLC: Glucose; GLC6p: Glucose-6-phosphate; Gln: Glutamine; Glu: Glutamic acid; GluSA: Glutamate-1-semialdehyde; Gly: Glycine; GSH: Reduced glutathione; GSSG: Glutathione disulfide; HC: Homocysteine; Hx: Hypoxanthine; Ile: Isoleucine; IsoCit: Isocitrate; Kyn: Kynurenine; Lac: Lactic acid; Leu: Leucine; Lys: Lysine; Mal: Malate; Met: Methionine; MTA: 5-Methylthioadenosine; NADPH: Nicotinamide-adenine-dinucleotidephosphate; NAM: N-acetylmethionine; NAPhe: N-acetylphenylalanine; OA: Oxaloacetate; OC: Osteocalcin; OH-PA: 4-hydroxyphenylacetate; OH-PL: 3-(4-hydroxyphenyl)lactate; Orn: Ornithine; Phe: Phenylalanine; PL: Phenyllactate; PP: Phenylpyruvate; Pro: Proline; Pyr: Pyruvic acid; PyrGln: Pyroglutamate; SAH: S-adenosylhomocysteine; SAM: S-adenosylmethionine; Sar: Sarcosine; Ser: Serine; Suc: Succinic acid; TMA: Trimethylamine; TMAO: Trimethylamine N-oxide; TML: N-6-trimethyllysine; Trp: Tryptophan; TrpB: Tryptophan Betaine; Tyr: Tyrosine; Val: Valine; VitB3: Vitamin B3 (nicotinamide); VitC: Vitamin C; VitE: Vitamin E.

Figure 2

Clustering of daily metabolite analyses during the TPs. Bold and italicized: Day of nutritional assessment using the SGA tool. mNUTRIC: Modified Nutrition Risk in Critically Ill; SGA: Subjective Global Assessment; TP: Time period.

Figure 3

Risk of malnutrition biomarker identification using PLS-DA. PLS-DA was used to determine any relation between the risk of malnutrition (as defined by the mNUTRIC score) and the lipoprotein and small metabolite data. A VIP value was calculated to rank the top 15 lipoproteins and small metabolites according to their prognostic importance for the risk of malnutrition. The boxes on the right indicate the relative concentrations of the lipoprotein/small metabolite in the risk for malnutrition groups. For this analysis, the Q² value is 0.04. L1AB: Apo-B Subfraction of LDL-1; L1CH: Cholesterol Subfraction of LDL-1; L1FC: Free Cholesterol Subfraction of LDL-1; L1PL: Phospholipids Subfraction of LDL-1; L1PN: LDL-1 Particle Number; L4FC: Free Cholesterol Subfraction of LDL-4; L5TG: Triglycerides Subfraction of LDL-5; mNUTRIC: Modified Nutrition Risk in Critically Ill; PLS-DA: Partial Least Squares Discriminant Analysis; V5FC: Free Cholesterol Subfraction of VLDL-5; VIP: Variable Importance in Projection.

Figure 4

Malnutrition based on ICU day 5 biomarkers using PLS-DA. PLS-DA was used to relate the diagnosis of malnutrition on day 5 of ICU admission (defined by the SGA score) to the lipoprotein and small metabolite data. A VIP value was calculated to rank the top 15 lipoproteins and small metabolites according to their prognostic importance for the diagnosis of malnutrition. The boxes on the right indicate the relative concentrations of the lipoprotein/small metabolite in the nutritional status groups. For this analysis, the Q² value was 0.09. H2A1: Apo-A1 Subfraction of HDL-2; ICU: Intensive Care Unit; IDPL: Lipoprotein Main Fractions, Phospholipids, IDL; IDTG: Lipoprotein Main Fractions, Triglycerides, IDL; L1FC: Free Cholesterol Subfraction of LDL-1; L2TG: Triglycerides Subfraction of LDL-2; L3CH: Cholesterol Subfraction of LDL-3; L4TG: Triglycerides Subfraction of LDL-4; L5TG: Triglycerides Subfractions of LDL-5; PLS-DA: Partial Least Squares Discriminant Analysis; SGA: Subjective Global Assessment; V1CH: Cholesterol Subfractions of VLDL-1; V3FC: Free Cholesterol Subfraction of VLDL-3; V4CH: Cholesterol Subfraction of VLDL-4; V5FC: Free Cholesterol Subfraction of VLDL-5; V5PL: Phospholipids Subfraction of VLDL-5; VIP, Variable Importance in Projection; VLPN: VLDL Particle Number.