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. 2021 Dec 21;12(1):1. doi: 10.3390/metabo12010001

Table 3.

Metabolomics-assisted prognostication of patients with sepsis non-survivors.

Settings Age (Age Range)
(Sample Size)		 APACHE-II
Score		 Samples Since Admission Methods Major Findings in Non-Survivors Interpretation Citation
Serum Plasma Blood Metabolic Pathways Decreased Increased
48-H mortality 67 ± 15 (9)
vs.
63 ± 18 (26)		 26 ± 6
vs.
20 ± 8		 ✓
within 48-H before death		 Targeted
(LC-MS/MS)		 Amino acids and amines -

  • S-(3-methyl-butanoyl)dihydro-lipoamide-E

 Amino acids and phospholipids could indicate the possibility of death within 48-H in patients with sepsis [10]
Phospholipids -

  • Phosphatidyl-glycerol(22:2

  • (13Z,16Z)/0:0)

  • GPC
7-D mortality 60 (36–80)
(9)
vs.
60 (27–84)
(13)		 31 (16–46)
vs.
22 (14–38)		 ✓
within 48 h = D1, D3, and D7 		Targeted
(LC-MS/MS)		 Persisted D1 to D7 Fatty acids and proresolving lipids signal 7-D mortality in critically-ill patients with sepsis [60]
Fatty acids -

  • Prostaglandin F2α

  • Leukotriene B4

  • Resolvin E1

  • Resolvin D5

  • 17R-Protectin D1
At D1
Fatty acids -

  • 7-HDHA

  • 17-HDHA

  • 15-HEPE

  • 18-HEPE

  • 15-HETE
-

  • Protectin D1
At D3
Fatty acids -

  • 17-HDHA

  • 18-HEPE

  • 5-HETE

  • 15-HETE

  • 5S,12S-diHETE
-

  • 17-epi-Resolvin D1

  • 17-epi-Protectin D1
At D7
Fatty acids -

  • 4S,14S-diHDHA

  • 5S,15S-diHETE
-

  • Resolvin E2
28-D mortality 69 ± 17
(31)
vs.
56 ± 19
(90)		 23 ± 8
vs.
15 ± 7		 ✓
H0
and H24		 ✓
H0
and H24		 - Untargeted (UPLC-MS/MS
and
GC-MS)
- Targeted (UPLC-MS/MS)		 Persisted At H0 to H24 28-D mortality could be predicted by several amino acids, amines, fatty acids, and glycolysis metabolites [61]
Amino acids and amines -

  • N-Acetylthreonine

  • 1-Methylimidazole acetate

  • N-Acetylalanine

  • Hydroxyproline

  • Prolylhydroxy-proline

  • SDMA

  • AC

  • C3, C4, C5, C5:1
Fatty acids -

  • AC

  • C6, C8, C10, C16, C18

  • 3-Hydroxy-2-ethyl-propionate
Glycolysis -

  • Erythronate

  • N-acetylneura-minate

  • Arbitol

  • AC C2
TCA cycle -

  • Malate
At H0
Fatty acids -

  • AC C12
At H24
Amino acids and amines -

  • α-Hydroxyiso-valerate

  • Glutaroylcarnitine

  • Hydroxyisovalero-ylcarnitine
Fatty acids -

  • Hexadecanedioate
Phospholipids

  • 1-Arachido-nyl-GPE

  • 1-Palmitoyl-GPC

  • 1-Stearoyl-GPC

  • 1-Eicosatri-enoyl-GPC

  • 1-Arachido-noyl-GPC

 -
28-D mortality T: 58 ± 15
(30)
vs.
53 ± 14
(60)
V: 69 ± 16
(34)
vs.
58 ± 17
(115)		 30 ± 11
vs.
23 ± 9
23 ± 8
vs.
15 ± 7		 ✓
H0		 Targeted
(GC-MS and
LC-MS)		 Amino acids and amines -

  • Ornithine

  • Kynurenine

  • AC C3, C4, C5, C5-OH, C5:1

  • β-hydroxyiso-valerate

  • N-acetylalanine

  • N-acetylserine

  • α-Hydroxy-isovalerate

  • γ-glutamylphenyl-alanine

  • γ-glutamyltyrosine

 Non-surviving 28-D sepsis patients had specific changes in amino acids, fatty acids, glycolysis, and bile acids’ metabolic pathways, as well as an increase in aromatic microbial metabolites [62]
Fatty acids -

  • AC C6
Phospholipids

  • 1-arachidonyl-GPE (20:4)

  • 1-arachidonyl-GPC (20:4)

  • 1-linoleoyl-GPC (18:2)

  • 2-palmitoyl-GPC (16:0)

  • 1-palmitoyl-GPC (16:0)

  • 1-stearoyl-GPC (18:0)

 -
Glycolysis
Aromatic microbial metabolites		 -

-

  • Sucrose

  • Lactate

  • 3-(4-hydroxyphenyl) lactic acid
28-D mortality 61 ± 21
(15)
vs.
54 ± 23
(20)		 22 ± 8
vs.
10 ± 5		 ✓
within 24H = D1, D3, D5, D7, D10, and D14		 Targeted
(LC-MS/MS)		 At certain time points Amino acids could indicate the possibility of death in septic patients [11]
Amino acids and amines

  • Arginine

  • Glutamate

  • Serine

  • Phosphoserine

  • Taurine

  • Tryptophan

  • α-Aminoadipic acid

  • Cystathionine

  • Ethanolamine

  • Phenylalanine
28-D mortality 68 (51–75)
(31)
vs.
63 (53–74)
(89)		 12 (8–9)
vs.
9 (6–13)		 ✓
within
24H = D1, D3, D7		 Targeted
(LC-MS/MS)		 Amino acids and amines

  • SDMA

  • ADMA

 High level of plasma SDMA and ADMA can predict sepsis non-survival [66]
28-D mortality 70 ± 13
(21)
vs.
72 ± 15
(69)		 26 ± 9
vs.
23 ± 8		 ✓
H0		 Targeted
(UHPLC-MS)		 Glycolysis -

  • AC C2

 Acetylcarnitine can forecast 28-D mortality in patients with sepsis [63]
28-D mortality 67 ± 14
(54)
vs.
62 ± 19
(134)		 22 (18–30)
vs.
18 (13–24)		 ✓
H0		 Targeted (LC-MS) Amino acids and amines -

  • Isoleucine

  • Alanine

 Particular metabolites can forecast 28-D mortality in sepsis patients [64]
Phospholipids

  • LysoPC C22:0

  • LysoPC C24:0

 -
Glycolysis -

  • Lactate

  • Pyruvate

  • AC C2
30-D mortality 55 (17–80)
(39)
vs.
54 (20–91)
(63)		 N/A
vs.
N/A		 ✓
D1, D4,
and D11		 Targeted
(LC-MS/MS)
Lipids		 Persisted along D1 to D11 [8]
Fatty acids and phospholipids -

  • Total ceramides-to-SM ratio/total LysoPC-to-PC ratio
90-D mortality 75 ± 13
(30)
vs.
71 ± 13
(63)		 9 ± 4 $
vs.
5 ± 4 $ 		✓
D1		 Targeted
(UPLC-MS)		 Amino acids and amine -

  • Phenylalanine

  • Leucine

 In sepsis patients, 90-D mortality can be expected by phenylalanine and leucine [65]

Continuous data are presented in mean ± SD, otherwise reported as median and IQR1-3. $ Sequential Organ Failure Assessment (SOFA) score. Abbreviations: 7-HOCA, 7-α-hydroxy-3-oxo-4-cholestenoate; APACHE-II score, Acute Physiology and Chronic Health Evaluation-II score; ADMA, asymmetric dimethylarginine; C, number of carbons in the fatty acid side chain; D, Day; GPC, Glycerophosphocholine; GPE, Glycerophosphoethanolamine; H, Hour; HDHA, Hydroxydocosahexaenoate; HEPE; Hydroxyeicosapentaenoate; HETE; Hydroxyeicosatetraenoate; LysoPC, lysophosphatidylcholine; LC-MS/MS, liquid chromatography-tandem mass spectrometry; SDMA, symmetric dimethylarginine; UHPLC-MS, Ultra-high performance liquid chromatography mass spectrometry; UPLC-MS, Ultra-performance liquid chromatography-mass spectrometry; T, training cohort; V, validation cohort.