Past Experiences for Future Applications of Metabolomics in Critically Ill Patients with Sepsis and Septic Shocks
Abstract
:1. Introduction
2. The Role of Microbiota and Its Metabolites in the Development of Sepsis and Septic Shock
3. Metabolomics for Sepsis Diagnosis
3.1. Alterations of Amino Acids and Amines in Sepsis
3.1.1. A Decrease in Cysteine and Lysine
3.1.2. An Increase in Glycine, Serine, Polyamines, and Amino Acid-Derived Acylcarnitines
3.2. Alterations of Fatty Acids and Their Related Metabolites in Sepsis
3.2.1. A Decrease of Eicosanoids
3.2.2. An Increase in Free Fatty Acids
3.2.3. An Alteration of Fatty Acid-Derived Acylcarnitines and Ceramides
3.3. Alterations of Phospholipids in Sepsis
3.3.1. A Decrease in Sphingomyelines and Lysophosphatidylcholines
3.3.2. An Increase in Cardiolipins
3.3.3. An Alteration of Phosphatidylcholines
4. Metabolomics for Septic Shock Diagnosis
4.1. Alterations of Amino Acids and Amines in Septic Shock
4.1.1. A Decrease in Branched-Chain Amino Acids, Glutamine, Glutamate, Arginine, and Proline
4.1.2. An Increase in Aromatic Amino Acids
4.2. Alterations of Glycolysis-Related Metabolites in Septic Shock
5. Metabolomics for Prognostication Patients with Sepsis
5.1. Alterations of Amino Acids and Amines in Sepsis Non-Survivors
5.1.1. A Decrease in Taurine, Tryptophan, Glutamate, Arginine, and Serine
5.1.2. An Increase in S-(3-Methyl-butanoyl)-dihydrolipoamide-E, Amino Acid-Derived Acylcarnitines, and Symmetric Dimethylarginine and Asymmetric Dimethylarginine
5.2. Alterations of Fatty Acids and Their Related Metabolites in Sepsis Non-Survivors
5.3. Alteration of Phospholipids in Sepsis Non-Survivors
5.4. Alterations of Glycolysis-Related Metabolites in Sepsis Non-Survivors
5.5. Alterations of Aromatic Microbial Metabolites in Sepsis Non-Survivors
6. Metabolomics for Prognostication Patients with Septic Shock
6.1. Alterations of Amino Acids and Amines in Septic Shock Non-Survivors
6.1.1. A Decrease in Dimethylamine and Citrulline
6.1.2. An Increase in Symmetric Dimethylarginine, Total Dimethylarginine, and Tyrosine
6.1.3. An Alternation of Phenylalanine and Methionine
6.2. Alterations of Fatty Acid-Related Metabolites in Septic Shock Non-Survivors
6.3. Alterations of Phospholipids in Septic Shock Non-Survivors
6.4. Alterations of Glycolysis-Related Metabolites and TCA Cycle Metabolites in Septic Shock Non-Survivors
7. Metabolomics for Monitoring Treatment Response in Sepsis and Septic Shock
8. Conclusions
9. Limitation and Future Direction of the Metabolomic Research in Sepsis
Author Contributions
Funding
Conflicts of Interest
References
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Age (Sample Size) | APACHE-II Score | Samples Since Admission | Methods | Major Findings in Sepsis Group | Interpretation | Citation | ||||
---|---|---|---|---|---|---|---|---|---|---|
Serum | Plasma | Others | Metabolic Pathways | Decreased | Increased | |||||
N/A (102) vs. N/A (56) | N/A vs. N/A | ✓ D1 | Targeted (LC-MS/MS) | At D1 | Patients with sepsis had increased ceramides, but decreased phospholipids when compared to patients without sepsis | [8] | ||||
Fatty acids |
|
| ||||||||
Phospholipids |
| |||||||||
T: 64 ± 11 (30) vs. 67 ± 10 (33) V: 64 ± 15 (39) vs. 67 ± 10 (41) | 23 ± 8 vs. 18 ± 7 26 ± 9 vs. 19 ± 7 | ✓ within 24 h/ at onset of SIRS | Targeted (LC-MS/MS) | Fatty acids | - |
| Fatty acids and phospholipids are potential markers for discriminating sepsis from SIRS | [9] | ||
Phospholipids | - |
| ||||||||
64 ± 17 (35) vs. 59 ± 19 (15) | 22 ± 7 vs. 11 ± 9 | ✓ within 24 h | Targeted (LC-MS/MS) | Amino acids and amine |
|
| Amino acids and lactitol dihydrate could differentiate sepsis from SIRS | [10] | ||
Others |
|
| ||||||||
57 ± 22 (35) vs. 47 ± 13 (14) | 18 ± 8 vs. 9 ± 3 | ✓ within 24 h | Targeted (LC-MS/MS) | Amino acids and amine |
|
| Critically ill patients with sepsis had a wide range of amino acid spectral changes that differ from SIRS | [11] | ||
T: 70 ± 17 (123) vs. 63 ± 16 (42) V: 64 ± 24 (59) vs. 60 ± 18 (2) | 11 ± 6 vs. 11 ± 8 13 ± 11 vs. 9 ± 6 | ✓ within 24 h | Targeted (LC-MS/MS) | Amino acids and amine | - |
| Amino acids, fatty acids, and phospholipids can potentially be used as sepsis biomarkers | [12] | ||
Fatty acids |
|
| ||||||||
Phospholipids |
|
| ||||||||
56 ± 18 (20) vs. 58 ± 11 (20) | 15 ± 6 vs. N/A | ✓ within 36 h | Targeted (LC-MS and GC-MS) | Phospholipids |
C16:0/20:1, C16:0/20:3
|
C16:0/18:2, C16:0/20:5 | Fatty acids and phospholipids detected in plasma and erythrocytes could signal sepsis vs. non-sepsis | [13] | ||
Erythrocytes ✓ within 36 h | GC-MS | Fatty acids |
DHA (C22:6 n-3) |
| ||||||
Phospholipids |
|
C16:0/20:4, C16:0/20:5
|
Age (Age Range) (Sample Size) | APACH-II Score | Samples Since Admission | Methods | Major Findings in Septic Shock Groups | Interpretation | Citation | |||
---|---|---|---|---|---|---|---|---|---|
Serum | Plasma | Metabolic Pathways | Decreased | Increased | |||||
62 (55–73) (39) vs. 66 (56–71) (20) | 23 (16–31) vs. 14 (13–17) | ✓ within 24 h | Targeted (1H-NMRS) | Amino acids and amines |
|
| Septic shock patients had different patterns in amino acids, fatty acids, and TCA cycle metabolites | [23] | |
Fatty acids | - |
| |||||||
Glycolysis |
|
| |||||||
TCA cycle | - |
| |||||||
62 (56–73) (37) vs. 66 (56–71) (20) | 23 (16–31) vs. 14 (13–17) | ✓ within 24 h | ✓ within 24 h | Targeted (1H- NMRS) | Amino acids and amines |
|
| Septic shock patients had different patterns of metabolites, particularly amino acids | [42] |
Glycolysis |
|
|
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 | - |
| Amino acids and phospholipids could indicate the possibility of death within 48-H in patients with sepsis | [10] | ||
Phospholipids | - |
| |||||||||
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 | - |
| |||||||||
At D1 | |||||||||||
Fatty acids | - |
| |||||||||
- |
| ||||||||||
At D3 | |||||||||||
Fatty acids | - |
| |||||||||
- |
| ||||||||||
At D7 | |||||||||||
Fatty acids | - |
| |||||||||
- |
| ||||||||||
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 | - |
| |||||||||
Fatty acids | - |
| |||||||||
Glycolysis | - |
| |||||||||
TCA cycle | - |
| |||||||||
At H0 | |||||||||||
Fatty acids | - |
| |||||||||
At H24 | |||||||||||
Amino acids and amines | - |
| |||||||||
Fatty acids | - |
| |||||||||
Phospholipids |
| - | |||||||||
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 | - |
| 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 | - |
| |||||||||
Phospholipids |
| - | |||||||||
Glycolysis Aromatic microbial metabolites | - - |
| |||||||||
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 |
|
| |||||||||
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 |
| 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 | - |
| 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 | - |
| Particular metabolites can forecast 28-D mortality in sepsis patients | [64] | ||
Phospholipids |
| - | |||||||||
Glycolysis | - |
| |||||||||
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 | - |
| |||||||||
90-D mortality | 75 ± 13 (30) vs. 71 ± 13 (63) | 9 ± 4 $ vs. 5 ± 4 $ | ✓ D1 | Targeted (UPLC-MS) | Amino acids and amine | - |
| In sepsis patients, 90-D mortality can be expected by phenylalanine and leucine | [65] |
Settings | Age (Age Range) (Sample Size) | APACHE-II Score | Samples Since Admission | Methods | Major Findings in Non-Survivors (NS) | Interpretation | Citation | ||||
---|---|---|---|---|---|---|---|---|---|---|---|
Serum | Plasma | Urine | Metabolic Pathways | Decreased | Increased | ||||||
ICU mortality | 63 (60–77) * (8) * | 26 (18–31) * | ✓ within 24 h | ✓ within 24 h | Targeted (1H-NMRS) | Amino acids and amines |
| - | Non-survivors in septic shock had high levels of 2-Hydrocyiso-valerate and fructose | [42] | |
Fatty acids | - |
| |||||||||
Glycolysis | - |
| |||||||||
24-H mortality | 72 ± 0.4 (30) vs. 69 ± 0.3 (40) | 12 ± 0.6 $ vs. 11 ± 0.7 $ | ✓ H0 and H24 of vaso-pressor initiation | Targeted (1H-NMRS) | At H0; | Non-surviving patients with 24-H septic shock can be forecasted by amino acids, TCA cycle metabolites, and fatty acids pathways | [86] | ||||
Amino acids and amines | - |
| |||||||||
Glycolysis | - |
| |||||||||
TCA cycle | - |
| |||||||||
At H24; | |||||||||||
Amino acids and amines | - |
| |||||||||
Fatty acids | - |
| |||||||||
Glycolysis | - |
| |||||||||
TCA cycle | - |
| |||||||||
∆H24-H0 in nonsurvivors; | |||||||||||
Amino acids and amines | - |
| |||||||||
Glycolysis | - |
| |||||||||
TCA cycle | - |
| |||||||||
Others |
|
| |||||||||
∆H24-H0 in survivors; | |||||||||||
Amino acids and amines |
| - | |||||||||
Glycolysis |
| - | |||||||||
TCA cycle |
| - | |||||||||
7-D mortality | 66 ± 1 (21) vs. 64 ± 1 (29) | 68 ± 2 # vs. 54 ± 2 # | ✓ H0 | Untargeted (UPLC-MS) | Amino acids and amines |
|
| Non-surviving 7-D septic shock patients demonstrated several precise metabolomics signals from amino acids, TCA cycle, fatty acids, and phospholipids pathways | [87] | ||
Fatty acids |
|
| |||||||||
Phospholipids |
|
| |||||||||
Glycolysis |
|
| |||||||||
TCA cycle | - |
| |||||||||
28-D mortality | 70 ± 12 (11) vs. 61 ± 15 (9) | 12 ± 2 vs. 11 ± 2 | ✓ D1 and D7 | Targeted (LC-MS/MS) | At D1 | Long chain PC and LysoPC metabolites had predictive capability for 28-D mortality patients in septic shock | [88] | ||||
Phospholipids |
|
| |||||||||
Glycolysis |
| - | |||||||||
At D7 | |||||||||||
Amino acids and amines | - |
| |||||||||
Phospholipids |
| - | |||||||||
∆D7-D1 comparing between NS vs. S | |||||||||||
↔ vs. ↓ | |||||||||||
Amino acids and amines |
| - | |||||||||
↔ vs. ↑ | ↑ vs. ↑↑ | ||||||||||
Phospholipids |
|
| |||||||||
↓vs. ↔ | |||||||||||
Phospholipids |
| - | |||||||||
28-D mortality | 64 ± 17 (8) vs. 66 ± 14 (9) | D1: 12 ± 3 $ vs. 11 ± 2 $ D7: 9 ± 5 $ vs. 5 ± 2$ | ✓ at Shock Dx | Targeted (LC-MS/MS) | Crude ratio of D7/D1 | The ratios of particular amino acids and phospholipids can determine 28-D mortality in septic shock patients | [89] | ||||
Amino acids and amines | - |
| |||||||||
Phospholipids |
|
| |||||||||
Ratio of D7/D1 discriminated by multivariate analysis | |||||||||||
Amino acids and amines |
|
| |||||||||
Phospholipids |
|
| |||||||||
30-D mortality | 65 (37–79) (12) vs. 60 (24–80) (48) | 21 ± 5 vs. 19 ± 6 | ✓ H0 and H24 | Untargeted (1H-NMRS) | Amino acids and amines |
| - | Particular amino acids, glycolytic metabolites, and alcohol can predict 30-D mortality in septic shock patients | [90] | ||
Glycolysis | - |
| |||||||||
90-D mortality | 70 ± 12 (11) vs. 61 ± 15 (9) | 12 ± 2 vs. 11 ± 2 | ✓ D1 and D7 | Targeted (LC-MS/MS) | At D1 | Long chain PC and LysoPC metabolites had predictive capability for 90-D mortality in septic shock patients | [88] | ||||
Phospholipids |
| - | |||||||||
At D7 | |||||||||||
Phospholipids |
|
| |||||||||
∆D7-D1 comparing between NS vs. S | |||||||||||
↔ vs. ↓ | |||||||||||
Amino acids and amines |
| - | |||||||||
↔ vs. ↑ | ↑ vs. ↑↑ | ||||||||||
Phospholipids |
|
| |||||||||
↔ (↓) vs. ↔ (↑) | |||||||||||
Phospholipids |
| - | |||||||||
1-Y mortality | 69 (61–77) (4) vs. 58 (50–65) (7) | 15 (14–17) $ vs. 14 (9–14) $ | ✓ H0, H24, and H48 after l-carnitine infusion | Untargeted (LC-MS) | Amino acids and amines |
|
| 1-Y mortality in septic shock patients can be determined by certain amino acids, fatty acids, and peptide/short chain proteins | [91] | ||
Fatty acids | - |
|
Settings | Studies Groups | Age (Age Range) (Sample Size) | APACHE- II Score | Samples | Methods | Major Findings in Responder Groups | Interpretation | Citation | |||
---|---|---|---|---|---|---|---|---|---|---|---|
Serum | Plasma | Metabolic Pathway | Decreased | Increased | |||||||
l-carnitine responders vs. placebo in septic shock patients treated with vasopressor | Low ketones vs. High ketones categorized by 3-hydroxy-butyrate (cut-off= 153 μM) | 60 (52–68) (15) vs. 69 (60–74) (15) | 10 (9–14) $ vs. 13 (8–14) $ | ✓ H0, H24, and H48 after l-carnitine infusion | Untargeted (1H-NMRS) | At H24 | Pharmacometa-bolomics can be used to guide responses to l-carnitine treatment | [99] | |||
Amino acids and amines | - |
| |||||||||
Fatty acids |
| - | |||||||||
Glycolysis |
| - | |||||||||
At H48 | |||||||||||
Fatty acids |
| - | |||||||||
Glycolysis |
| - | |||||||||
Characterized response to therapy in patients with septic shock | Response (R) vs. Non-response (NR) to therapy | 67 (61–75) (14) vs. 75 (66–82) (7) | 35 (31–38) vs. 38 (37–39) | ✓ H0 and H48 after resus-citation | Untargeted (LC-MS/MS) | At H0, R vs. NR | Metabolomics from particular pathways including amino acids, fatty acids, phospholipids, and TCA cycle had potential roles for treatment monitoring in patients with septic shock | [100] | |||
Amino acids and amines |
| - | |||||||||
Fatty acids | - |
| |||||||||
Glycolysis |
| - | |||||||||
In R, H48 vs. H0; | |||||||||||
Amino acids and amines |
|
| |||||||||
Fatty acids |
| - | |||||||||
TCA cycle |
| - | |||||||||
In NR, H48 vs. H0; | |||||||||||
Amino acids and amines | - |
| |||||||||
Fatty acids |
| - | |||||||||
Comparing R vs. NR overtime | |||||||||||
↓ vs. ↓↓ | ↓ vs. ↑ | ||||||||||
Fatty acids |
| ||||||||||
Targeted (LC-MS) | In R, H48 vs. H0; | ||||||||||
Amino acids and amines |
|
| |||||||||
Phospholipids | - |
| |||||||||
In NR, H48 vs. H0; | |||||||||||
Amino acids and amines |
|
| |||||||||
Phospholipids |
|
| |||||||||
Comparing R vs. NR overtime; | |||||||||||
↑ vs. ↑↑ | |||||||||||
Amino acid and amines |
| - | |||||||||
↑ vs. ↓ | ↑↑ vs. ↑ | ||||||||||
Phospholipids |
|
| |||||||||
At H48, R vs. NR; | |||||||||||
Amino acids and amines |
|
| |||||||||
Phospholipids | - |
|
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Trongtrakul, K.; Thonusin, C.; Pothirat, C.; Chattipakorn, S.C.; Chattipakorn, N. Past Experiences for Future Applications of Metabolomics in Critically Ill Patients with Sepsis and Septic Shocks. Metabolites 2022, 12, 1. https://doi.org/10.3390/metabo12010001
Trongtrakul K, Thonusin C, Pothirat C, Chattipakorn SC, Chattipakorn N. Past Experiences for Future Applications of Metabolomics in Critically Ill Patients with Sepsis and Septic Shocks. Metabolites. 2022; 12(1):1. https://doi.org/10.3390/metabo12010001
Chicago/Turabian StyleTrongtrakul, Konlawij, Chanisa Thonusin, Chaicharn Pothirat, Siriporn C. Chattipakorn, and Nipon Chattipakorn. 2022. "Past Experiences for Future Applications of Metabolomics in Critically Ill Patients with Sepsis and Septic Shocks" Metabolites 12, no. 1: 1. https://doi.org/10.3390/metabo12010001