Cerebrospinal fluid metabolic profiling reveals divergent modulation of pentose phosphate pathway by midazolam, propofol and dexmedetomidine in patients with subarachnoid hemorrhage: a cohort study
Abstract Background Agitation is common in subarachnoid hemorrhage (SAH), and sedation with midazolam, propofol and dexmedetomidine is essential in agitation management. Previous research shows the tendency of dexmedetomidine and propofol in improving long-term outcome of SAH patients, whereas midaz...
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| Format: | Article |
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BMC
2022-01-01
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| Series: | BMC Anesthesiology |
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| Online Access: | https://doi.org/10.1186/s12871-022-01574-z |
| _version_ | 1819231255363846144 |
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| author | Yi-Chen Li Rong Wang Ji-Ye A Run-Bin Sun Shi-Jie Na Tao Liu Xuan-Sheng Ding Wei-Hong Ge |
| author_facet | Yi-Chen Li Rong Wang Ji-Ye A Run-Bin Sun Shi-Jie Na Tao Liu Xuan-Sheng Ding Wei-Hong Ge |
| author_sort | Yi-Chen Li |
| collection | DOAJ |
| description | Abstract Background Agitation is common in subarachnoid hemorrhage (SAH), and sedation with midazolam, propofol and dexmedetomidine is essential in agitation management. Previous research shows the tendency of dexmedetomidine and propofol in improving long-term outcome of SAH patients, whereas midazolam might be detrimental. Brain metabolism derangement after SAH might be interfered by sedatives. However, how sedatives work and whether the drugs interfere with patient outcome by altering cerebral metabolism is unclear, and the comprehensive view of how sedatives regulate brain metabolism remains to be elucidated. Methods For cerebrospinal fluid (CSF) and extracellular space of the brain exchange instantly, we performed a cohort study, applying CSF of SAH patients utilizing different sedatives or no sedation to metabolomics. Baseline CSF metabolome was corrected by selecting patients of the same SAH and agitation severity. CSF components were analyzed to identify the most affected metabolic pathways and sensitive biomarkers of each sedative. Markers might represent the outcome of the patients were also investigated. Results Pentose phosphate pathway was the most significantly interfered (upregulated) pathway in midazolam (p = 0.0000107, impact = 0.35348) and propofol (p = 0.00000000000746, impact = 0.41604) groups. On the contrary, dexmedetomidine decreased levels of sedoheptulose 7-phosphate (p = 0.002) and NADP (p = 0.024), and NADP is the key metabolite and regulator in pentose phosphate pathway. Midazolam additionally augmented purine synthesis (p = 0.00175, impact = 0.13481) and propofol enhanced pyrimidine synthesis (p = 0.000203, impact = 0.20046), whereas dexmedetomidine weakened pyrimidine synthesis (p = 0.000000000594, impact = 0.24922). Reduced guanosine diphosphate (AUC of ROC 0.857, 95%CI 0.617–1, p = 0.00506) was the significant CSF biomarker for midazolam, and uridine diphosphate glucose (AUC of ROC 0.877, 95%CI 0.631–1, p = 0.00980) for propofol, and succinyl-CoA (AUC of ROC 0.923, 95%CI 0.785–1, p = 0.000810) plus adenosine triphosphate (AUC of ROC 0.908, 95%CI 0.6921, p = 0.00315) for dexmedetomidine. Down-regulated CSF succinyl-CoA was also associated with favorable outcome (AUC of ROC 0.708, 95% CI: 0.524–0.865, p = 0.029333). Conclusion Pentose phosphate pathway was a crucial target for sedatives which alter brain metabolism. Midazolam and propofol enhanced the pentose phosphate pathway and nucleotide synthesis in poor-grade SAH patients, as presented in the CSF. The situation of dexmedetomidine was the opposite. The divergent modulation of cerebral metabolism might further explain sedative pharmacology and how sedatives affect the outcome of SAH patients. |
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| language | English |
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| spelling | doaj.art-3f1278d148c24f428cc387fda1633aa42022-12-21T17:48:26ZengBMCBMC Anesthesiology1471-22532022-01-0122111210.1186/s12871-022-01574-zCerebrospinal fluid metabolic profiling reveals divergent modulation of pentose phosphate pathway by midazolam, propofol and dexmedetomidine in patients with subarachnoid hemorrhage: a cohort studyYi-Chen Li0Rong Wang1Ji-Ye A2Run-Bin Sun3Shi-Jie Na4Tao Liu5Xuan-Sheng Ding6Wei-Hong Ge7Department of Pharmacy, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical SchoolDepartment of Neurosurgery, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical SchoolKey Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityKey Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityDepartment of Neurosurgery, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical SchoolDepartment of Neurosurgery, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical SchoolDepartment of Basic Medicine and Clinical Pharmacy, China Pharmaceutical UniversityDepartment of Pharmacy, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical SchoolAbstract Background Agitation is common in subarachnoid hemorrhage (SAH), and sedation with midazolam, propofol and dexmedetomidine is essential in agitation management. Previous research shows the tendency of dexmedetomidine and propofol in improving long-term outcome of SAH patients, whereas midazolam might be detrimental. Brain metabolism derangement after SAH might be interfered by sedatives. However, how sedatives work and whether the drugs interfere with patient outcome by altering cerebral metabolism is unclear, and the comprehensive view of how sedatives regulate brain metabolism remains to be elucidated. Methods For cerebrospinal fluid (CSF) and extracellular space of the brain exchange instantly, we performed a cohort study, applying CSF of SAH patients utilizing different sedatives or no sedation to metabolomics. Baseline CSF metabolome was corrected by selecting patients of the same SAH and agitation severity. CSF components were analyzed to identify the most affected metabolic pathways and sensitive biomarkers of each sedative. Markers might represent the outcome of the patients were also investigated. Results Pentose phosphate pathway was the most significantly interfered (upregulated) pathway in midazolam (p = 0.0000107, impact = 0.35348) and propofol (p = 0.00000000000746, impact = 0.41604) groups. On the contrary, dexmedetomidine decreased levels of sedoheptulose 7-phosphate (p = 0.002) and NADP (p = 0.024), and NADP is the key metabolite and regulator in pentose phosphate pathway. Midazolam additionally augmented purine synthesis (p = 0.00175, impact = 0.13481) and propofol enhanced pyrimidine synthesis (p = 0.000203, impact = 0.20046), whereas dexmedetomidine weakened pyrimidine synthesis (p = 0.000000000594, impact = 0.24922). Reduced guanosine diphosphate (AUC of ROC 0.857, 95%CI 0.617–1, p = 0.00506) was the significant CSF biomarker for midazolam, and uridine diphosphate glucose (AUC of ROC 0.877, 95%CI 0.631–1, p = 0.00980) for propofol, and succinyl-CoA (AUC of ROC 0.923, 95%CI 0.785–1, p = 0.000810) plus adenosine triphosphate (AUC of ROC 0.908, 95%CI 0.6921, p = 0.00315) for dexmedetomidine. Down-regulated CSF succinyl-CoA was also associated with favorable outcome (AUC of ROC 0.708, 95% CI: 0.524–0.865, p = 0.029333). Conclusion Pentose phosphate pathway was a crucial target for sedatives which alter brain metabolism. Midazolam and propofol enhanced the pentose phosphate pathway and nucleotide synthesis in poor-grade SAH patients, as presented in the CSF. The situation of dexmedetomidine was the opposite. The divergent modulation of cerebral metabolism might further explain sedative pharmacology and how sedatives affect the outcome of SAH patients.https://doi.org/10.1186/s12871-022-01574-zSubarachnoid hemorrhageSedationMidazolamPropofolDexmedetomidineMetabolomics |
| spellingShingle | Yi-Chen Li Rong Wang Ji-Ye A Run-Bin Sun Shi-Jie Na Tao Liu Xuan-Sheng Ding Wei-Hong Ge Cerebrospinal fluid metabolic profiling reveals divergent modulation of pentose phosphate pathway by midazolam, propofol and dexmedetomidine in patients with subarachnoid hemorrhage: a cohort study BMC Anesthesiology Subarachnoid hemorrhage Sedation Midazolam Propofol Dexmedetomidine Metabolomics |
| title | Cerebrospinal fluid metabolic profiling reveals divergent modulation of pentose phosphate pathway by midazolam, propofol and dexmedetomidine in patients with subarachnoid hemorrhage: a cohort study |
| title_full | Cerebrospinal fluid metabolic profiling reveals divergent modulation of pentose phosphate pathway by midazolam, propofol and dexmedetomidine in patients with subarachnoid hemorrhage: a cohort study |
| title_fullStr | Cerebrospinal fluid metabolic profiling reveals divergent modulation of pentose phosphate pathway by midazolam, propofol and dexmedetomidine in patients with subarachnoid hemorrhage: a cohort study |
| title_full_unstemmed | Cerebrospinal fluid metabolic profiling reveals divergent modulation of pentose phosphate pathway by midazolam, propofol and dexmedetomidine in patients with subarachnoid hemorrhage: a cohort study |
| title_short | Cerebrospinal fluid metabolic profiling reveals divergent modulation of pentose phosphate pathway by midazolam, propofol and dexmedetomidine in patients with subarachnoid hemorrhage: a cohort study |
| title_sort | cerebrospinal fluid metabolic profiling reveals divergent modulation of pentose phosphate pathway by midazolam propofol and dexmedetomidine in patients with subarachnoid hemorrhage a cohort study |
| topic | Subarachnoid hemorrhage Sedation Midazolam Propofol Dexmedetomidine Metabolomics |
| url | https://doi.org/10.1186/s12871-022-01574-z |
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