Systemic role of orexin A, substance P, bradykinin, and DABK in severe COVID-19 and 2.5-yr follow-ups: an observational study
Background: Orexin A regulates sleep–wake cycles, arousal, and energy homeostasis, linking it to the renin–angiotensin system and substance P. Dysfunction in these pathways occurs in acute and long-term COVID-19, including post-COVID syndrome. Methods: This observational study analysed plasma orexin...
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Elsevier
2025-06-01
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| Series: | BJA Open |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772609625000395 |
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| author | Ulrike Heinicke Steven R. Talbot Filippos Thanasis Elisabeth H. Adam Andreas von Knethen Andrea U. Steinbicker Sebastian Zinn Kai Zacharowski Armin N. Flinspach |
| author_facet | Ulrike Heinicke Steven R. Talbot Filippos Thanasis Elisabeth H. Adam Andreas von Knethen Andrea U. Steinbicker Sebastian Zinn Kai Zacharowski Armin N. Flinspach |
| author_sort | Ulrike Heinicke |
| collection | DOAJ |
| description | Background: Orexin A regulates sleep–wake cycles, arousal, and energy homeostasis, linking it to the renin–angiotensin system and substance P. Dysfunction in these pathways occurs in acute and long-term COVID-19, including post-COVID syndrome. Methods: This observational study analysed plasma orexin A, substance P, bradykinin, and des-Arg9-bradykinin (DABK) in 78 ICU COVID-19 patients, 14 survivors of severe COVID-19 (2.5-yr follow-ups), and 14 healthy controls. Results: During acute COVID-19, bradykinin and substance P were significantly reduced, whereas DABK was elevated compared with healthy controls and 2.5-yr follow-ups. Orexin A concentration correlated with ICU survival (Cohen’s d=0.4), length of stay (LOS; r=–0.26, P=0.02), and sedation concentrations. Intriguingly, substance P plasma concentrations were elevated in 2.5-yr follow-ups. Plasma orexin A, substance P, and bradykinin increased with lower Richmond Agitation–Sedation Score (RASS): a combination of orexin A, substance P, and bradykinin concentrations at RASS –3 to –5 distinguished survivors from non-survivors of COVID-19 when categorised by age. Conclusions: Changes in the bradykinin axis, affecting substance P and orexin A signalling, are associated with severe COVID-19, ICU LOS, and survival. Elevated substance P concentrations in the 2.5-yr follow-up cohort may be associated with physical, cognitive, and neuropsychological impairments commonly seen in post-ICU syndrome and post-COVID syndrome. The predictive values of orexin A, substance P, bradykinin, and DABK and the complex interplay between the renin–angiotensin system and the orexinergic system in severe, critical illnesses or viral diseases will be investigated in future studies. |
| format | Article |
| id | doaj-art-3f53c62df8954188bfeb573eaf51f431 |
| institution | OA Journals |
| issn | 2772-6096 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | BJA Open |
| spelling | doaj-art-3f53c62df8954188bfeb573eaf51f4312025-08-20T02:05:11ZengElsevierBJA Open2772-60962025-06-011410041510.1016/j.bjao.2025.100415Systemic role of orexin A, substance P, bradykinin, and DABK in severe COVID-19 and 2.5-yr follow-ups: an observational studyUlrike Heinicke0Steven R. Talbot1Filippos Thanasis2Elisabeth H. Adam3Andreas von Knethen4Andrea U. Steinbicker5Sebastian Zinn6Kai Zacharowski7Armin N. Flinspach8Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany; Corresponding author.Institute for Laboratory Animal Science, Hannover Medical School, Hannover, GermanyDepartment of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, GermanyDepartment of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, GermanyDepartment of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, GermanyDepartment of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, GermanyDepartment of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany; Columbia University Medical Center, Department of Anesthesiology, New York, NY, USADepartment of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany; Fraunhofer – Institute for Translational Medicine and Pharmacology (ITMP), Frankfurt am Main, GermanyDepartment of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, GermanyBackground: Orexin A regulates sleep–wake cycles, arousal, and energy homeostasis, linking it to the renin–angiotensin system and substance P. Dysfunction in these pathways occurs in acute and long-term COVID-19, including post-COVID syndrome. Methods: This observational study analysed plasma orexin A, substance P, bradykinin, and des-Arg9-bradykinin (DABK) in 78 ICU COVID-19 patients, 14 survivors of severe COVID-19 (2.5-yr follow-ups), and 14 healthy controls. Results: During acute COVID-19, bradykinin and substance P were significantly reduced, whereas DABK was elevated compared with healthy controls and 2.5-yr follow-ups. Orexin A concentration correlated with ICU survival (Cohen’s d=0.4), length of stay (LOS; r=–0.26, P=0.02), and sedation concentrations. Intriguingly, substance P plasma concentrations were elevated in 2.5-yr follow-ups. Plasma orexin A, substance P, and bradykinin increased with lower Richmond Agitation–Sedation Score (RASS): a combination of orexin A, substance P, and bradykinin concentrations at RASS –3 to –5 distinguished survivors from non-survivors of COVID-19 when categorised by age. Conclusions: Changes in the bradykinin axis, affecting substance P and orexin A signalling, are associated with severe COVID-19, ICU LOS, and survival. Elevated substance P concentrations in the 2.5-yr follow-up cohort may be associated with physical, cognitive, and neuropsychological impairments commonly seen in post-ICU syndrome and post-COVID syndrome. The predictive values of orexin A, substance P, bradykinin, and DABK and the complex interplay between the renin–angiotensin system and the orexinergic system in severe, critical illnesses or viral diseases will be investigated in future studies.http://www.sciencedirect.com/science/article/pii/S2772609625000395acute respiratory distress syndromedeep sedationdes-Arg9-bradykininintensive care unitorexin Apost-acute COVID-19 syndrome |
| spellingShingle | Ulrike Heinicke Steven R. Talbot Filippos Thanasis Elisabeth H. Adam Andreas von Knethen Andrea U. Steinbicker Sebastian Zinn Kai Zacharowski Armin N. Flinspach Systemic role of orexin A, substance P, bradykinin, and DABK in severe COVID-19 and 2.5-yr follow-ups: an observational study BJA Open acute respiratory distress syndrome deep sedation des-Arg9-bradykinin intensive care unit orexin A post-acute COVID-19 syndrome |
| title | Systemic role of orexin A, substance P, bradykinin, and DABK in severe COVID-19 and 2.5-yr follow-ups: an observational study |
| title_full | Systemic role of orexin A, substance P, bradykinin, and DABK in severe COVID-19 and 2.5-yr follow-ups: an observational study |
| title_fullStr | Systemic role of orexin A, substance P, bradykinin, and DABK in severe COVID-19 and 2.5-yr follow-ups: an observational study |
| title_full_unstemmed | Systemic role of orexin A, substance P, bradykinin, and DABK in severe COVID-19 and 2.5-yr follow-ups: an observational study |
| title_short | Systemic role of orexin A, substance P, bradykinin, and DABK in severe COVID-19 and 2.5-yr follow-ups: an observational study |
| title_sort | systemic role of orexin a substance p bradykinin and dabk in severe covid 19 and 2 5 yr follow ups an observational study |
| topic | acute respiratory distress syndrome deep sedation des-Arg9-bradykinin intensive care unit orexin A post-acute COVID-19 syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S2772609625000395 |
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