Publication date: Jun 01, 2025

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. This observational study analysed plasma orexin A, substance P, bradykinin, and des-Arg-bradykinin (DABK) in 78 ICU COVID-19 patients, 14 survivors of severe COVID-19 (2. 5-yr follow-ups), and 14 healthy controls. 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. 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.

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