Combined effects of HCRTR1/2 gene variants and non-genetic factors on sleep-wake transition and hemodynamic stability during propofol, dexmedetomidine, and remifentanil anesthesia.

1. Pharmacol Rep. 2025 Aug;77(4):1050-1062. doi: 10.1007/s43440-025-00740-7. Epub 2025 May 29. Combined effects of HCRTR1/2 gene variants and non-genetic factors on sleep-wake transition and hemodynamic stability during propofol, dexmedetomidine, and remifentanil anesthesia. Zheng Z(#)(1)(2)(3)(4), Xue F(#)(5), Wang H(#)(6), Gu Q(1)(2), Hu R(5), Li X(3)(4), Huang M(1)(2), Huang W(5), Wang Z(7), Li J(8)(9). Author information: (1)Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan Dong Road, Guangzhou, Guangdong, 510006, China. (2)Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China. (3)Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. (4)Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. (5)Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, Guangdong, 510080, China. (6)Department of Pharmacy, Shenzhen Second People's Hospital, Shenzhen, Guangdong, China. (7)Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, Guangdong, 510080, China. wzhxing@mail.sysu.edu.cn. (8)Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan Dong Road, Guangzhou, Guangdong, 510006, China. lijiali5@mail.sysu.edu.cn. (9)Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China. lijiali5@mail.sysu.edu.cn. (#)Contributed equally BACKGROUND: Propofol-remifentanil-dexmedetomidine-based total intravenous anesthesia is widely utilized in clinical practice. However, maintaining safety during the sleep-wake transition and ensuring hemodynamic stability continues to pose significant challenges. This study aimed to investigate the impact of genes that are expressed specifically in orexinergic neurons on interindividual variability in the time to loss of consciousness (LOC), time to wake, and cardiovascular fluctuations. METHODS: A total of 250 patients were included in the study. Gene polymorphisms were detected using the Agena Bioscience MassARRAY system. Anesthesia induction began with propofol and was maintained with propofol and remifentanil. Dexmedetomidine was administered before anesthesia induction. The time to LOC, time to wake, heart rate (HR), and mean arterial pressure (MAP) were documented. RESULTS: HCRTR2 (Hypocretin receptor 2) rs2292040 and rs76380807 were significantly associated with the time to LOC, and HCRTR2 rs7774031 was correlated with the time to wake. HCRTR2 rs3122162, rs3122169, and rs74296544 were correlated with HR fluctuations, and HCRTR1 (Hypocretin receptor 1) rs2176807, rs2271933, rs871634, and HCRTR2 rs74296544 were associated with MAP fluctuations. Multiple linear regression analysis revealed that the Target-controlled infusion (TCI) plasma concentration (Cp) of propofol > 4 µg ml- 1 at the time of LOC and dexmedetomidine were influencing factors for the time to LOC, whereas HCRTR2 rs7774031 influenced the time to wake. Baseline HR, baseline MAP, dexmedetomidine, HCRTR2 rs3122162, and HCRTR1 rs2176807 were predictive factors for cardiovascular susceptibility. The predictive models for the time to LOC, time to wake, mean HR, and mean MAP fluctuations accounted for 41.89%, 3.36%, 35.56%, and 47.41% of variations, respectively. CONCLUSIONS: Genetic variants of HCRTR1 and HCRTR2 may affect sleep-wake transition and hemodynamic stability during propofol, dexmedetomidine, and remifentanil anesthesia. © 2025. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences. DOI: 10.1007/s43440-025-00740-7 PMID: 40439868 [Indexed for MEDLINE] Conflict of interest statement: Declarations. Competing interests: The authors declare no competing interests.