Abstract
Background
Etorphine, a highly potent opioid, disrupts multiple steps of the oxygen cascade, including alveolar ventilation, pulmonary gas exchange, systemic oxygen transport, and tissue-level oxygen utilisation, resulting in hypoxaemia and cellular hypoxia during immobilisation of wild ungulates. To evaluate potential mitigating agents, a randomised, prospective, controlled crossover design was used in etorphine-immobilised sheep (0.05 mg·kg−1, intramuscularly, n = 6). After etorphine administration, animals received either the serotonergic agonist BIMU-8 (1.5 mg·kg−1), the alpha-2 adrenoceptor antagonist vatinoxan (0.15 mg·kg−1), or sterile water (control) intravenously with a four-week washout period. Immobilisation was reversed with naltrexone 19 min after treatment administration. Sequential steps of the oxygen cascade were assessed using thoracic electrical impedance-derived variables (respiratory rate (RREIT) and tidal impedance variation (TIV)) for ventilation, blood gas analysis and venous admixture for pulmonary gas exchange, oxygen delivery (DO2) for oxygen transport, and oxygen extraction ratio (ER) for tissue oxygen utilisation. Measurements were obtained at baseline, after etorphine administration, at five-minute intervals following treatment, and after naltrexone. Data was analysed using linear mixed-effects models.
Results
Etorphine induced respiratory depression, characterised by reduced RREIT (p < 0.001) and TIV (p = 0.01), and impaired gas exchange, indicated by increased venous admixture (p < 0.001) compared with baseline, causing hypercapnia and hypoxaemia in all treatments. Neither BIMU-8 nor vatinoxan improved these variables compared with the control. Consequently, progressive decreases in arterial partial pressure of oxygen (F3,90 = 104.82, p < 0.001) were observed across treatments during immobilisation, resulting in persistently reduced DO2 (F3,84 = 51.55, p < 0.001) and increased ER (F3,90 = 8.09, p < 0.001) at similar levels in all treatments. All variables normalised after naltrexone administration.
Conclusions
Etorphine profoundly impaired multiple sequential steps of the oxygen cascade in sheep, resulting in hypoxaemia, reduced DO2, and compensatory increases in ER. BIMU-8 and vatinoxan did not effectively mitigate these disturbances at any level of the cascade compared with the control. Future research is needed to develop targeted strategies that address the key mechanisms underlying the disruptions in the oxygen cascade during etorphine immobilisation.
Abbreviations
- PBC:
-
Pre-Bötzinger complex
- PaO2 :
-
Arterial partial pressure of oxygen
- CO:
-
Cardiac output
- DO2 :
-
Oxygen delivery
- VO2 :
-
Oxygen consumption
- ER:
-
Oxygen extraction ratio
- 5-HT4:
-
5-hydroxytryptamine 4
- CaO2 :
-
Arterial oxygen content
- EIT:
-
Electrical impedance tomography
- RREIT :
-
Respiratory rate
- TIV:
-
Tidal impedance variation
- BL:
-
Baseline
- PE:
-
Post-etorphine
- PT:
-
Post-treatment
- PN:
-
Post-naltrexone
- AU:
-
Arbitrary units
- TIVMIN :
-
Minute tidal impedance variation
- PaCO2 :
-
Arterial partial pressure of carbon dioxide
- △Z:
-
Total impedance change
- Qs/Qt:
-
Venous admixture
- SaO2 :
-
Arterial oxygen saturation
- SvO2 :
-
Mixed venous oxygen saturation
- CvO2 :
-
Mixed venous oxygen content
Acknowledgements
We would like to thank Dr. Giovannini and Boehringer Ingelheim for the generous provision of the protocol for the synthesis of BIMU-8, and the Institute of Chemistry of Renewable Resources, BOKU University, Vienna for providing the infrastructure required for the synthesis of BIMU-8 and Magdaléna Labíková for synthesis BIMU-8. We would also like to thank Vetcare Ltd, Finland for providing vatinoxan; and the Equine University Clinic of the Vetmeduni Vienna for providing the infrastructure for the experiments and Manuela Habe, Peter Steiger and Viola Bouvier for their animal training and animal husbandry; We furthermore thank Lisa Ebenhofer, Cosima Gösele and Lisa Stahl for their contribution to the experimental work in the course of their diploma theses. We would also like to thank Felix Knauer for his statistical support.
Funding
This work was funded by a scholarship of the Chulabhorn Royal Academy, Bangkok, Thailand. The funding institution played no role in the study design or reporting of the study.
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All procedures were approved by the Ethics and Animal Welfare Committee of the University of Veterinary Medicine, Vienna in accordance with the University’s guidelines for Good Scientific Practice and authorized by the Austrian Federal Ministry of Education, Science and Research (BMBWF 2023 − 0.276.137) in accordance with current legislation. The study was conducted and reported in accordance with the ARRIVE (2.0) guidelines.
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Rattanathanya, H., Binetti, A., Pohlin, F. et al. Effects of a selective 5-HT4 agonist and an alpha-2 adrenoceptor antagonist on etorphine-induced impairment across the oxygen cascade in immobilised sheep (Ovis aries): a randomised, prospective, and controlled trial. BMC Vet Res (2026). https://doi.org/10.1186/s12917-026-05790-4
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DOI: https://doi.org/10.1186/s12917-026-05790-4