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

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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 (RR EIT ) and tidal impedance variation (TIV)) for ventilation, blood gas analysis and venous admixture for pulmonary gas exchange, oxygen delivery (DO 2 ) 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 RR EIT ( 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 (F 3,90 = 104.82, p < 0.001) were observed across treatments during immobilisation, resulting in persistently reduced DO 2 (F 3,84 = 51.55, p < 0.001) and increased ER (F 3,90 = 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 DO 2 , 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.

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