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Background: In mammals, homeostasis and survival are dependent on effective trans-membrane movement of ions and enzyme function, which are labile to extreme acid-base changes, but operate efficiently within a narrow regulated pH range. Research in patients demonstrating a pH shifts outside the narrow regulated range decreased the cardiac output and systemic vascular resistance and altered the oxygen binding to haemoglobin. These cardiopulmonary observations may be applicable to the risks associated with anaesthesia and performance of wildlife ungulates on game farms. The aim of this study was to compare blood pH changes over time in impala immobilised and anaesthetised with two different drug protocols (P-TMP - immobilisation: thiafentanil-medetomidine; maintenance: propofol-ketamine-medetomidine; P-EME - immobilisation: etorphine-medetomidine; maintenance: etorphine-ketamine-medetomidine). Additionally, we discuss the resultant blood pH using both the Henderson-Hasselbalch and the Stewart approaches. Two data collection time points were defined, Time1 before maintenance of general anaesthesia and Time 2 at end of maintenance of general anaesthesia. We hypothesise that blood pH would not be different between drug protocols and would not change over time., Results: Significant differences were detected over time but not between the two drug protocols. Overall, the blood pH decreased over time from 7.37 ± 0.04 to 7.31 ± 0.05 (p = 0.001). Overall, over time arterial partial pressure of carbon dioxide changed from 51.3 ± 7.5 mmHg to 72.6 ± 12.4 mmHg (p < 0.001); strong ion difference from 44.6 ± 2.4 mEq/L to 46.9 ± 3.1 mEq/L (p < 0.001); anion gap from 15.0 ± 3.1 mEq/L to 10.9 ± 2.2 mEq/L (p < 0.001); and total weak acids from 16.1 ± 1.2 mmol/L to 14.0 ± 1.1 mmol/L (p < 0.001). The bicarbonate changed from 29.6 ± 2.7 mEq/L to 36.0 ± 4.1 mEq/L (p < 0.001); and lactate changed from 2.9 ± 1.5 mEq/L to 0.3 ± 0.03 mEq/L (p < 0.001) over time., Conclusions: The profound increase in the partial pressure of carbon dioxide that worsened during the total intravenous anaesthesia in both protocols initiated a substantial metabolic compensatory response to prevent severe acidaemia. This compensation resulted in a clinically acceptable mild acidaemic state, which worsened over time but not between the protocols, in healthy impala. However, these important compensatory mechanisms require normal physiological function and therefore when immobilising ill or anorexic wild ungulates their acid-base status should be carefully assessed.