Background Early diagnosis of shock is a predetermining factor for a good prognosis in intensive care. An elevated central venous to arterial PCO 2 difference (PCO 2) over 0.8 kPa (6 mm Hg) is indicative of low blood flow states. Disturbances around the time of blood sampling could result in inaccurate calculations of PCO 2, thereby misrepresenting the patient status. This study aimed to determine the influences of acute changes in ventilation on PCO 2 and understand its clinical implications. Methods To investigate the isolated effects of changes in ventilation on PCO 2, eight pigs were studied in a prospective observational cohort. Arterial and central venous catheters were inserted following anaesthetisation. Baseline ventilator settings were titrated to achieve an EtCO 2 of 5±0.5 kPa (V T = 8 mL/kg, Freq = 14 ± 2/min). Blood was sampled simultaneously from both catheters at baseline and 30, 60, 90, 120, 180 and 240 s after a change in ventilation. Pigs were subjected to both hyperventilation and hypoventilation, wherein the respiratory frequency was doubled or halved from baseline. PCO 2 changes from baseline were analysed using repeated measures ANOVA with post-hoc analysis using Bonferroni's correction. Results PCO 2 at baseline for all pigs was 0.76±0.29 kPa (5.7±2.2 mm Hg). Following hyperventilation, there was a rapid increase in the PCO 2, increasing maximally to 1.35±0.29 kPa (10.1±2.2 mm Hg). A corresponding decrease in the PCO 2 was seen following hypoventilation, decreasing maximally to 0.23±0.31 kPa (1.7±2.3 mm Hg). These changes were statistically significant from baseline 30 s after the change in ventilation. Conclusion Disturbances around the time of blood sampling can rapidly affect the PCO 2, leading to inaccurate calculations of the PCO 2, resulting in misinterpretation of patient status. Care should be taken when interpreting blood gases, if there is doubt as to the presence of acute and transient changes in ventilation.