Hypercapnia in the critically ill: insights from the bench to the bedside

Carbon dioxide (CO₂) has long been considered, at best, a waste by-product of metabolism, and at worst, a toxic molecule with serious health consequences if physiological concentration is dysregulated. However, clinical observations have revealed that 'permissive' hypercapnia, the deliberate allowance of respiratory produced CO₂ to remain in the patient, can have anti-inflammatory effects that may be beneficial in certain circumstances. In parallel, studies at the cell level have demonstrated the profound effect of CO₂ on multiple diverse signalling pathways, be it the effect from CO₂ itself specifically or from the associated acidosis it generates. At the whole organism level, it now appears likely that there are many biological sensing systems designed to respond to CO₂ concentration and tailor respiratory and other responses to atmospheric or local levels. Animal models have been widely employed to study the changes in CO₂ levels in various disease states and also to what extent permissive or even directly delivered CO₂ can affect patient outcome. These findings have been advanced to the bedside at the same time that further clinical observations have been elucidated at the cell and animal level. Here we present a synopsis of the current understanding of how CO₂ affects mammalian biological systems, with a particular emphasis on inflammatory pathways and diseases such as lung specific or systemic sepsis. We also explore some future directions and possibilities, such as direct control of blood CO₂ levels, that could lead to improved clinical care in the future.