Carbon dioxide (CO2) is the “waste product” of aerobic respiration. In health, arterial carbon dioxide tension (PaCO2) is tightly regulated, with minute ventilation potently enhanced in response to small elevations in CO2 tension. In critical illness its role is becoming better understood; indeed, in survivors of cardiac arrest, elevated CO2 is associated with a higher incidence of reported near-death experiences.1 Although usually well tolerated, hypercapnia traditionally has been considered to be an adverse event. In fact, the extent and severity of acidosis are predictive of adverse outcome in diverse clinical contexts, including cardiac arrest,2,3 sepsis,4–6 and in neonatal practice.7 Traditional approaches to CO2 management in the operating room and for patients with acute respiratory failure generally focused on the deleterious effects of hypercapnia, traditionally targeting therefore normocapnia or even hypocapnia.
This approach, however, has been increasingly questioned. The potential for high tidal volumes to injure the lung directly, a phenomenon termed ventilator-induced lung injury, is clear from experimental8,9 and clinical10–14 studies. Current “protective” ventilator strategies mandate lower tidal volumes (VT), and generally necessitate hypoventilation and tolerance of hypercapnia. This “permissive hypercapnia” has been accepted progressively in critical care for adult, pediatric, and neonatal patients requiring mechanical ventilation.
The potential for mechanical ventilation to contribute to lung and systemic organ injury and to worsen outcome in patients with the acute respiratory distress syndrome (ARDS) is clear. The use of high VT may cause injury via several mechanisms.8,9 Increased mechanical stress may activate the cellular and humoral immune response directly in the lung.8,15–17 Intrapulmonary mediators and pathogens, such as prostaglandins,18 cytokines,19 endotoxins,20 and bacteria,21 have been demonstrated to access the systemic circulation following high-stretch mechanical ventilation. The demonstration that mechanical ventilation may cause systemic organ dysfunction in animal models could explain in part the high rate of multiorgan failure in ARDS.22 In current practice, hypercapnia is tolerated as the lesser of two evils so as to realize the benefits of lower tidal volumes.23,24
Conventionally, the protective effect of ventilator strategies incorporating permissive hypercapnia is solely secondary to lower tidal volume, with hypercapnia being permitted so as to achieve this goal. Protective ventilator strategies that involve hypoventilation cause both limitation of lung stretch and elevation of arterial PCO2; thus, low tidal volume is distinct from elevated PCO2 and, by manipulation of respiratory variables (frequency, VT, dead space, and inspired CO2), can to some extent be controlled separately.
If hypercapnia were proven to have independent benefit, then deliberately elevating PaCO2, termed therapeutic hypercapnia, might provide an additional advantage over reducing VT...