Bench-to-bedside review: hypercapnic acidosis in lung injury--from 'permissive' to 'therapeutic'

Abstract

Modern ventilation strategies for patients with acute lung injury and acute respiratory distress syndrome frequently result in hypercapnic acidosis (HCA), which is regarded as an acceptable side effect ('permissive hypercapnia'). Multiple experimental studies have demonstrated advantageous effects of HCA in several lung injury models. To date, however, human trials studying the effect of carbon dioxide per se on outcome in patients with lung injury have not been performed. While significant concerns regarding HCA remain, in particular the possible unfavorable effects on bacterial killing and the inhibition of pulmonary epithelial wound repair, the potential for HCA in attenuating lung injury is promising. The underlying mechanisms by which HCA exerts its protective effects are complex, but dampening of the inflammatory response seems to play a pivotal role. After briefly summarizing the physiological effects of HCA, a critical analysis of the available evidence on the potential beneficial effects of therapeutic HCA from in vitro, ex vivo and in vivo lung injury models and from human studies will be reviewed. In addition, the potential concerns in the clinical setting will be outlined.

Figure 1

Modulating effect of hypercapnic acidosis on the inflammatory response. NF-κB can be activated by multiple stimuli, such as endotoxin (lipopolysaccharide), reactive oxygen species (ROS) and cytokines (IL-1β and TNF-α). Subsequently, phosphorylation of IκB (inhibitory proteins κB) occurs followed by its degradation, allowing NF-κB to be transported to the cell nucleus where it binds to specific promoter sites and activates transcription of target genes. Following activation of NF-κB, both intra- and extracellular feedback mechanism will subsequently regulate NF-κB activation, with IL-1β and TNF-α providing positive extracellular feedback. The potential mechanism by which hypercapnic acidosis (HCA) inhibits NF-κB activation appears to involve suppression of the degradation of IκB-α. Subsequently, this will result in suppressed production of IL-1β, IL-6, IL-8 and TNF-α. Suppression of intercellular adhesion molecule (ICAM)-1 and IL-8 will subsequently lead to inhibition of neutrophil adherence. HCA may also offer protection against ROS-mediated lung injury by inhibiting xanthine oxidase (XO).

Figure 2

Effect of hypercapnic acidosis on lung tissue cytokines in ventilated mice. Effect of 2 hours of normo- and hypercapnic mechanical ventilation on ventilation-induced lung tissue cytokine release using identical ventilator settings. *P <0.05 versus control; ⁺P <0.05, 0.06% CO₂ versus 2% CO₂ versus 4% CO₂. KC, keratinocyte-derived chemokine. This figure is reproduced with permission of the publisher. (Halbertsma FJ, Vaneker M, Pickkers P, et al. Hypercapnic acidosis attenuates the pulmonary innate immune response in ventilated healthy mice. Crit Care Med 2008, 36:2403-2406.).