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Therapeutic hypercapnia (TH), an intentional inhalation of CO(2), has been shown to improve pulmonary function in certain models of lung injury. We tested the null hypothesis that TH does not improve hyperoxic lung injury in neonatal rats. The prospective, randomized study was set at Research laboratory in Children's Hospital. Forty-five newborn rats were randomly assigned to three groups (n = 15/group), and exposed to 96 h of normoxia (FiO(2) = 0.21), hyperoxia (FiO(2) > 0.98), and TH (FiO(2) = 0.95, FiCO(2) = 0.05). Lung histology, wet-weight to dry-weight ratio, and concentrations of pro- and anti-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha, and IL-10) were used to evaluate pulmonary damage. Using a scale of 0-4, the total scores for lungs hypercellularity, inflammation, and hemorrhage was significantly increased from a median value of 1.5 in normoxia to 2.5 in hyperoxia (P < 0.05) and 3.0 with TH (P < 0.001, nonparametric ANOVA). The interstitial space relative to the alveolar space, as a measure of hypercellularity, was increased by 18% during hyperoxia and by 44% with TH compared with normoxia. TH significantly increased the size of the interstitial space by 22% compared with hyperoxia (P < 0.001). The lung wet-weight to dry-weight ratio was increased by 10% in both hyperoxic groups (P < 0.001). Both hyperoxic groups showed significant reductions in the concentration of IL-1beta compared with normoxia (P < 0.001), whereas the ratio of IL-1beta to IL-10 was significantly decreased, indicating an anti-inflammatory trend. TH does not prevent histological manifestations of hyperoxic lung injury in spontaneously breathing neonatal rats and may worsen the outcome.

Objectives: Hypercapnia is known to modulate inflammation in lungs. However, the effect of hypocapnia and hypercapnia on blood cytokine production during sepsis is not well understood. We hypothesized that CO2 modulates ex vivo inflammatory cytokine production during endotoxin stimulation. To test this hypothesis, we measured the production of pro- and anti-inflammatory cytokines in endotoxin-stimulated human whole blood cultures under hypercapnic, normocapnic, and hypocapnic conditions., Design: Prospective randomized study., Setting: Basic research laboratory., Subjects: Ten male and 10 female volunteers., Interventions: Venous blood samples, taken from volunteers were cultured at 37 degrees C, under hypocapnic (2% CO2), normocapnic (5% CO2), and hypercapnic (7% CO2) conditions, with and without endotoxin stimulation. After 24 hrs of incubation, each culture's supernatant was analyzed for tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interleukin-10, and interferon-gamma concentrations by enzyme-linked immunosorbent assay. Data were analyzed using nonparametric repeated measures of analysis of variance followed by Dunn's multiple comparisons test. Analysis of variance with Bonferroni correction was used to compare gender differences in cytokine concentrations. The Pearson test was used to estimate correlation between hydrogen ion and individual cytokine concentrations., Measurements and Main Results: Concentrations of the proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta and of the anti-inflammatory cytokine interleukin-10 under hypercapnic condition were significantly decreased (p < 0.05, 0.01, and 0.001, respectively) for both genders when compared with either normocapnic or hypocapnic conditions. Concentrations of tumor necrosis factor-alpha and interleukin-1beta were significantly higher in men. In women, concentrations of interleukin-6 were significantly decreased under hypercapnic condition when compared with hypocapnic condition. An inverse relationship was found between hydrogen ion concentration and concentrations of tumor necrosis factor-alpha and interleukin-10., Conclusions: Our results are consistent with the hypothesis that CO2 can affect the production of pro- and anti-inflammatory cytokines after ex vivo stimulation with endotoxin.