Effects of High Pco2 on Ventilated Preterm Lamb Lungs

Abstract

High PCO 2 levels attenuate reperfusion injury and ventilationinduced injury in isolated and perfused lungs. We asked whether premature lambs could tolerate 6 h of ventilation with a PCO 2 Ͼ80 mm Hg and whether the high PCO 2 modulated the ventilatorinduced injury. Preterm surfactant-treated lambs were ventilated for 30 min with a high tidal volume (VT) to induce lung injury. The lambs then were ventilated for 5.5 h with a VT of 6 -9 mL/kg to achieve a PCO 2 of 40 -50 mm Hg in the control group. CO 2 was added to the ventilator circuit of a high PCO 2 group to maintain an average PCO 2 of 95 Ϯ 5 mm Hg. The high PCO 2 lambs had heart rates, blood pressures, plasma cortisol values, and oxygenation equivalent to the control lambs. The lungs of the high PCO 2 group had significantly higher gas volumes and had less lung injury by histopathology. Indicators of inflammation (white blood cells, hydrogen peroxide production, and IL-1␤ and IL-8 cytokine mRNA expression in cells from the alveolar wash) qualitatively indicated less injury in the high PCO 2 group, although the differences were not significant. Preterm lambs tolerated a very high PCO 2 without physiologic compromise for 6 h. The high PCO 2 may attenuate ventilator-induced lung injury in the preterm. BPD in preterm infants is highly associated with the use of mechanical ventilation and supplemental oxygen (1, 2). Efforts to decrease the incidence of BPD have included attempts to avoid mechanical ventilation with the use of continuous positive airway pressure (3), different techniques for mechanical ventilation such as high-frequency oscillatory ventilation (4), and lower VT ventilation resulting in higher PCO 2 values (5). In the mature lung, ventilator-mediated injury increases if the lung is inadequately inflated at end-expiration or overinflated at end-inspiration (6, 7). Attempts to decrease lung distention by decreasing VT will result in increases in PCO 2 , referred to as "permissive hypercapnia" (8). Laffey et al. (9) recently extended this concept to "therapeutic hypercapnia" by demonstrating that reperfusion injury of the lung can be prevented if the injury and reperfusion occur in the presence of a PCO 2 of 80 mm Hg. This work demonstrates that high PCO 2 can protect the lung from reperfusion injury, most likely via attenuation of free radical damage. This effect has also been reported for reperfusion injury of other organ systems, such as the brain and heart in adult and newborn animal models (10, 11). Broccard et al. (12) recently reported that high PCO 2 also minimized ventilatorinduced lung injury in isolated and perfused lungs. However, a protective effect of high PCO 2 values has not been demonstrated for ventilator-induced injury in vivo in animals or for the preterm lung. Therefore, we ventilated surfactant-treated preterm lambs to achieve normal PCO 2 values or equivalently ventilated other lambs with supplemental CO 2 to evaluate the tolerance of the preterm to high PCO 2 and the effect of the high PCO 2 on indicators of lung injury. MET...

Hypercapnic Acidosis Impairs Plasma Membrane Wound Resealing in Ventilator-injured Lungs

“…Our results confirm earlier reports from other injury models, that CO 2 influences vascular barrier function and thereby the mechanics of the injured lung (4)(5)(6)(7)(8)(9). However, we also show that CO 2 tension influences the probability that injured cells will repair plasma membrane defects.…”

“…Concern about detrimental effects of acidemia on renal and cardiovascular function have motivated attempts to enhance CO 2 removal by tracheal gas insufflation (2) and have led to unsubstantiated recommendations about the use of bicarbonate buffers in hypercapnic patients (3). More recent data suggest that hypercapnia may actually protect the lung from certain manifestations of ischemiareperfusion, endotoxin, and mechanical ventilation-related injury (4)(5)(6)(7)(8)(9). Hypocapnia, in contrast, and correction of acidemia may be harmful (10)(11)(12).…”

Therapeutic Hypercapnia Is Not Protective in the in vivo Surfactant-Depleted Rabbit Lung

“…CO 2 has been traditionally considered to play a passive role in the improved outcome observed with protective ventilatory strategies, and was thus termed permissive hypercapnia (2). However, deliberate elevation of CO 2 -therapeutic hypercapnia-directly attenuated acute lung injury after free radical generation (19), as well as both primary and secondary ischemiareperfusion-induced acute lung injury (17)(18)(19). In the clinical context, the original reports of deliberate addition of inspired CO 2 were in patients with posttraumatic lung injury (34), in whom the elevated CO 2 appeared to improve cardiac output and oxygenation.…”

“…Second, alteration of PaCO 2 has important effects on gas exchange (15,16) because hypocapnia worsens oxygenation whereas hypercapnia may enhance tissue oxygenation. Third, elevated CO 2 can exert direct antiinflammatory effects in lung injury (17)(18)(19). Antioxidant effects of hypercapnia or acidosis have also been demonstrated in cell culture (20), and because many of these inflammatory processes may be operational in stretch-induced injury, their modulation by CO 2 suggests that elevation of PaCO 2 could have protective effects in VALI.…”

“…Antioxidant effects of hypercapnia or acidosis have also been demonstrated in cell culture (20), and because many of these inflammatory processes may be operational in stretch-induced injury, their modulation by CO 2 suggests that elevation of PaCO 2 could have protective effects in VALI. Fourth, deliberate elevation of CO 2 -"therapeutic hypercapnia"-protects against primary and secondary ischemiareperfusion-induced lung injury (17)(18)(19), and protective effects have been reported for systemic ischemic injury (21). In addition, two recent studies reported that hypercapnic acidosis protects against stretch-induced lung injury ex vivo (22) and in vivo (23).…”