Lung-protective Ventilation in Acute Respiratory Distress Syndrome
Protection by Reduced Lung Stress or by Therapeutic Hypercapnia?

Keith G. Hickling

Department of Intensive Care, University of Otago, Dunedin, New Zealand

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Mechanical ventilation using inappropriate settings can produce acute parenchymal lung injury and an acute inflammatory response in the lung. The associated release of cytokines into alveoli and the systemic circulation (1, 2) may contribute to multiple organ dysfunction (3, 4) and mortality in acute respiratory distress syndrome (ARDS). "Lung-protective" ventilation strategies attempt to avoid these consequences by limiting peak lung distension and preventing end-expiratory collapse, accepting the hypercapnia that often results; such strategies reduced mortality rate in ARDS in two randomized trials (5, 6). Hypercapnia is generally regarded as an undesirable consequence of limiting alveolar stress, but in a series of studies, Laffey, Kavanagh and colleagues have questioned whether hypercapnic acidosis per se may contribute to the benefits of lung-protective ventilation. They showed that in isolated perfused rabbit lungs, respiratory acidosis protected the lung from ischemia-reperfusion injury (7), whereas respiratory alkalosis potentiated the injury (8). The protective effect of respiratory acidosis was associated with inhibition of xanthine oxidase (7), and was prevented by buffering the acidosis (9); i.e., the protection resulted from the acidosis rather than hypercapnia. In this issue of the Journal (pp. 2287-2294) (10), they extend these observations to intact anesthetized rabbits. The control and study groups received identical ventilation, but in the study group the inspired CO₂ concentration was increased, producing "therapeutic hypercapnia" (Pa_CO2 approximately 105 mm Hg, pH 7.05). Left lung ischemia and reperfusion were then induced by clamping the left hilum for 75 min, then releasing the left hilum and ligating the right hilum. After a further 90 min, the left lung was evaluated. The hypercapnic group showed substantially lower concentrations of protein and tumor necrosis factor-alpha (TNF-) in lung lavage fluid, less pulmonary edema, better lung compliance, lower lung 8-isoprostane and nitrotyrosine concentrations (suggesting less lipid peroxidation and peroxynitrite-induced injury, respectively), and less apoptosis than the control group.

The study group also showed less increase in blood lactate concentration, but the cause and significance of the elevated lactate concentration are not clear. The animals were not severely hypoxemic, but cardiac output could have fallen (it was not measured) after reperfusion of the left lung, and could have been better maintained in the hypercapnic group (11). Tissue oxygen unloading may also have been facilitated in the hypercapnic group (12). However, as the authors acknowledge, the rate of lactate production and clearance are both affected by acid-base disturbances (13), and the animals received infusions of lactated Ringer's solution. Therefore, the difference between groups may have been caused by different lactate kinetics resulting from the pH difference. We should be cautious in attributing it to the prevention of dysoxia or other systemic "protective" effects of hypercapnic acidosis, as suggested by the authors.

However, other studies have suggested cytoprotective effects from acidosis. In a series of experiments, Lemasters and colleagues showed that cultured cells remained viable during 5 h of total anoxia providing the intracellular pH remained low. If the intracellular pH increased during anoxia or after reoxygenation, cell death occurred (14). These effects were independent of changes in intracellular Ca²⁺, and also occurred in an isolated perfused heart model (14). Acidosis suppresses the respiratory burst (15) and cytokine expression (16) in macrophages. Laffey and Kavanagh have discussed other studies suggesting cytoprotection by hypercapnic acidosis (17). Therefore, although it seems improbable that all of the apparent benefit of lung protective ventilation is a direct consequence of hypercapnia, the hypothesis addressed by Laffey and colleagues is an important and reasonable one. If "lung-protective ventilation" in ARDS does reduce pulmonary and systemic inflammation (2), and perhaps multiple organ dysfunction (3, 4), hypercapnic acidosis per se could conceivably be partly responsible, perhaps by downregulating inflammatory cells (15, 16), and possibly other mechanisms, as well as by inhibition of xanthine oxidase. This possibility deserves further study.

The intriguing findings in the study of Laffey and coworkers (10) raise a number of important questions. Would hypercapnia provide similar protection in other models of lung injury, and what other mechanisms may be involved? Would protection still occur if hypercapnia was induced after ischemia-reperfusion (or other insults) rather than before, as in this study? How long will the effect persist? The inhibition of xanthine oxidase appeared to result mainly from extracellular acidosis, and so may persist until renal compensation occurs. However, other effects of acidosis, including suppression of the respiratory burst and cytokine expression by macrophages (15, 16), probably result from intracellular acidosis. Intracellular acidosis is corrected much more rapidly during hypercapnia (within a few hours) than the extracellular acidosis, by active membrane ion exchangers that protect intracellular pH. Would metabolic acidosis produce the same effect? Finally, if the protective effect does occur in models of lung injury other than ischemia-reperfusion, and in patients, would it result in improved outcome? Would any possible adverse systemic effects of acute hypercapnia offset the benefit? Apart from its contraindication in intracranial hypertension and, perhaps, severe cardiac disease, the greatest concern most clinicians have about hypercapnia appears to be the possibility of acidosis- induced myocardial depression. Yet in clinical studies, almost all patients managed with permissive hypercapnia have sustained an increase in cardiac output after hypercapnia, associated with increased endogenous plasma catecholamine concentrations (11).

Acute hypercapnia causes extremely complex physiologic derangements, probably affecting all cells and organ systems. Although these are poorly understood, some (including possible downregulation of inflammatory cells) could be detrimental, and the degree of harm or benefit could vary in different clinical circumstances. Until we have a better understanding of the cellular and systemic effects of hypercapnia, including the apparent cytoprotective effects and their mechanisms, we can not consider a clinical trial of therapeutic hypercapnia (the intentional elevation of Pa_CO2 above that resulting from lung-protective ventilation). However, a clinical trial of buffering of the acidosis during lung-protective ventilation in ARDS with permissive hypercapnia could be justified now. Buffering may have adverse effects on gas exchange and tissue oxygenation (12) and, perhaps, could eliminate or reduce the protective effects suggested by Laffey and coworkers (10). A clinical trial is due.

	References

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