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Respiratory failure patients treated with mechanical ventilation may have fewer ventilator-induced lung injuries if air volumes and pressures are limited. Traditional mechanical ventilation requires high airway pressures to move large amounts of air in and out of the lungs, which may cause lung damage. Researchers reviewed published medical research on the effects of air pressure limitation, high levels of carbon dioxide in the blood (hypercapnia), and ventilator-induced lung injury. Animal research studies found that mechanical ventilation that overfills the air sacs in the lungs can cause injury. Patients with adult respiratory distress syndrome have both normal and damaged lung tissue, which reduces lung capacity. This makes the lungs more susceptible to injury from the high air volumes used in mechanical ventilation. Permissive hypercapnia minimizes overfilling of air sacs by limiting the airway pressure or volume. Some human studies of permissive hypercapnia revealed improved patient survival over model-based predictors of death rates., Objective.--To evaluate the potential efficacy of pressure limitation with permissive hypercapnia in the treatment of acute respiratory failure/adult respiratory distress syndrome on the basis of current theories of ventilator-induced lung injury, potential complications of systemic hypercarbia, and available human outcome studies. Data Sources.--Articles were identified through MEDLINE, reference citations of published data, and consultation with authorities in their respective fields. Study Selection.--Animal model experimentation and human clinical trials were selected on the basis of whether they addressed the questions of pressure limitation with or without hypercapnia, the pathophysiologic effects of hypercapnia, or the concept of ventilator-induced parenchymal lung injury. Frequently cited references were preferentially included. Data Extraction.--Datawere analyzed with particular emphasis on obtaining the following variables from the clinical studies: peak inspiratory pressures, tidal volumes, minute ventilation, and [PCO.sub.2]. Quantitative aspects of respiratory physiology were used to analyze the theoretical effects of permissive hypercapnia on ventilatory requirements in normal and injured lungs. Data Synthesis.--Extensive animal model data support the hypothesis that ventilator-driven alveolar overdistention can induce significant parenchymal lung injury. The heterogeneous nature of lung injury in adult respiratory distress syndrome, with its small physiologic lung volume, may render the lung susceptible to this type of injury through the use of conventional tidal volumes (10 to 15 mukg). Permissive hypercapnia is an approach whereby alveolar overdistention is minimized through either pressure or volume limitation, and the potential deleterious consequences of respiratory acidosis are accepted. Uncontrolled human trials of explicit or implicit permissive hypercapnia have demonstrated improved survival in comparison with models of predictive mortality. Conclusions.--Avoidance of alveolar overdistention through pressure or volume limitation has significant support based on animal models and computer simulation. Deleterious effects of the associated hypercarbia in severe lung injury do not appear to be a significant limiting factor in preliminary human clinical trials. Although current uncontrolled studies suggest benefit, controlled trials are urgently needed to confirm these findings before adoption of the treatment can be endorsed. (JAMA.1994;272:957-962)