Prolonged hypercapnic acidosis worsened bacterial infection-induced lung injury. Our findings suggest an immunosuppressive effect of hypercapnic acidosis and have important implications for protective ventilation strategies that permit hypercapnic acidosis in patients with adult respiratory distress syndrome and in the management of hypercapnic acidosis during infective exacerbations of chronic obstructive pulmonary disease and other lung diseases.

Background Little information is available about the geo-economic variations in demographics, management, and outcomes of patients with acute respiratory distress syndrome (ARDS). We aimed to characterise the effect of these geo-economic variations in patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE). Methods LUNG SAFE was done during 4 consecutive weeks in winter, 2014, in a convenience sample of 459 intensivecare units in 50 countries across six continents. Inclusion criteria were admission to a participating intensive-care unit (including transfers) within the enrolment window and receipt of invasive or non-invasive ventilation. One of the trial's secondary aims was to characterise variations in the demographics, management, and outcome of patients with ARDS. We used the 2016 World Bank countries classification to define three major geo-economic groupings, namely European high-income countries (Europe-High), high-income countries in the rest of the world (rWORLD-High), and middle-income countries (Middle). We compared patient outcomes across these three groupings. LUNG SAFE is registered with ClinicalTrials.gov, number NCT02010073. Findings Of the 2813 patients enrolled in LUNG SAFE who fulfilled ARDS criteria on day 1 or 2, 1521 (54%) were recruited from Europe-High, 746 (27%) from rWORLD-High, and 546 (19%) from Middle countries. We noted significant geographical variations in demographics, risk factors for ARDS, and comorbid diseases. The proportion of patients with severe ARDS or with ratios of the partial pressure of arterial oxygen (PaO 2) to the fractional concentration of oxygen in inspired air (F I O 2) less than 150 was significantly lower in rWORLD-High countries than in the two other regions. Use of prone positioning and neuromuscular blockade was significantly more common in Europe-High countries than in the other two regions. Adjusted duration of invasive mechanical ventilation and length of stay in the intensive-care unit were significantly shorter in patients in rWORLD-High countries than in Europe-High or Middle countries. High gross national income per person was associated with increased survival in ARDS; hospital survival was significantly lower in Middle countries than in Europe-High or rWORLD-High countries. Interpretation Important geo-economic differences exist in the severity, clinician recognition, and management of ARDS, and in patients' outcomes. Income per person and outcomes in ARDS are independently associated.

"Permissive hypercapnia" is an inherent element of accepted protective lung ventilation. However, there are no clinical data evaluating the efficacy of hypercapnia per se, independent of ventilator strategy. In the absence of such data, it is necessary to determine whether the potential exists for an active role for hypercapnia, distinct from the demonstrated benefits of reduced lung stretch. In this review, we consider four key issues. First, we consider the evidence that protective lung ventilatory strategies improve survival and we explore current paradigms regarding the mechanisms underlying these effects. Second, we examine whether hypercapnic acidosis may have effects that are additive to the effects of protective ventilation. Third, we consider whether direct elevation of CO(2), in the absence of protective ventilation, is beneficial or deleterious. Fourth, we address the current evidence regarding the buffering of hypercapnic acidosis in ARDS. These perspectives reveal that the potential exists for hypercapnia to exert beneficial effects in the clinical context. Direct administration of CO(2) is protective in multiple models of acute lung and systemic injury. Nevertheless, several specific concerns remain regarding the safety of hypercapnia. At present, protective ventilatory strategies that involve hypercapnia are clinically acceptable, provided the clinician is primarily targeting reduced tidal stretch. There are insufficient clinical data to suggest that hypercapnia per se should be independently induced, nor do outcome data exist to support the practice of buffering hypercapnic acidosis. Rapidly advancing basic scientific investigations should better delineate the advantages, disadvantages, and optimal use of hypercapnia in ARDS.

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We conclude that hypercapnic acidosis did not alter the magnitude of the lung injury induced by intratracheal E. coli instillation in the presence or absence of antibiotics.