Intensive Care Med (2004) 30:347–356 DOI 10.1007/s00134-003-2051-1 REVIEW John G. Laffey Donall O’Croinin Paul McLoughlin Brian P. Kavanagh Permissive hypercapnia — role in protective lung ventilatory strategies Received: 16 June 2003 Accepted: 29 September 2003 Published online: 14 January 2004  Springer-Verlag 2004 J. G. Laffey ( ) ) Department of Anaesthesia, University College Hospital, Galway and Clinical Sciences Institute, National University of Ireland, Galway, Ireland e-mail: john.laffey@nuigalway.ie Tel.: +353-91-544608 Fax: +353-91-544908 D. O’Croinin · P. McLoughlin Department of Physiology, University College Dublin, Dublin, Ireland B. P. Kavanagh Department of Critical Care Medicine and The Lung Biology Program, The Research Institute, The Hospital for Sick Children; and Program in Critical Care Medicine, University of Toronto, Toronto, Canada Abstract ‘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 neces- sary to determine whether the poten- tial exists for an active role for hypercapnia, distinct from the dem- onstrated benefits of reduced lung stretch. In this review, we consider four key issues. First, we consider the evidence that protective lung venti- latory strategies improve survival and we explore current paradigms re- garding 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 buff- ering 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. Nev- ertheless, several specific concerns remain regarding the safety of hy- percapnia. 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 sug- gest that hypercapnia per se should be independently induced, nor do out- come data exist to support the prac- tice of buffering hypercapnic acidosis. Rapidly advancing basic scientific investigations should better delineate the advantages, disadvan- tages, and optimal use of hypercapnia in ARDS. Keywords Hypercapnic acidosis · Mechanical ventilation · Acute lung injury · ARDS · Ventilation-induced lung injury · Buffering Introduction ‘Permissive hypercapnia’ is an inherent element of accepted protective lung ventilatory strategies. However, the precise role of hypercapnia remains unclear, with no clinical data comparing the efficacy of protective lung ventilatory strategies in the presence and absence of hypercapnia. Furthermore, it is unlikely that such a trial will be carried out, at least in the medium term. In the absence of such data, it is appropriate to investigate whether the potential exists for an active role for hypercapnia per se, distinct from the demonstrated benefits of reduced lung stretch. This review first considers the evidence that protective lung ventilatory strategies reduce lung injury and improve survival. We examine current paradigms regarding the mechanisms underlying this protective effect, and the passive role presently attributed to hypercapnia. We focus on whether