Curley et al. Critical Care 2011, 15:212 http://ccforum.com/content/15/2/212

REVIEW Can ‘permissive’ hypercapnia modulate the severity of sepsis-induced ALI/ARDS? Gerard Curley, Mairead Hayes, and John G Laff ey*

This article is one of eleven reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2011 (Springer Verlag) and co-published as a series in Critical Care. Other articles in the series can be found online at http://ccforum.com/series/annual. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901

Introduction contribute to the pathogenesis of lung and systemic organ Ventilatory strategies that reduce lung stretch by reduc- injury, leading to multiple organ failure and death. Th e ing tidal and minute ventilation, which results in a potential for hypercapnia and/or its associated acidosis to ‘permissive’ hypercapnic acidosis, improve outcome in potently inhibit the immune response is increasingly patients with acute lung injury/acute respiratory distress recognized [6,7]. Where the host immune response is a syndrome (ALI/ARDS) [1,2]. Reassuringly, evidence from major contribu tor to injury, such as in non-septic ALI/ clinical studies attests to the safety and lack of detri- ARDS, these eff ects would be expected to result in mental eff ects of hypercapnic acidosis [2]. Of particu lar potential benefi t. Th is has been demonstrated clearly in importance, a secondary analysis of data from the relevant pre-clinical ALI/ARDS models, where hyper- ARDSnet tidal volume study [1] demonstrated that the capnic acidosis has been demonstrated to attenuate ALI presence of hypercapnic acidosis at the time of randomi- induced by free radicals [8], pulmonary [9] and systemic zation was associated with improved patient survival in ischemia-reperfusion [10], pulmonary endo toxin instilla- patients who received high tidal volume ventilation [3]. tion [11], and excessive lung stretch [12]. Th e protective Th ese fi ndings have resulted in a shift in paradigms eff ects of hypercapnic acidosis in these models appear regarding hypercapnia – from avoidance to tolerance – due, at least in part, to its anti-infl ammatory eff ects. with hypercapnia increasingly permitted in order to Th e eff ects of hypercapnia in sepsis-induced lung realize the benefi ts of low lung stretch. Consequently, low injury, where a robust immune response to microbial tidal and minute volume ventilation and the accom- infec tion is central to bacterial clearance and recovery, is panying `permissive’ hypercapnia are now the standard less clear. Of concern, severe sepsis-induced organ of care for patients with ALI/ARDS, and are increasingly failure, whether pulmonary or systemic in origin, is the used in the ventilatory management of a diverse range of leading cause of death in critically ill adults and children diseases leading to acute severe respira tory failure, inclu- [13]. Sepsis-induced ARDS is associated with the highest d ing asthma and chronic obstructive pulmonary disease. mortality rates. Evidence suggests that approximately Th e infl ammatory response plays a central role in the 40% of patients with severe sepsis develop ARDS [13]. pathogenesis of injury and in the repair process in ALI/ Furthermore, infection frequently complicates critical ARDS [4]. Infl ammation is a highly conserved process in illness due to other causes, with an infection prevalence evolution, which is essential for survival. It functions to of over 44% reported in this population [14]. Th ese issues resolve the injurious process, facilitate repair, and return underline the importance of understanding the eff ects of the host to a state of homeostasis. Th e ideal infl ammatory hypercapnia on the immune response, and the implica- process is rapid, causes focused destruction of pathogens, tions of these eff ects in the setting of sepsis. yet is specifi c and ultimately self-limiting [5]. In contrast, when the infl ammatory response is dysregulated or persis- Hypercapnia and the innate immune response tent, this can lead to excessive host damage, and Function of the innate immune response Th e immune system can be viewed as having two inter- connected branches, namely the innate and adaptive *Correspondence: john.laff [email protected] Department of Anestheisa, Clinical Sciences Institute, National University, Galway, immune responses [5]. Th e innate immune system is an Ireland ancient, highly conserved response, being present in © 2011 Springer-Verlag Berlin Heidelberg. This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Curley et al. Critical Care 2011, 15:212 Page 2 of 9 http://ccforum.com/content/15/2/212

some form in all metazoan organisms. Th is response is The cellular innate immune response activated by components of the wall of invading micro- Neutrophils and macrophages are important eff ectors of organisms, such as lipopolysaccharide (LPS) or peptido- the innate immune response in the setting of bacterial glycan, following the binding of these pathogen-asso- infection. Neutrophils rapidly migrate from the blood- ciated molecular patterns to pattern recognition recep- stream to areas of infection, and rapidly phagocytose tors, such as the Toll-like receptors (TLRs) on tissue invading microorganisms. Tissue macrophages and their macrophages. Th e innate immune response is also activa- blood borne monocyte counterparts are activated by ted by endogenous `danger’ signals, such as mitochon- bacterial products such as endotoxin, and coordinate the drial components [15], providing an elegant explanation activation of the adaptive immune response in the setting for why non-septic insults can also lead to organ injury of infection by presenting foreign antigen to lymphocytes and dysfunction. An infl ammatory cascade is then and secreting chemokines. Both monocytes and initiated, involving cytokine signaling activation of macrophages phagocytose and kill pathogens by similar phago cytes that kill bacteria, as is activation of the (later) mechanisms but at a slower rate than neutrophils. adaptive immune response. Hypercapnic acidosis may impact on the cellular immune response via both direct and indirect mecha- Activation of the innate immune response nisms. Hypercapnic acidosis inhibits neutrophil expres- Hypercapnic acidosis has been demonstrated to inhibit sion of the chemokines, selectins and intercellular multiple components of the host innate immune res- adhesion molecules [16,20], which facilitate neutrophil ponses. Activation of the innate immune response binding to the endothelium and migration out of the initiates a conserved signaling cascade that culminates in vascular system. Th e potential for hypercapnic acidosis the activation of transcription factors, such as nuclear to inhibit neutrophil chemotaxis and migration to the factor kappa-B (NF-κB) [5]. Th ese transcription factors site of injury has been confi rmed in vivo, where hyper- drive the expression of multiple genes that activate and capnic acidosis inhibits pulmonary neutrophil infi ltration regulate the pro-infl ammatory and repair processes. in response to endotoxin instillation [11]. Hypercapnic Increasing evidence suggests that hypercapnic acidosis acidosis directly impairs neutrophil phagocytosis in vitro directly inhibits the activation of NF-κB [16]. Intriguingly, [23]. Th is inhibitory eff ect appears to be a function of the this eff ect of hypercapnic acidosis may be a property of acidosis per se, with buff ering restoring neutrophil the CO2 rather than its associated acidosis [17–19]. If phagocytosis [24]. Hypercapnic acidosis also inhibits confi rmed, this fi nding suggests the presence of a phagocytosis of opsonized polystyrene beads by human molecular CO2 sensor in mammalian cells. Th is mecha- alveolar macrophages, although the levels of CO2 utilized nism of action of hypercapnic acidosis has been demon- to demonstrate this eff ect were well beyond the range strated to underlie some of the anti-infl ammatory eff ects encountered clinically [19]. of hypercapnia [16], and to be a key mechanism by which Neutrophils and macrophages kill ingested bacteria by hypercapnia – whether buff ered or not – reduces producing free radicals such as superoxide, hydrogen pulmonary epithelial wound healing [18]. peroxide, and hypochlorous acid, and releasing these into the phagosome. Th is is a pH-dependent process, with Coordination of the innate immune response free radical production decreased at low pH [25]. Hyper- Hypercapnic acidosis also interferes with coordination of capnic acidosis inhibits the generation of oxidants such the innate immune response by reducing cytokine signal- as superoxide by unstimulated neutrophils and by ing between immune eff ector cells. Hypercapnic acidosis neutrophils stimulated with opsonized Escherichia coli or reduces neutrophil [20] and macrophage [21] production with phorbol esters [20]. In contrast, hypocapnic alkalosis of pro-infl ammatory cytokines such as tumor necrosis stimulates neutrophil oxidant generation [20]. Inhibition factor (TNF)-α, interleukin (IL)-1β, IL-8 and IL-6. Hyper- of the intracellular pH changes with acetazolamide capnic acidosis reduced endotoxin stimulated macro- attenuated these eff ects. More recently, hypercapnic phage release of TNFα and IL-1β in vitro [21]. Peritoneal acidosis has been demonstrated to reduce oxidative macrophages incubated under hypercapnic conditions reactions in the endotoxin injured lung by a mechanism demonstrated a prolonged reduction in endotoxin- involving inhibition of myeloperoxidase-dependent stimulated TNF-α and IL-1β release [22]. In contrast, a oxida tion [26]. Th e potential for hypercapnic acidosis to recent study reported rapid onset and rapid reversibility reduce free radical formation, while benefi cial where host of IL-6 inhibition by hypercapnia in mature macrophage oxidative injury is a major component of the injury stimulated with LPS [19]. Th e mechanism underlying process, may be disadvantageous in sepsis, where free hypercapnic acidosis-mediated inhibition of cytokine radicals are necessary to cause bacterial injury and death. and chemokine production appears to be mediated at Neutrophil apoptosis following phagocytic activity least in part via inhibition of activation of NF-κB. generally occurs within 48 hours of release into the Curley et al. Critical Care 2011, 15:212 Page 3 of 9 http://ccforum.com/content/15/2/212

circulation. Conversely, neutrophil death via necrosis anaerobic E. coli growth occurs at a CO2 tension (PCO2) causes release of intracellular contents, including harmful of 0.05 atmospheres, which is similar to the PCO2 in the enzymes, which can cause tissue destruction. Neutrophils gut. Th e aerobic growth rate of E. coli was not inhibited appear to have an increased probability of dying by by a PCO2 of 0.2 atmospheres but was inhibited at partial necrosis following intracellular acidifi cation during pressures above 0.6 atmospheres [33]. It is important to phagocytosis [27]. Hypercapnic acidosis may, therefore, remember that these levels are extremely high in the increase the probability of neutrophil cell death occurring context of human physiology. via necrosis rather than apoptosis. Of concern, however, is the demonstration by Pugin et al. that more clinically relevant degrees of metabolic Hypercapnia and the adaptive immune response acidosis can directly enhance bacterial proliferation in Th e adaptive immune system is activated by the innate vitro [34]. Cultured lung epithelial cells exposed to cyclic response following activation of pattern recognition stretch similar to that seen with mechanical ventilation receptors that detect molecular signatures from micro- produced a lactic acidosis that markedly enhanced the bial pathogens. Specifi c major histocompatibility complex growth of E. coli [34]. Th is was a direct eff ect of hydrogen molecules on T and B lymphocytes also bind microbial ions, as direct acidifi cation of the culture medium to a components. Th ese activation events lead to the genera- pH of 7.2 with hydrochloric acid enhanced E. coli growth. tion of T and B lymphocyte-mediated immune responses In contrast, alkalinizing the pH of conditioned media over a period of several days. from stretched lung cells abolished the enhancement of Much of the focus to date regarding the eff ects of E. coli growth. A range of Gram-positive and Gram- hypercapnic acidosis on immune response to injury and/ negative bacteria (including E. coli, Proteus mirabilis, or infection has been on the innate immune response. Serratia rubidaea, Klebsiella pneumoniae, Enterococcus Less is known about the eff ects of hypercapnic acidosis faecalis, and Pseudomonas aeruginosa) isolated from on adaptive or acquired immunity. However, important patients with ventilator-associated pneumonia (VAP), clues as to the potential for hypercapnic acidosis to grew better in acidifi ed media (Fig. 1). Interestingly, this modulate the adaptive response come from the cancer eff ect was not seen with a methicillin resistant Staphylo- literature. Th e tumor microenvironment is characterized coccus aureus (MRSA) strain, which appeared to grow by poor vascularization, resulting in tissue hypoxia and best at an alkaline pH [34]. acidosis. In a situation analogous to sepsis, acidosis in Th e eff ects of hypercapnic acidosis on bacterial this setting may hamper the host immune response to proliferation at levels encountered in the context of tumor cells, potentially leading to increased tumor permissive hypercapnia are unclear. Th e net eff ect is growth and spread. Th e cytotoxic activity of human likely to be a combination of the eff ects of the acidosis lympho kine activated killer cells and natural killer cells is and of the hypercapnia. Nevertheless, the demonstration diminished at acidic pH [28]. Metabolic acidosis reduces that clinically relevant levels of metabolic acidosis lysis of various tumor cell lines by cytotoxic T-lympho- enhance bacterial growth is of concern. cytes [29]. In contrast, the motility of IL-2-stimulated lymphocytes appears to be stimulated in the presence of Implications for hypercapnia in sepsis an acidifi ed extracellular matrix and severe extracellular Immunocompetence is essential to an eff ective host acidosis (pH 6.5) also appears to enhance the antigen response to microbial infection. Hypercapnia and/or presenting capacity of dendritic cells [30]. Th e net eff ect acidosis may modulate the interaction between host and of these contrasting actions of metabolic acidosis on the bacterial pathogen via several mechanisms, resulting in a adaptive immune response is unclear. However, the broad based suppression of the infl ammatory response. demonstration that hypercapnic acidosis enhanced systemic tumor spread in a murine model [31] raises Hypercapnia, acidosis and the host response clear concerns regarding the potential for hypercapnic Th e initial host response to invading pathogens is domi- acidosis to suppress cell-mediated immunity. nated by neutrophil activation, migration to the infective site, and phagocytosis and killing of bacteria. Compart- Hypercapnia and acidosis modulate bacterial mentalized release of neutrophil proteolytic enzymes and proliferation myeloperoxidase-dependent oxygen radicals results in Carbon dioxide has broadly similar eff ects within the eff ective pathogen destruction. However, excessive various families of microorganisms, but the sensitivity to release of these potent mediators into the extracellular

CO2 varies across the families, e.g., yeasts are quite space results in damage to host tissue and worsening ALI. resistant to the inhibitory eff ects of CO2, Gram-positive Consistent with this is the fi nding that recovery of organisms are somewhat less resistant, and Gram- neutrophil count in neutropenic patients worsens the negative organisms are the most vulnerable [32]. Optimal severity of ALI [35]. Hypercapnic acidosis may reduce Curley et al. Critical Care 2011, 15:212 Page 4 of 9 http://ccforum.com/content/15/2/212

Early versus late bacterial infection Th e eff ects of this hypercapnic acidosis-induced immune modulation may vary depending upon the stage of the infective process. Th e anti-infl ammatory properties of hypercapnic acidosis may reduce the intensity of the initial host response to infection, thus attenuating tissue damage (Fig. 2). However, the mechanisms whereby bac- teria mediate tissue injury are complex and not limited to the contribution from an excessive host response. In late or prolonged pneumonia, in which tissue injury from direct bacterial spread and invasion makes a signifi cant contribution, hypercapnic acidosis might impair bactericidal host responses. In the absence of eff ective antibiotic therapy, this may lead to enhanced bacterial spread and replication leading to more severe tissue destruction and lung and systemic organ injury (Fig. 2).

Impact on repair following injury Hypercapnic acidosis has been demonstrated to retard the repair process following lung cell and tissue injury. Hypercapnia slowed resealing of stretch-induced cell membrane injuries [37] and inhibited the repair of pulmo nary epithelial wounds [18] by a mechanism involving inhibition of the NF-κB pathway. Th ese fi ndings raise the potential that hypercapnic acidosis could lead to increased bacterial translocation through defects in the pulmonary epithelium, while also delaying the recovery process following a septic insult. Recent studies in relevant preclinical models have signifi cantly advanced our understanding of the eff ects of hypercapnic acidosis in both pulmonary and systemic sepsis-induced ALI/ARDS. Th ese studies reveal the Figure 1. Bacterial pathogens proliferate more rapidly in the importance of severity, site, and stage of the infective setting of metabolic acidosis. All bacterial strains tested, except for process, the need for antibiotic therapy, and the utility of a methicillin-resistant S. aureus, had a marked growth advantage at buff ering the hypercapnic acidosis in this setting. moderately acidic pH levels (7.2–7.6) relevant to the clinical setting. Gram-negative bacteria are represented by dark blue bars while Hypercapnia in pulmonary sepsis Gram-positive bacteria are represented by light blue bars. From [34] with permission. Early lung infection Th e eff ect of hypercapnic acidosis on pneumonia-induced ALI appears to depend on the stage and severity of the infection. In an acute severe bacterial pneumonia- the potential for damage to host tissue during the induced lung injury, hypercapnic acidosis improved response to infection, by reducing lung neutrophil physio logical indices of injury [38]. Intriguingly, these recruit ment [10], adherence [16], intracellular pH protective eff ects were mediated by a mechanism inde- regulation [12], oxidant generation [8], and phagocytosis pen dent of neutrophil function. In contrast, hypercapnic [23]. Th ese mechanisms are considered to underlie some acidosis did not alter the magnitude of lung injury in a of the protective eff ects of hypercapnic acidosis in non- less severe acute bacterial pneumonia [39]. Importantly sepsis induced ALI [7]. However, these eff ects of hyper- these in vivo studies showed no increase in bacterial capnic acidosis may be detrimental in sepsis, given the count in animals exposed to hypercapnic acidosis, a central role of neutrophil mediated phagocytosis of reassuring fi nding given concerns regarding retardation microbial pathogens and activation of the cytokine of the host bactericidal response and potential bacterial cascade to the host response to infection. In this context, proliferation. defects in neutrophil function are associated with In the clinical setting, many critically ill patients will increased sepsis severity and worse outcome [36]. have established infection at the time of presentation. Curley et al. Critical Care 2011, 15:212 Page 5 of 9 http://ccforum.com/content/15/2/212

Figure 2. Potential mechanisms underlying the eff ects of hypercapnic acidosis in sepsis. Panel A represents early sepsis, in which hypercapnic acidosis may reduce the host infl ammatory response and decrease the contribution of bacterial toxin mediated injury to tissue injury and damage. This might result in an overall decrease in lung injury. Panel B represents late or prolonged bacterial sepsis, where a hypercapnic acidosis-mediated decrease in the host response to bacterial infection might result in unopposed bacterial proliferation, thereby increasing direct bacterial tissue invasion and injury, and worsening lung injury. ALI: acute lung injury; HCA: hypercapnic acidosis.

Th us animal models of established bacterial pneumonia, evidenced by impaired phagocytotic ability in neutrophils in which hypercapnic acidosis was introduced several isolated from hypercapnic rats [23]. Of importance to the hours following induction of infection with E. coli, more clinical context, the use of appropriate antibiotic therapy closely resemble the clinical setting. In an established abolished these deleterious eff ects of hypercapnia, pneumonia model, hypercapnic acidosis induced after reducing lung damage and lung bacterial load to levels the development of a signifi cant pneumonia-induced comparable to those seen with normocapnia. lung injury reduced physiological indices of lung injury Th ese fi ndings have been confi rmed and considerably [40]. Of importance, these protective eff ects of hyper cap- expanded in a recent study of hypercapnia in the fruit fl y nic acidosis were enhanced in the presence of appropriate [41]. Helenius et al., in a series of elegant in vivo studies, antibiotic therapy [40]. Again, reassuringly, lung bacterial found that prolonged hypercapnia decreased expression loads were similar in the hypercapnic acidosis and of specifi c anti-microbial peptides in Drosophilia normo capnia groups [40]. melano gaster [41]. Hypercapnia decreased bacterial resistance in adult fl ies exposed to pathogens as Prolonged lung infection evidenced by increased bacterial loads and increased In an animal model of prolonged untreated pneumonia, mortality in fl ies inoculated with E. faecalis, A. tume- sustained hypercapnic acidosis worsened histological and faciens, or S. aureus [41]. Th e previously demon strated physiological indices of lung injury, including compliance, suppressive eff ects of hypercapnic acidosis on the NF-κB arterial oxygenation, alveolar wall swelling and neutrophil pathway appeared to underlie the decreased resistance to infi ltration [23]. Of particular concern to the clinical infection [41]. Th ese fi ndings raise signifi cant concerns setting, hypercapnic acidosis was associated with a higher regarding the safety of hypercapnia in the setting of lung bacterial count. Th e mechanism underlying this eff ect prolonged pneumonia, particularly in the absence of appeared to be inhibition of neutrophil function, as eff ective antibiotic therapy. Curley et al. Critical Care 2011, 15:212 Page 6 of 9 http://ccforum.com/content/15/2/212

Hypercapnia in systemic sepsis A growing body of evidence attests to a benefi cial role of hypercapnia in the setting of systemic sepsis. Improve- ments in hemodynamic parameters and lung injury have been demonstrated in evolving, established, and pro- longed systemic sepsis in animal models. Th is is in contrast to the detrimental eff ects of hypercapnic acidosis seen in prolonged pulmonary sepsis, suggesting that the eff ects of hypercapnic acidosis depend not only on the stage of the infective process, but also on the site of the primary infection.

Early systemic sepsis Hypercapnic acidosis reduces the severity of early septic shock and lung injury induced by systemic sepsis. In a rodent model of peritoneal sepsis induced by cecal ligation and puncture, hypercapnic acidosis slowed the development of hypotension, preserved central venous oxygen saturation, and attenuated the rise in serum lactate compared to control conditions, in the fi rst 3 hours post injury [42]. Th e severity of early lung injury Figure 3. Insuffl ation of CO into the peritoneal cavity improves was reduced as evidenced by a decrease in the alveolar- 2 survival following cecal ligation and puncture-induced systemic arterial oxygen gradient, and reduced lung permeability, sepsis. Animals were fi rst subjected to cecal ligation and puncture. compared to normocapnia. Alveolar neutrophil concen- Four hours later, animals underwent a laparotomy and induction of tration was reduced by hypercapnic acidosis but IL-6 and a CO2 pneumoperitoneum (laparotomy + CO2), laparotomy alone, or TNF-α were unchanged [42]. Of importance, there were no laparotomy; survival was determined over the following 8 days. no diff erences in bacterial loads in the lung, blood, or Modifi ed from [31] with permission. peritoneum in the hypercapnia group.

Prolonged systemic sepsis abdominal sepsis-induced lung and systemic organ

Using an ovine model of fecal peritonitis, Wang et al injury. Insuffl ation of CO2 into the peritoneal cavity prior compared the eff ects of hypercapnic acidosis with those to laparotomy for endotoxin contamination increased of dobutamine [43]. Over an 18-hour study period, animal survival [44]. Most recently, CO2 pneumo peri- hypercapnic acidosis resulted in improved hemo- toneum has been demonstrated to increase survival in dynamics of a magnitude comparable to that of dobu- mice with polymicrobial peritonitis induced by cecal tamine. Compared with normocapnia, both hypercapnic ligation and puncture (Fig. 3) [31]. Th ese protective acidosis and dobutamine raised cardiac index and eff ects of intraperitoneal carbon dioxide insuffl ation systemic oxygen delivery and reduced lactate levels. In appear be due to the immunomodulatory eff ects of addition, hypercapnic acidosis attenuated indices of lung hyper capnic acidosis, which include an IL-10 mediated injury, including lung edema, alveolar-arterial oxygen downregulation of TNF-α [44]. Importantly, these eff ects partial pressure diff erence and shunt fraction. Hyper- appear to be mediated by the localized peritoneal capnic acidosis did not decrease survival time compared acidosis, rather than by any systemic eff ect. to normo capnia in this setting [43]. In a more prolonged systemic sepsis model, Costello et al. demonstrated that Buff ering hypercapnic acidosis in sepsis sustained hypercapnic acidosis reduced histological Th e immunomodulatory eff ects of hypercapnic acidosis indices of lung injury compared with normocapnia in in sepsis may occur as a function of either hypercapnia or rodents following cecal ligation and puncture [42]. acidosis. As discussed, evidence suggests that hyper- Reassuringly there was no evidence of an increased capnic acidosis exerts certain eff ects via its associated bacterial load in the lung, blood, or peritoneum of acidosis [24], while other eff ects appear be a function of animals exposed to hypercapnia. the hypercapnia per se [17]. Buff ered hypercapnia, i.e., hypercapnia in the presence of normal pH, may be seen Intraperitoneal hypercapnia in ALI/ARDS patients as a renal compensatory measure,

Direct intra-abdominal administration of CO2 – by or as a result of the administration of bicarbonate, a means of a pneumoperitoneum – reduces the severity of common clinical practice in the ICU, and one that was Curley et al. Critical Care 2011, 15:212 Page 7 of 9 http://ccforum.com/content/15/2/212

permitted in the ARDSnet tidal volume study [1]. Aside and also on whether the acidosis produced by the from well established concerns regarding the use of hypercapnia is buff ered or not. Hypercapnic acidosis sodium bicarbonate, there is evidence from animal models appears to protect the lung from injury induced by of lung and systemic sepsis that the anti-infl am matory and evolving or more established lung and systemic bacterial protective eff ects of hypercapnic acidosis are lost with sepsis in relevant pre-clinical models. In contrast, the buff ering. Th is has signifi cant implications in clinical eff ects of hypercapnic acidosis in prolonged untreated scenarios where the buff ering of hypercapnia resulting bacterial sepsis appear to diff er depending on the source from protective ventilator strategies is considered. of the infection, with the immunosuppressive eff ects of hypercapnic acidosis worsening lung injury in the setting Pulmonary sepsis of prolonged pneumonia. Th is deleterious eff ect is In rodent models of acute pneumonia induced by intra- abrogated by eff ective antibiotic therapy. In contrast, tracheal E. coli and by endotoxin, buff ered hypercapnia hyper capnic acidosis reduced lung damage caused by worsened lung injury [24]. Compared with normocapnic pro longed systemic sepsis, again highlighting the poten- controls, buff ered hypercapnia increased multiple indices tial importance of the source of infection. Finally, buff er- of lung injury including arterial oxygenation, lung compli- ing of the acidosis induced by hypercapnia does not ance, pro-infl ammatory pulmonary cytokine concen- confer signifi cant benefi t in the setting of lung or trations, and measurements of structural lung damage. In systemic sepsis, and may actually worsen lung injury in these experiments, buff ered hypercapnia was established the setting of pneumonia. in the animals by exposure to hypercapnic conditions until Taken together, recent experimental fi ndings in renal buff ering to normal pH had occurred, thus avoiding relevant pre-clinical models provide some reassurance the confounding eff ects of exogenous acid or alkali regarding the safety of hypercapnia in sepsis, particularly administration. Th is contrasts with the protective eff ects in early pneumonia, and in the setting of abdominal of hypercapnic acidosis in similar models [11,38]. Of note, sepsis. However, in the setting of prolonged pneumonia, buff ered hypercapnia did not reduce the phagocytic the immunosuppressive eff ects of hypercapnia remain a capacity of neutrophils, and did not increase lung bacterial concern. While the use of ventilation strategies resulting load in these studies [24]. in hypercapnia is clearly justifi ed in patient with ALI/ ARDS, care is warranted in the setting of sepsis. Th e Systemic sepsis fi nding that deleterious eff ects of hypercapnia in the In a study designed to assess the contribution of acidosis setting of prolonged pneumonia are abrogated by appro- versus hypercapnia to the eff ects of hypercapnic acidosis priate antibiotic therapy is of importance. on the lung and hemodynamic profi le in systemic sepsis, Clinicians should carefully consider the use of early Higgins et al. exposed rats to environmental hypercapnia empiric antibiotic therapy in hypercapnic ALI/ARDS until renal buff ering had restored pH to the normal range patients in whom sepsis is suspected or confi rmed. [45]. Both buff ered hypercapnia and hypercapnic acidosis However, concerns persist, particularly where antibiotic reduced the severity of early shock and attenuated the cover may be suboptimal, or the bacteria are more increase in serum lactate compared with normocapnia. resistant to antibiotic therapy. Th e fi ndings that hyper- In contrast, buff ered hypercapnia did not attenuate capnia may increase septic lung injury in the setting of physiologic or histologic indices of lung injury in these prolonged pneumonia is also of relevance to other patient studies [45]. Reassuringly, there was no evidence to groups, such as patients with infective exacerbations of suggest that buff ered hypercapnia worsened the degree chronic obstructive airways disease. of lung injury compared to normocapnia, and buff ered hypercapnia did not increase the bacterial load in the Conclusion lungs or the bloodstream [45]. Hypercapnia is an integral component of protective lung ventilatory strategies in patients with severe respiratory Hypercapnia and sepsis: where are we now? failure. Th e potential for hypercapnia to modulate the Th e generally benefi cial eff ects of hypercapnic acidosis in immune response, and the mechanisms underlying these the setting of experimental non-septic infl ammatory eff ects are increasingly well understood. Th e fi ndings that injury contrast with a more complex spectrum of eff ects hypercapnic acidosis is protective in systemic sepsis, and in the setting of live bacterial infection. Hypercapnia and/ in the earlier phases of pneumonia-induced sepsis, or acidosis exert diverse – and potentially confl icting – provide reassurance regarding the safety of hypercapnia eff ects on the innate and adaptive immune responses. in the clinical setting. However, the potential for hyper- Overall, hypercapnic acidosis appears to suppress the capnic acidosis to worsen injury in the setting of pro- immune response, although the net eff ect of its multiple longed lung sepsis must be recognized. Additional actions appears to vary depending on the site of infection studies are needed to further elucidate the mechanisms Curley et al. Critical Care 2011, 15:212 Page 8 of 9 http://ccforum.com/content/15/2/212

underlying the eff ects of hypercapnia and acidosis in the 18. O’Toole D, Hassett P, Contreras M, et al.: Hypercapnic acidosis attenuates setting of sepsis-induced lung injury. pulmonary epithelial wound repair by an NF-kappaB dependent mechanism. Thorax 2009, 64:976–982. 19. Wang N, Gates KL, Trejo H, et al.: Elevated CO2 selectively inhibits Acknowledgement interleukin-6 and tumor necrosis factor expression and decreases This work was supported by funding from the Health Research Board, Dublin, phagocytosis in the macrophage. Faseb J 2010, 24:2178–2190. Ireland (Grant No: RP/2008/193), and the European Research Council, Brussels, 20. Coakley RJ, Taggart C, Greene C, McElvaney NG, O’Neill SJ: Ambient pCO2 Belgium, under the Framework 7 Programme (Grant No: ERC-2007-StG modulates intracellular pH, intracellular oxidant generation, and 207777). interleukin-8 secretion in human neutrophils. J Leukoc Biol 2002, 71:603–610. Competing interests 21. West MA, Baker J, Bellingham J: Kinetics of decreased LPS-stimulated The authors declare that they have no competing interests. cytokine release by macrophages exposed to CO2. J Surg Res 1996, 63:269–274. List of abbreviations used 22. Gupta A, Watson DI: Eff ect of laparoscopy on immune function. Br J Surg ALI: acute lung injury; ARDS: acute respiratory distress syndrome; IL: 2001, 88:1296–1306. interleukin; LPS: lipopolysaccharide; MRSA: methicillin resistant Staphylococcus 23. O’Croinin DF, Nichol AD, Hopkins N, et al.: Sustained hypercapnic acidosis aureus; NF-κB: nuclear factor kappa-B; TLR: toll-like receptor; TNF: tumor during pulmonary infection increases bacterial load and worsens lung necrosis factor; VAP: ventilator-associated pneumonia. injury. Crit Care Med 2008, 36:2128–2135. 24. Nichol AD, O’Cronin DF, Howell K, et al.: Infection-induced lung injury is Published: 22 March 2011 worsened after renal buff ering of hypercapnic acidosis. Crit Care Med 2009, 37:2953–2961. 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