Introduction
Ventilatory strategies that reduce lung stretch by reducing tidal and minute ventilation,
which results in a 'permissive' hypercapnic acidosis, improve outcome in patients
with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) [1,2]. Reassuringly,
evidence from clinical studies attests to the safety and lack of detrimental effects
of hypercapnic acidosis [2]. Of particular importance, a secondary analysis of data
from the ARDSnet tidal volume study [1] demonstrated that the presence of hypercapnic
acidosis at the time of randomization was associated with improved patient survival
in patients who received high tidal volume ventilation [3]. These findings have resulted
in a shift in paradigms regarding hypercapnia - from avoidance to tolerance - with
hypercapnia increasingly permitted in order to realize the benefits of low lung stretch.
Consequently, low tidal and minute volume ventilation and the accompanying 'permissive'
hypercapnia are now the standard of care for patients with ALI/ARDS, and are increasingly
used in the ventilatory management of a diverse range of diseases leading to acute
severe respiratory failure, including asthma and chronic obstructive pulmonary disease.
The inflammatory response plays a central role in the pathogenesis of injury and in
the repair process in ALI/ARDS [4]. Inflammation is a highly conserved process in
evolution, which is essential for survival. It functions to resolve the injurious
process, facilitate repair, and return the host to a state of homeostasis. The ideal
inflammatory process is rapid, causes focused destruction of pathogens, yet is specific
and ultimately self-limiting [5]. In contrast, when the inflammatory response is dysregulated
or persistent, this can lead to excessive host damage, and contribute to the pathogenesis
of lung and systemic organ injury, leading to multiple organ failure and death. The
potential for hypercapnia and/or its associated acidosis to potently inhibit the immune
response is increasingly recognized [6,7]. Where the host immune response is a major
contributor to injury, such as in non-septic ALI/ARDS, these effects would be expected
to result in potential benefit. This has been demonstrated clearly in relevant pre-clinical
ALI/ARDS models, where hypercapnic acidosis has been demonstrated to attenuate ALI
induced by free radicals [8], pulmonary [9] and systemic ischemia-reperfusion [10],
pulmonary endotoxin instillation [11], and excessive lung stretch [12]. The protective
effects of hypercapnic acidosis in these models appear due, at least in part, to its
anti-inflammatory effects.
The effects of hypercapnia in sepsis-induced lung injury, where a robust immune response
to microbial infection is central to bacterial clearance and recovery, is less clear.
Of concern, severe sepsis-induced organ failure, whether pulmonary or systemic in
origin, is the leading cause of death in critically ill adults and children [13].
Sepsis-induced ARDS is associated with the highest mortality rates. Evidence suggests
that approximately 40% of patients with severe sepsis develop ARDS [13]. Furthermore,
infection frequently complicates critical illness due to other causes, with an infection
prevalence of over 44% reported in this population [14]. These issues underline the
importance of understanding the effects of hypercapnia on the immune response, and
the implications of these effects in the setting of sepsis.
Hypercapnia and the innate immune response
Function of the innate immune response
The immune system can be viewed as having two inter-connected branches, namely the
innate and adaptive immune responses [5]. The innate immune system is an ancient,
highly conserved response, being present in some form in all metazoan organisms. This
response is activated by components of the wall of invading micro-organisms, such
as lipopolysaccharide (LPS) or peptidoglycan, following the binding of these pathogen-associated
molecular patterns to pattern recognition receptors, such as the Toll-like receptors
(TLRs) on tissue macrophages. The innate immune response is also activated by endogenous
'danger' signals, such as mitochondrial components [15], providing an elegant explanation
for why non-septic insults can also lead to organ injury and dysfunction. An inflammatory
cascade is then initiated, involving cytokine signaling activation of phagocytes that
kill bacteria, as is activation of the (later) adaptive immune response.
Activation of the innate immune response
Hypercapnic acidosis has been demonstrated to inhibit multiple components of the host
innate immune responses. Activation of the innate immune response initiates a conserved
signaling cascade that culminates in the activation of transcription factors, such
as nuclear factor kappa-B (NF-κB) [5]. These transcription factors drive the expression
of multiple genes that activate and regulate the pro-inflammatory and repair processes.
Increasing evidence suggests that hypercapnic acidosis directly inhibits the activation
of NF-κB [16]. Intriguingly, this effect of hypercapnic acidosis may be a property
of the CO2 rather than its associated acidosis [17-19]. If confirmed, this finding
suggests the presence of a molecular CO2 sensor in mammalian cells. This mechanism
of action of hypercapnic acidosis has been demonstrated to underlie some of the anti-inflammatory
effects of hypercapnia [16], and to be a key mechanism by which hypercapnia - whether
buffered or not - reduces pulmonary epithelial wound healing [18].
Coordination of the innate immune response
Hypercapnic acidosis also interferes with coordination of the innate immune response
by reducing cytokine signaling between immune effector cells. Hypercapnic acidosis
reduces neutrophil [20] and macrophage [21] production of pro-inflammatory cytokines
such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8 and IL-6. Hypercapnic
acidosis reduced endotoxin stimulated macro-phage release of TNFα and IL-1β in vitro
[21]. Peritoneal macrophages incubated under hypercapnic conditions demonstrated a
prolonged reduction in endotoxin-stimulated TNF-α and IL-1β release [22]. In contrast,
a recent study reported rapid onset and rapid reversibility of IL-6 inhibition by
hypercapnia in mature macrophage stimulated with LPS [19]. The mechanism underlying
hypercapnic acidosis-mediated inhibition of cytokine and chemokine production appears
to be mediated at least in part via inhibition of activation of NF-κB.
The cellular innate immune response
Neutrophils and macrophages are important effectors of the innate immune response
in the setting of bacterial infection. Neutrophils rapidly migrate from the blood-stream
to areas of infection, and rapidly phagocytose invading microorganisms. Tissue macrophages
and their blood borne monocyte counterparts are activated by bacterial products such
as endotoxin, and coordinate the activation of the adaptive immune response in the
setting of infection by presenting foreign antigen to lymphocytes and secreting chemokines.
Both monocytes and macrophages phagocytose and kill pathogens by similar mechanisms
but at a slower rate than neutrophils.
Hypercapnic acidosis may impact on the cellular immune response via both direct and
indirect mechanisms. Hypercapnic acidosis inhibits neutrophil expression of the chemokines,
selectins and intercellular adhesion molecules [16,20], which facilitate neutrophil
binding to the endothelium and migration out of the vascular system. The potential
for hypercapnic acidosis to inhibit neutrophil chemotaxis and migration to the site
of injury has been confirmed in vivo, where hypercapnic acidosis inhibits pulmonary
neutrophil infiltration in response to endotoxin instillation [11]. Hypercapnic acidosis
directly impairs neutrophil phagocytosis in vitro [23]. This inhibitory effect appears
to be a function of the acidosis per se, with buffering restoring neutrophil phagocytosis
[24]. Hypercapnic acidosis also inhibits phagocytosis of opsonized polystyrene beads
by human alveolar macrophages, although the levels of CO2 utilized to demonstrate
this effect were well beyond the range encountered clinically [19].
Neutrophils and macrophages kill ingested bacteria by producing free radicals such
as superoxide, hydrogen peroxide, and hypochlorous acid, and releasing these into
the phagosome. This is a pH-dependent process, with free radical production decreased
at low pH [25]. Hypercapnic acidosis inhibits the generation of oxidants such as superoxide
by unstimulated neutrophils and by neutrophils stimulated with opsonized Escherichia
coli or with phorbol esters [20]. In contrast, hypocapnic alkalosis stimulates neutrophil
oxidant generation [20]. Inhibition of the intracellular pH changes with acetazolamide
attenuated these effects. More recently, hypercapnic acidosis has been demonstrated
to reduce oxidative reactions in the endotoxin injured lung by a mechanism involving
inhibition of myeloperoxidase-dependent oxidation [26]. The potential for hypercapnic
acidosis to reduce free radical formation, while beneficial where host oxidative injury
is a major component of the injury process, may be disadvantageous in sepsis, where
free radicals are necessary to cause bacterial injury and death.
Neutrophil apoptosis following phagocytic activity generally occurs within 48 hours
of release into the circulation. Conversely, neutrophil death via necrosis causes
release of intracellular contents, including harmful enzymes, which can cause tissue
destruction. Neutrophils appear to have an increased probability of dying by necrosis
following intracellular acidification during phagocytosis [27]. Hypercapnic acidosis
may, therefore, increase the probability of neutrophil cell death occurring via necrosis
rather than apoptosis.
Hypercapnia and the adaptive immune response
The adaptive immune system is activated by the innate response following activation
of pattern recognition receptors that detect molecular signatures from microbial pathogens.
Specific major histocompatibility complex molecules on T and B lymphocytes also bind
microbial components. These activation events lead to the generation of T and B lymphocyte-mediated
immune responses over a period of several days.
Much of the focus to date regarding the effects of hypercapnic acidosis on immune
response to injury and/or infection has been on the innate immune response. Less is
known about the effects of hypercapnic acidosis on adaptive or acquired immunity.
However, important clues as to the potential for hypercapnic acidosis to modulate
the adaptive response come from the cancer literature. The tumor microenvironment
is characterized by poor vascularization, resulting in tissue hypoxia and acidosis.
In a situation analogous to sepsis, acidosis in this setting may hamper the host immune
response to tumor cells, potentially leading to increased tumor growth and spread.
The cytotoxic activity of human lymphokine activated killer cells and natural killer
cells is diminished at acidic pH [28]. Metabolic acidosis reduces lysis of various
tumor cell lines by cytotoxic T-lymphocytes [29]. In contrast, the motility of IL-2-stimulated
lymphocytes appears to be stimulated in the presence of an acidified extracellular
matrix and severe extracellular acidosis (pH 6.5) also appears to enhance the antigen
presenting capacity of dendritic cells [30]. The net effect of these contrasting actions
of metabolic acidosis on the adaptive immune response is unclear. However, the demonstration
that hypercapnic acidosis enhanced systemic tumor spread in a murine model [31] raises
clear concerns regarding the potential for hypercapnic acidosis to suppress cell-mediated
immunity.
Hypercapnia and acidosis modulate bacterial proliferation
Carbon dioxide has broadly similar effects within the various families of microorganisms,
but the sensitivity to CO2 varies across the families, e.g., yeasts are quite resistant
to the inhibitory effects of CO2, Gram-positive organisms are somewhat less resistant,
and Gram-negative organisms are the most vulnerable [32]. Optimal anaerobic E. coli
growth occurs at a CO2 tension (PCO2) of 0.05 atmospheres, which is similar to the
PCO2 in the gut. The aerobic growth rate of E. coli was not inhibited by a PCO2 of
0.2 atmospheres but was inhibited at partial pressures above 0.6 atmospheres [33].
It is important to remember that these levels are extremely high in the context of
human physiology.
Of concern, however, is the demonstration by Pugin et al. that more clinically relevant
degrees of metabolic acidosis can directly enhance bacterial proliferation in vitro
[34]. Cultured lung epithelial cells exposed to cyclic stretch similar to that seen
with mechanical ventilation produced a lactic acidosis that markedly enhanced the
growth of E. coli [34]. This was a direct effect of hydrogen ions, as direct acidification
of the culture medium to a pH of 7.2 with hydrochloric acid enhanced E. coli growth.
In contrast, alkalinizing the pH of conditioned media from stretched lung cells abolished
the enhancement of E. coli growth. A range of Gram-positive and Gram-negative bacteria
(including E. coli, Proteus mirabilis, Serratia rubidaea, Klebsiella pneumoniae, Enterococcus
faecalis, and Pseudomonas aeruginosa) isolated from patients with ventilator-associated
pneumonia (VAP), grew better in acidified media (Figure 1). Interestingly, this effect
was not seen with a methicillin resistant Staphylococcus aureus (MRSA) strain, which
appeared to grow best at an alkaline pH [34].
Figure 1
Bacterial pathogens proliferate more rapidly in the setting of metabolic acidosis.
All bacterial strains tested, except for a methicillin-resistant S. aureus, had a
marked growth advantage at moderately acidic pH levels (7.2-7.6) relevant to the clinical
setting. Gram-negative bacteria are represented by dark blue bars while Gram-positive
bacteria are represented by light blue bars. From [34] with permission.
The effects of hypercapnic acidosis on bacterial proliferation at levels encountered
in the context of permissive hypercapnia are unclear. The net effect is likely to
be a combination of the effects of the acidosis and of the hypercapnia. Nevertheless,
the demonstration that clinically relevant levels of metabolic acidosis enhance bacterial
growth is of concern.
Implications for hypercapnia in sepsis
Immunocompetence is essential to an effective host response to microbial infection.
Hypercapnia and/or acidosis may modulate the interaction between host and bacterial
pathogen via several mechanisms, resulting in a broad based suppression of the inflammatory
response.
Hypercapnia, acidosis and the host response
The initial host response to invading pathogens is dominated by neutrophil activation,
migration to the infective site, and phagocytosis and killing of bacteria. Compartmentalized
release of neutrophil proteolytic enzymes and myeloperoxidase-dependent oxygen radicals
results in effective pathogen destruction. However, excessive release of these potent
mediators into the extracellular space results in damage to host tissue and worsening
ALI. Consistent with this is the finding that recovery of neutrophil count in neutropenic
patients worsens the severity of ALI [35]. Hypercapnic acidosis may reduce the potential
for damage to host tissue during the response to infection, by reducing lung neutrophil
recruitment [10], adherence [16], intracellular pH regulation [12], oxidant generation
[8], and phagocytosis [23]. These mechanisms are considered to underlie some of the
protective effects of hypercapnic acidosis in nonsepsis induced ALI [7]. However,
these effects of hypercapnic acidosis may be detrimental in sepsis, given the central
role of neutrophil mediated phagocytosis of microbial pathogens and activation of
the cytokine cascade to the host response to infection. In this context, defects in
neutrophil function are associated with increased sepsis severity and worse outcome
[36].
Early versus late bacterial infection
The effects of this hypercapnic acidosis-induced immune modulation may vary depending
upon the stage of the infective process. The anti-inflammatory properties of hypercapnic
acidosis may reduce the intensity of the initial host response to infection, thus
attenuating tissue damage (Figure 2). However, the mechanisms whereby bacteria 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 significant contribution, hypercapnic acidosis might impair
bactericidal host responses. In the absence of effective antibiotic therapy, this
may lead to enhanced bacterial spread and replication leading to more severe tissue
destruction and lung and systemic organ injury (Figure 2).
Figure 2
Potential mechanisms underlying the effects of hypercapnic acidosis in sepsis. Panel
A represents early sepsis, in which hypercapnic acidosis may reduce the host inflammatory
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.
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 pulmonary epithelial wounds [18]
by a mechanism involving inhibition of the NF-κB pathway. These findings 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 significantly advanced our understanding
of the effects of hypercapnic acidosis in both pulmonary and systemic sepsis-induced
ALI/ARDS. These studies reveal the importance of severity, site, and stage of the
infective process, the need for antibiotic therapy, and the utility of buffering the
hypercapnic acidosis in this setting.
Hypercapnia in pulmonary sepsis
Early lung infection
The effect of hypercapnic acidosis on pneumonia-induced ALI appears to depend on the
stage and severity of the infection. In an acute severe bacterial pneumonia-induced
lung injury, hypercapnic acidosis improved physiological indices of injury [38]. Intriguingly,
these protective effects were mediated by a mechanism independent of neutrophil function.
In contrast, hypercapnic acidosis did not alter the magnitude of lung injury in a
less severe acute bacterial pneumonia [39]. Importantly these in vivo studies showed
no increase in bacterial count in animals exposed to hypercapnic acidosis, a reassuring
finding given concerns regarding retardation of the host bactericidal response and
potential bacterial proliferation.
In the clinical setting, many critically ill patients will have established infection
at the time of presentation. Thus animal models of established bacterial pneumonia,
in which hypercapnic acidosis was introduced several hours following induction of
infection with E. coli, more closely resemble the clinical setting. In an established
pneumonia model, hypercapnic acidosis induced after the development of a significant
pneumonia-induced lung injury reduced physiological indices of lung injury [40]. Of
importance, these protective effects of hypercapnic acidosis were enhanced in the
presence of appropriate antibiotic therapy [40]. Again, reassuringly, lung bacterial
loads were similar in the hypercapnic acidosis and normocapnia groups [40].
Prolonged lung infection
In an animal model of prolonged untreated pneumonia, sustained hypercapnic acidosis
worsened histological and physiological indices of lung injury, including compliance,
arterial oxygenation, alveolar wall swelling and neutrophil infiltration [23]. Of
particular concern to the clinical setting, hypercapnic acidosis was associated with
a higher lung bacterial count. The mechanism underlying this effect appeared to be
inhibition of neutrophil function, as evidenced by impaired phagocytotic ability in
neutrophils isolated from hypercapnic rats [23]. Of importance to the clinical context,
the use of appropriate antibiotic therapy abolished these deleterious effects of hypercapnia,
reducing lung damage and lung bacterial load to levels comparable to those seen with
normocapnia.
These findings have been confirmed and considerably expanded in a recent study of
hypercapnia in the fruit fly [41]. Helenius et al., in a series of elegant in vivo
studies, found that prolonged hypercapnia decreased expression of specific anti-microbial
peptides in Drosophilia melanogaster [41]. Hypercapnia decreased bacterial resistance
in adult flies exposed to pathogens as evidenced by increased bacterial loads and
increased mortality in flies inoculated with E. faecalis, A. tumefaciens, or S. aureus
[41]. The previously demonstrated suppressive effects of hypercapnic acidosis on the
NF-κB pathway appeared to underlie the decreased resistance to infection [41]. These
findings raise significant concerns regarding the safety of hypercapnia in the setting
of prolonged pneumonia, particularly in the absence of effective antibiotic therapy.
Hypercapnia in systemic sepsis
A growing body of evidence attests to a beneficial role of hypercapnia in the setting
of systemic sepsis. Improvements in hemodynamic parameters and lung injury have been
demonstrated in evolving, established, and prolonged systemic sepsis in animal models.
This is in contrast to the detrimental effects of hypercapnic acidosis seen in prolonged
pulmonary sepsis, suggesting that the effects 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 first 3 hours post injury [42]. The severity of early
lung injury was reduced as evidenced by a decrease in the alveolar-arterial oxygen
gradient, and reduced lung permeability, compared to normocapnia. Alveolar neutrophil
concentration was reduced by hypercapnic acidosis but IL-6 and TNF-α were unchanged
[42]. Of importance, there were no differences in bacterial loads in the lung, blood,
or peritoneum in the hypercapnia group.
Prolonged systemic sepsis
Using an ovine model of fecal peritonitis, Wang et al compared the effects of hypercapnic
acidosis with those of dobutamine [43]. Over an 18-hour study period, hypercapnic
acidosis resulted in improved hemodynamics of a magnitude comparable to that of dobutamine.
Compared with normocapnia, both hypercapnic acidosis and dobutamine raised cardiac
index and systemic oxygen delivery and reduced lactate levels. In addition, hypercapnic
acidosis attenuated indices of lung injury, including lung edema, alveolar-arterial
oxygen partial pressure difference and shunt fraction. Hypercapnic acidosis did not
decrease survival time compared to normocapnia in this setting [43]. In a more prolonged
systemic sepsis model, Costello et al. demonstrated that sustained hypercapnic acidosis
reduced histological indices of lung injury compared with normocapnia in rodents following
cecal ligation and puncture [42]. Reassuringly there was no evidence of an increased
bacterial load in the lung, blood, or peritoneum of animals exposed to hypercapnia.
Intraperitoneal hypercapnia
Direct intra-abdominal administration of CO2 - by means of a pneumoperitoneum - reduces
the severity of abdominal sepsis-induced lung and systemic organ injury. Insuation
of CO2 into the peritoneal cavity prior to laparotomy for endotoxin contamination
increased animal survival [44]. Most recently, CO2 pneumoperitoneum has been demonstrated
to increase survival in mice with polymicrobial peritonitis induced by cecal ligation
and puncture (Figure 3) [31]. These protective effects of intraperitoneal carbon dioxide
insufflation appear be due to the immunomodulatory effects of hypercapnic acidosis,
which include an IL-10 mediated downregulation of TNF-α [44]. Importantly, these effects
appear to be mediated by the localized peritoneal acidosis, rather than by any systemic
effect.
Figure 3
Insufflation of CO2 into the peritoneal cavity improves survival following cecal ligation
and puncture-induced systemic sepsis. Animals were first subjected to cecal ligation
and puncture. Four hours later, animals underwent a laparotomy and induction of a
CO2 pneumoperitoneum (laparotomy + CO2), laparotomy alone, or no laparotomy; survival
was determined over the following 8 days. Modified from [31] with permission.
Buffering hypercapnic acidosis in sepsis
The immunomodulatory effects of hypercapnic acidosis in sepsis may occur as a function
of either hypercapnia or acidosis. As discussed, evidence suggests that hypercapnic
acidosis exerts certain effects via its associated acidosis [24], while other effects
appear be a function of the hypercapnia per se [17]. Buffered hypercapnia, i.e., hypercapnia
in the presence of normal pH, may be seen in ALI/ARDS patients as a renal compensatory
measure, or as a result of the administration of bicarbonate, a common clinical practice
in the ICU, and one that was permitted in the ARDSnet tidal volume study [1]. Aside
from well established concerns regarding the use of sodium bicarbonate, there is evidence
from animal models of lung and systemic sepsis that the anti-inflammatory and protective
effects of hypercapnic acidosis are lost with buffering. This has significant implications
in clinical scenarios where the buffering of hypercapnia resulting from protective
ventilator strategies is considered.
Pulmonary sepsis
In rodent models of acute pneumonia induced by intra-tracheal E. coli and by endotoxin,
buffered hypercapnia worsened lung injury [24]. Compared with normocapnic controls,
buffered hypercapnia increased multiple indices of lung injury including arterial
oxygenation, lung compliance, pro-inflammatory pulmonary cytokine concentrations,
and measurements of structural lung damage. In these experiments, buffered hypercapnia
was established in the animals by exposure to hypercapnic conditions until renal buffering
to normal pH had occurred, thus avoiding the confounding effects of exogenous acid
or alkali administration. This contrasts with the protective effects of hypercapnic
acidosis in similar models [11,38]. Of note, buffered hypercapnia did not reduce the
phagocytic capacity of neutrophils, and did not increase lung bacterial load in these
studies [24].
Systemic sepsis
In a study designed to assess the contribution of acidosis versus hypercapnia to the
effects of hypercapnic acidosis on the lung and hemodynamic profile in systemic sepsis,
Higgins et al. exposed rats to environmental hypercapnia until renal buffering had
restored pH to the normal range [45]. Both buffered hypercapnia and hypercapnic acidosis
reduced the severity of early shock and attenuated the increase in serum lactate compared
with normocapnia. In contrast, buffered hypercapnia did not attenuate physiologic
or histologic indices of lung injury in these studies [45]. Reassuringly, there was
no evidence to suggest that buffered hypercapnia worsened the degree of lung injury
compared to normocapnia, and buffered hypercapnia did not increase the bacterial load
in the lungs or the bloodstream [45].
Hypercapnia and sepsis: where are we now?
The generally beneficial effects of hypercapnic acidosis in the setting of experimental
non-septic inflammatory injury contrast with a more complex spectrum of effects in
the setting of live bacterial infection. Hypercapnia and/or acidosis exert diverse
- and potentially conflicting - effects on the innate and adaptive immune responses.
Overall, hypercapnic acidosis appears to suppress the immune response, although the
net effect of its multiple actions appears to vary depending on the site of infection
and also on whether the acidosis produced by the hypercapnia is buffered or not. Hypercapnic
acidosis appears to protect the lung from injury induced by evolving or more established
lung and systemic bacterial sepsis in relevant pre-clinical models. In contrast, the
effects of hypercapnic acidosis in prolonged untreated bacterial sepsis appear to
differ depending on the source of the infection, with the immunosuppressive effects
of hypercapnic acidosis worsening lung injury in the setting of prolonged pneumonia.
This deleterious effect is abrogated by effective antibiotic therapy. In contrast,
hypercapnic acidosis reduced lung damage caused by prolonged systemic sepsis, again
highlighting the potential importance of the source of infection. Finally, buffering
of the acidosis induced by hypercapnia does not confer significant benefit in the
setting of lung or systemic sepsis, and may actually worsen lung injury in the setting
of pneumonia.
Taken together, recent experimental findings in relevant pre-clinical models provide
some reassurance regarding the safety of hypercapnia in sepsis, particularly in early
pneumonia, and in the setting of abdominal sepsis. However, in the setting of prolonged
pneumonia, the immunosuppressive effects of hypercapnia remain a concern. While the
use of ventilation strategies resulting in hypercapnia is clearly justified in patient
with ALI/ARDS, care is warranted in the setting of sepsis. The finding that deleterious
effects of hypercapnia in the setting of prolonged pneumonia are abrogated by appropriate
antibiotic therapy is of importance.
Clinicians should carefully consider the use of early empiric antibiotic therapy in
hypercapnic ALI/ARDS patients in whom sepsis is suspected or confirmed. However, concerns
persist, particularly where antibiotic cover may be suboptimal, or the bacteria are
more resistant to antibiotic therapy. The findings that hypercapnia may increase septic
lung injury in the setting of prolonged pneumonia is also of relevance to other patient
groups, such as patients with infective exacerbations of chronic obstructive airways
disease.
Conclusion
Hypercapnia is an integral component of protective lung ventilatory strategies in
patients with severe respiratory failure. The potential for hypercapnia to modulate
the immune response, and the mechanisms underlying these effects are increasingly
well understood. The findings that hypercapnic acidosis is protective in systemic
sepsis, and in the earlier phases of pneumonia-induced sepsis, provide reassurance
regarding the safety of hypercapnia in the clinical setting. However, the potential
for hypercapnic acidosis to worsen injury in the setting of pro-longed lung sepsis
must be recognized. Additional studies are needed to further elucidate the mechanisms
underlying the effects of hypercapnia and acidosis in the setting of sepsis-induced
lung injury.
Competing interests
The authors declare that they have no competing interests.
List of abbreviations used
ALI: acute lung injury; ARDS: acute respiratory distress syndrome; IL: interleukin;
LPS: lipopolysaccharide; MRSA: methicillin resistant Staphylococcus aureus; NF-κB:
nuclear factor kappa-B; TLR: toll-like receptor; TNF: tumor necrosis factor; VAP:
ventilator-associated pneumonia.