REVIEW

CURRENT
OPINION Permissive hypercapnia: what to remember
Maya Contreras a, Claire Masterson a,b, and John G. Laffey a,b,c

Purpose of review
Hypercapnia is a central component of diverse respiratory disorders, while ‘permissive hypercapnia’ is
frequently used in ventilatory strategies for patients with severe respiratory failure. This review will present
data from recent studies relating to hypercapnia, focusing on issues that are of importance to
anesthesiologists caring for the surgical and/or critically ill patient.
Recent findings
Protective ventilatory strategies involving permissive hypercapnia are widely used in patients with severe
respiratory failure, particularly in acute respiratory distress syndrome, status asthmaticus, chronic obstructive
pulmonary disease and neonatal respiratory failure. The physiologic effects of hypercapnia are increasingly
well understood, and important recent insights have emerged regarding the cellular and molecular
mechanisms of action of hypercapnia and acidosis. Acute hypercapnic acidosis is protective in multiple
models of nonseptic lung injury. These effects are mediated in part through inhibition of the NF-kB
pathway. Hypercapnia-mediated NF-kB inhibition may also explain several deleterious effects, including
delayed epithelial wound healing and decreased bacterial killing, which has been demonstrated to cause
worse lung injury in prolonged untreated pneumonia models.
Summary
The mechanisms of action of hypercapnia and acidosis continue to be elucidated, and this knowledge is
central to determining the safety and therapeutic utility of hypercapnia in protective lung ventilatory
strategies.
Keywords
acidosis, acute lung injury, acute respiratory distress syndrome, hypercapnia, mechanical ventilation

INTRODUCTION considers the potential clinical implications of these

Permissive hypercapnia (PHC) results from lung findings for the management of patients with acute
protective mechanical ventilation approaches, lung injury. The experimental and clinical studies of
whereby elevated arterial CO2 is accepted to mini- special interest, published within the annual period
mize ventilator-induced lung injury (VILI). These of review, have been highlighted.
approaches have been demonstrated to improve the
outcome from acute respiratory distress syndrome
PHYSIOLOGY OF HYPERCAPNIA
(ARDS) [1,2]. Ventilation strategies incorporating
PHC are also well described in other diseases leading Hypercapnia exerts multiple physiologic effects on
to acute respiratory failure in adults and children, different organs, particularly the pulmonary, cardio-
including severe asthma and chronic obstructive vascular and cerebrovascular systems.
pulmonary disease (COPD). Paralleling these devel-
opments is a growing body of knowledge regarding
the mechanisms of action – both beneficial and
a
deleterious – of hypercapnia and its associated Department of Anesthesia, St Michael’s Hospital, bCritical Illness and
Injury Research Centre, Keenan Research Centre for Biomedical
acidosis, and extensive clinical experience attesting
Science, St. Michael’s Hospital and cDepartments of Anesthesia and
to the benign clinical profile of moderate hyper- Physiology, University of Toronto, Toronto, Canada
capnia, can be used to help guide the rational use of Correspondence to John G. Laffey, MD, FCAI, Department of Anesthe-
PHC at the bedside in the patient with severe sia, Critical Illness and Injury Research Centre, Keenan Research Centre
respiratory failure. for Biomedical Science, St Michael’s Hospital, University of Toronto,
This study reviews the physiology of hypercap- Toronto, Canada. Tel: +1 416 864 5071; e-mail: laffeyj@smh.ca
nia, discusses the insights gained to date from basic Curr Opin Anesthesiol 2015, 28:26–37
scientific studies of hypercapnia and acidosis and DOI:10.1097/ACO.0000000000000151

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 Permissive hypercapnia: what to remember Contreras et al.

directly relaxes small bronchi, and systemic hyper-

KEY POINTS capnia that indirectly can cause vagal nerve-
&&

Protective ventilatory strategies, which reduce lung mediated central airway constriction [10 ,12].
stretch, require tolerance of ‘permissive’ hypercapnia The effects of hypercapnia on the diaphragm are
and have improved outcome from ARDS. Evidence also complex. Older studies suggest that hypercapnic
supports the use of permissive hypercapnia strategies in acidosis (HCA) impairs diaphragmatic contractility
acute severe asthma and chronic obstructive airways and worsens diaphragmatic fatigue in spontaneously
disease. breathing individuals [15]. In recent studies, in which

The physiologic effects of hypercapnia are increasingly minute ventilation is controlled, HCA preserved dia-
well understood, while important recent insights have phragmatic contractility and prevented prolonged
emerged regarding the cellular and molecular ventilation-induced diaphragmatic dysfunction
mechanisms of action of hypercapnia and acidosis. &&
[16 ] by reducing diaphragmatic myosin loss and
&&

The protective effects of acute hypercapnic acidosis in inflammation [17 ]. The clinical impact of hyper-
diverse preclinical models are mediated through potent capnia on diaphragmatic function, especially with
effects on the host immune system, with key effects regard to weaning from mechanical ventilation, has
mediated through inhibition of the NF-kB pathway. yet to be elucidated.
Hypercapnia-mediated NF-kB inhibition may also
explain several deleterious effects, including delayed
epithelial wound healing and decreased bacterial Systemic hemodynamics and tissue
killing. oxygenation
HCA enhances tissue perfusion and oxygenation,

A clear understanding of the effects and mechanisms of
through multiple mechanisms. HCA increases car-
action of hypercapnia is central to determining its
safety and therapeutic utility. When using permissive diac output (CO), improves lung mechanics and
hypercapnia the clinician must decide for each specific ventilation–perfusion matching, increases periph-
patient what the appropriate trade-off is between the eral perfusion and enhances peripheral tissue hemo-
benefits of avoiding higher tidal volumes and the globin oxygen unloading (Bohr effect). Hypercapnia
cost – and benefits – of the associated hypercapnia. increases CO through increased sympathoadrenal

The potential for extracorporeal CO2 removal techno- activity despite directly decreasing myocardial con-
logies to facilitate even greater reductions in tidal and tractility [18]. Indeed, CO2 increases cardiac index
minute ventilation is clear, but awaits definitive studies. by 10–15% by each 10 mmHg of PaCO2 increase
[19,20], subcutaneous and muscle tissue oxygen
tension in both animals and humans [19–24]. In
contrast, even a short period of hypocapnic alkalosis
Pulmonary significantly reduces CO [20,25], portal blood flow,
gut perfusion and splanchnic oxygen delivery [25].
Moderate hypercapnia improves arterial oxygen- Hypoventilation-induced HCA preserves hemo-
ation in both normal [3–5] and diseased lungs dynamics in uncompensated experimental hemor-
[6,7] by reducing ventilation–perfusion heterogen- rhagic shock [26].
eity. An important recent experimental study Much attention has focused recently on the
suggests that CO2 directly affects lung compliance potential for hypercapnia-mediated enhanced tissue
&&
by modulating actin–myosin interactions [8 ]. perfusion to reduce postoperative wound infection.
Moderate hypercapnia increases, whereas hypocap- Fleischmann et al. [22] have shown in a small study
nia reduces lung parenchymal compliance, direct- that intraoperative hypercapnia was associated
ing ventilation to underventilated lung regions (low with significantly higher colon tissue oxygenation.
ventilation–perfusion) with higher alveolar pCO2, Similar observations have been reported in morbidly
resulting in better ventilation–perfusion matching. obese surgical patients [23]. However, a recent
Hypercapnia may also increase lung compliance multicenter randomized controlled trial (RCT),
through increased alveolar surfactant secretion including 1206 patients undergoing colon surgery,
and more effective surface tension-lowering proper- failed to demonstrate clear benefits of intraoperative
ties of surfactants under acidic conditions [9]. hypercapnia in surgical site infection (SSI) compared
CO2 tensions – both alveolar and systemic – with normocapnia [27 ].
&&

appear to modulate airway resistance. Hypocapnia

&&
causes bronchoconstriction [10 ], whereas hyper-
capnia has been shown to increase [11,12], decrease Cerebrovascular regulation
[13] or have little net effect [14] on lung resistance. Carbon dioxide is a key regulator of cerebrovascular
These variable responses appear to result from tone. For each 1 mmHg change in PaCO2, there is a 1
contrasting effects of alveolar hypercapnia, which to 2 ml/100 g/min change in global cerebral blood

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Thoracic anesthesia

flow [28]. Indeed, decreases in the reactivity of the inflammation and improves lung mechanics by
cerebral vasculature to CO2 may be a useful predic- inhibiting IkB-a degradation and nuclear p65 trans-
&&
tor of stroke risk [29 ]. These effects are mediated by location [49] (Fig. 1). The question whether the
extracellular pH rather than by direct changes in protective effect of HCA is mediated through CO2
PaCO2 [30]. Mechanisms leading to cerebral vaso- directly or pH in the context of VILI is still unknown.
dilatation or relaxation differ between adults and A recent study comparing the effect of HCA with
neonates. In adults, hypercapnia-induced vasodila- normocapnic metabolic acidosis found that meta-
tation is mediated, in part, by nitric oxide, whereas bolic acidosis exerted similar protection against VILI
in neonates, the main mediators are prostaglandins as HCA [48].
[28]. These mediators then activate K-ATP and K-Ca Of potential concern, hypercapnia may retard
channels through intracellular second messengers lung epithelial and cellular repair following stretch-
(cGMP/cAMP) resulting in decreased intracellular- induced injury. Doerr et al. [52] demonstrated first
Ca2þ and vasodilation [31]. that HCA impairs plasma membrane resealing in
HCA-mediated increases in cerebral blood flow VILI. HCA also delays epithelial wound closure in
are a clear concern in the setting of reduced intra- multiple pulmonary cell lines by reducing NF-kB-
cranial compliance. Indeed, traditional management dependent epithelial cell migration [53].
of traumatic brain injury frequently included sus-
tained hypocapnia to reduce cerebral blood volume
and control raised intracranial pressure [32]. How- Lung ischemia–reperfusion injury
ever, accumulating evidence has challenged this Lung ischemia–reperfusion is a key mechanism of
concept [33]. Sustained hypocapnia reduces cerebral injury in diverse clinical situations, including lung
O2 supply [34] and increases brain ischemia [35], transplantation, pulmonary embolism and ARDS.
increases vasospasm risk [36,37] and worsens HCA has been demonstrated to attenuate ische-
neuronal excitability [38], thereby potentiating mia–reperfusion-induced lung injury [54] by pre-
seizures [39]. More recent studies have shown that serving endothelial capillary barrier function and
prehospital severe hypocapnia in traumatic brain reducing lipid peroxidation, peroxynitrite pro-
injury patients worsens the outcome [40–42]. duction and apoptosis in lung tissue [55,58,61]
(Table 1). The dose–response characteristic of hyper-
capnia and its efficacy in pulmonary as well as
HYPERCAPNIA IN PRECLINICAL DISEASE systemic ischemia–reperfusion-induced lung injury
MODELS is well described [55,58,61]. Recent insights into the
Key insights into the effects of hypercapnia and protective mechanisms of HCA include the demon-
acidosis – potentially beneficial and harmful – have stration that hypercapnia suppressed T-cell function
&&
emerged from preclinical models, in which it is in post-lung transplantation [56 ]. Hypercapnia
possible to independently alter CO2 tension and also attenuated ischemia–reperfusion-induced
ventilation. NF-kB pathway activation and reduced lung inflam-
mation and apoptosis [62], through mechanisms
involving NF-kB inhibition and upregulation of
Ventilation-induced lung injury and repair the potent antioxidant enzyme, hemeoxygenase-1
&&
Substantial evidence demonstrates that moderate [57 ].
hypercapnia directly reduces VILI (Table 1) [43–50,
&& && &&
51 ,52–55,56 ,57 ,58]. Studies using clinically
more relevant (Vt) have further underlined the Sepsis
potential for hypercapnia to protect against mech- The potential for HCA to impair the host immune
anical stretch [46–49]. The biologic response to response in the setting of sepsis has raised serious
&&
cyclic stretch occurs through mechanosensors that concerns (Table 2) [63–67,68 ,69–75]. Accumulat-
transmit signals from the deformed extracellular ing data suggest that hypercapnia may result in net
matrix to the interior of the cell [49,50]. A recent benefit or harm depending on the site and duration
study has demonstrated that HCA prevents the of bacterial infection, the use of antibiotic therapy
stretch-induced activation of p44/42 MAP-kinase and whether the acidosis induced by hypercapnia is
&&
[51 ,59,60] (Fig. 1). Furthermore, hypercapnia buffered or not. In pneumonia models, HCA is
markedly reduced apoptosis, oxidative stress and protective in early [64] and more established infec-
inflammation by inhibiting the downward acti- tions [65]. In contrast, hypercapnia may be harmful
vation of the signal-regulating kinase 1 JNK/p38 in prolonged, untreated pneumonia, likely by
MAP-kinase pathway in alveolar epithelial cells reducing neutrophil-mediated and macrophage-
[50]. HCA also reduces stretch-induced lung mediated bacterial killing. This effect is completely

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 Permissive hypercapnia: what to remember Contreras et al.

Table 1. Summary of key publications on the effect and potential mechanisms of hypercapnia and/or acidosis in nonseptic
acute lung injury models
Experimental Applied CO2
Study model Injury concentration Effect

Broccard et al., Ex vivo (rabbit) VILI Targeted PaCO2: HCA reduced microvascular permeability, lung edema
2001 [43] 70–100 mmHg formation and BAL protein content in ex-vivo VILI.
Sinclair et al., In vivo (rabbit) VILI 12% HCA attenuated edema formation and histological injury in
2002 [44] VILI.
Laffey et al., In vivo (rabbit) VILI 12% HCA attenuated VILI in a clinically more relevant Vt ventilation
2003 [45] (12 ml/kg). HCA improved oxygenation and lung
mechanics.
Halbertsma In vivo (mouse) VILI 2, 4% HCA reduced BAL neutrophil count and cytokines (IL-b,
et al., 2008 TNF-a, IL-6, KC)
[46]
Peltekova In vivo (mouse) VILI Dose response curve HCA improved lung mechanics and permeability, reduced
et al., 2010 (0, 5, 12, 25%) BAL TNF-a, COX2 gene expression. HCA also increased
[47] nitrotyrosine formation.
Kapetanakis Ex vivo (rabbit) VILI Targeted pCO2: Normocapnic metabolic acidosis prevented lung edema
et al., 2011 100–130 mmHg formation to the same extent as HCA.
[48]
Contreras In-vivo (rat), in-vitro VILI 5% HCA reduced VILI, and BAL cytokines (IL-6, TNF-a, CINC-1).
et al., 2012 pulmonary epi- Moderate VILI prevented cytoplasmic IkB degradation and
[49] thelial cells nuclear p65 translocation. This was confirmed in in-vitro
stretch injury.
Yang et al., In-vivo (rat) and VILI Targeted paCO2 HCA attenuated microvascular leak, oxidative stress and
2013 [50] in-vitro alveolar 80–100 mmHg inflammation. HCA reduced caspase-3 activation
epithelial cells (apoptosis), MPO, MDA, enhanced SOD levels via
ASK-1-JNK/p38 pathway inhibition.
Otulakowski Ex-vivo (mouse), VILI 12% Hypercapnia prevented activation of EGFR and p44/42
et al., 2014 and in-vitro MAPK pathway in vitro. TNFR shedding (an ADAM-17
[51 ] alveolar targeted ligand induced by stretch injury) was reduced in
&&

epithelial cells vivo.

Doerr et al., Ex-vivo (rat) and VILI/plasma 12%, in-vitro pCO2: HCA reduced lung edema formation in vivo and plasma
2005 [52] in-vitro alveolar membrane 119 mmHg membrane resealing in vivo and in vitro.
epithelial cell resealing
O’Toole et al., In vitro Scratch 10,15% CO2 rather than pH reduced the rate of wound closure (cell
2009 [53] wound migration) in a dose-dependent manner via NF-kB pathway
inhibition.
Shibata et al., In vivo (rat) Free radical 25% HCA attenuated free radical-induced injury via inhibition of
1998 [54] endogenous xanthine oxidase and improved lung per-
meability.
Laffey et al., Ex vivo (rabbit) Pulmonary IR 12% HCA attenuated IR-induced lung and systemic injury. Reduced
2000 [55] BAL inflammation (TNF-a), 8-isoprostane and nitrotyrosine
generation in lung tissue. HCA reduced apoptosis.
Gao et al., In-vivo (rat) and in- Pulmonary IR 5% Hypercapnia decreased CD3þ/CD4þ T cell ratio, proinflam-
2014 [56 ] vitro T cells lung trans- matory cytokines and increased anti-inflammatory cytokines
&&

plant in vivo. CO2 inhibited CD28 and CD2, key molecules of T-

cell activation and acidosis reduced T-cell cytokine
production in vitro.
Wu et al., Ex-vivo (rat) and Pulmonary IR 5% HCA reduced lung permeability and inflammation. HCA also
2013 [57 ] in-vitro alveolar increased HO-1 activity via inhibition of the IKK-NF-kB
&&

epithelial cells pathway.

Laffey et al., In vivo (rat) Mesenteric IR Dose response curve HCA attenuated IR-induced microvascular leak, improved lung
2003 [58] (0, 2.5, 5, 10, mechanics and oxygenations. CO2 higher than 5% did not
20%), provided added benefit.

ADAM-17, ADAM metallopeptidase 17; ASK-1, apoptosis signal-regulating kinase-1; CINC-1, cytokine-induced neutrophil chemoattractant-1;
COX2, cyclooxygenase 2; EGRF, epidermal growth factor receptor; HO-1, heme oxygense-1; IkB, inhibitory kappa B; IL-b, interleukin b; IL-6, interleukin-6;
IR, ischemia–reperfusion; JNK, c-Jun N-terminal kinase; KC, keratocyte-derived chemokine; MDA, malondialdehyde; MPO, myeloperoxidase; NF-kB, nuclear
factor kappa B; p44/42 MAPKp44/p42 mitogen-activated protein kinase; SOD, superoxide dismutase; TNF-a, tumor necrosis factor-a; TNFR, tumor necrosis
factor receptor; VILI, ventilator-induced lung injury.

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Thoracic anesthesia

CO2

Ligand ADAM-17
Ligand
NF-κB Mechanical
EGFR pathway stretch
CO2 Endocytosis CO2
HCO3
Cytoplasm

Na, K- Non-
P ATPase
canonical ASK-1
sAC P
cAMP P Canonical

P P
P ReIB P38 JNK
P α-Adducin
PKA

Cleavage
p65
P44/42
MAPK CO2
P
PKC ERK 1/2
Translocation
p65 ReIB
Nucleus

ReIB

Inflammation
p65
Survival,
Proliferation, Apoptosis
Growth

FIGURE 1. Key intra-cellular signalling pathways modulated by CO2. Phosphorylation of P44/42 induced by stretch injury is
decreased with HCA by inhibition of ADAM-17, thereby reducing inflammation in alveolar epithelial cells. Clearance of lung
edema is decreased following the HCA-induced endocytosis of the Na,K-ATPase transporter. The translocation of anti-
inflammatory RelB is increased by HCA and HCA also can impair the translocation of the NF-kB protein p65. Apoptotic
signaling through the ASK1-JNK/p38 MAPK pathway is impaired by HCA, as shown by decreased levels of activated ASK-1,
p38 and JNK and decreased levels of cleaved caspase 3. ADAM-17, ADAM metallopeptidase 17; ASK-1, apoptosis signal-
regulating kinase-1; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; MAPK, mitogen-
activated protein kinase; NF-kB, nuclear factor kappa B; PKA, protein kinase A.

attenuated with antibiotic therapy [66]. These obser- organ injury induced by CLP sepsis. The beneficial
vations have recently been confirmed by Gates et al. effects of hypercapnia in systemic sepsis may relate
&&
[68 ]. Hypercapnia impaired neutrophil phagocy- to improved splanchnic microcirculatory oxygen-
tosis and bacterial killing capacity without affecting ation, counteracting the adverse hemodynamic
&& &&
neutrophil recruitment [68 ]. Importantly, hyper- effects of sepsis [76 ].
capnia increased bacterial load in lung, spleen and
liver, indicating significant level of systemic dissem-
&&
ination of bacterial sepsis [68 ]. Physiologic buffer- Pulmonary hypertension
ing has also been shown to be deleterious in Pulmonary hypertension is a common complication
Escherichia coli-induced pneumonia [67]. of many clinical syndromes including ARDS, COPD
In systemic sepsis, HCA has a more favorable and sepsis [77]. Although hypercapnia and acidosis
profile, protecting against early [70,71] and more should be clearly avoided in the context of severe
established [69] cecal ligation and puncture (CLP)- established pulmonary hypertension, experimental
induced septic shock. In prolonged CLP sepsis, the data suggest that hypercapnia may attenuate pul-
protective effect of hypercapnia on lung injury was monary hypertension-induced vascular remodeling
less marked [71]. Importantly, HCA did not alter and impaired right ventricular function [78–82].
BAL and peritoneal bacterial load in these studies. Peng et al. [80] recently demonstrated that hyper-
The potential for localized hypercapnia to exert capnia reverses both structural and functional
protective effects in the setting of experimental changes of hypoxia-induced pulmonary hyper-
abdominal sepsis has been demonstrated [72–74]. tension in juvenile rats by inhibition of RhoA/
More recently, Montalto et al. [75] CO2 demon- Rho-kinase pathways and augmentation of lung
strated that pneumoperitoneum may reduce distant tissue endothelial nitric oxide synthase and nitric

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 Permissive hypercapnia: what to remember Contreras et al.

Table 2. Summary of publications on the effect of hypercapnia and/or acidosis in live bacterial pneumonia and systemic
sepsis models
Study Animal model Injury Applied CO2 level Effect

Pulmonary sepsis
Ni Chonghaile In vivo (rat) Escherichia coli Inspired 5% CO2 HCA reduced lung injury
et al., 2008 [64] pneumonia induced by evolving E. coli
(early) pneumonia.
Chonghaile et al., In vivo (rat) E. coli pneumonia Inspired 5% CO2 HCA reduced lung injury
2008 [65] (established) induced by established E. coli
pneumonia.
O’Croinin et al., In vivo (rat) Prolonged E. coli Inspired 8% CO2 HCA worsened lung injury
2008 [66] pneumonia induced by prolonged
(48 h) untreated E. coli pneumonia.
Nichol et al., In vivo (rat) E. coli pneumonia Inspired 5% CO2, physiologic Buffered hypercapnia worsened
2009 [67] buffering E. coli pneumonia.
Gates et al., In vivo (mouse) Pseudomonas Inspired 10%, physiologic Buffered hypercapnia worsened
2013 [68 ] pneumonia buffering pseudomonas pneumonia.
&&

(96 h)
Systemic sepsis
Wang et al., In vivo (sheep) Fecal peritonitis Targeted paCO2 55–65 mmHg CO2 improved tissue oxygen-
2008 [69] ation in septic shock.
Costello et al., In vivo (rat) CLP sepsis, septic Inspired 5% CO2 CO2 decreased CLP sepsis-
2009 [70] shock (3, 6 h) induced lung injury.
Higgins et al., In vivo (rat) CLP sepsis (96 h) Inspired 5% CO2 Buffering ablates benefit of
2009 [71] CO2on lung injury in septic
shock.
Hanly et al., In vivo (rat) CLP sepsis (0.5 h) CO2 pneumoperitoneum CO2 pneumoperitoneum
2005 [72] decreased CLP-induced
mortality
Fuentes et al., In vivo (rat) Endotoxemia and CO2 pneumoperitoneum CO2 pneumoperitoneum
2006 [73] laparotomy (7 h) increased survival
Metzelder et al., In vivo (mouse) CLP sepsis, septic CO2 pneumoperitoneum CO2 pneumoperitoneum
2008 [74] shock (6 h to 7 increased survival
days)
Montalto et al., In vivo (rat) CLP sepsis and CO2 pneumoperitoneum CO2 pneumoperitoneum
2011 [75] laparotomy (7 h) decreased hepatic and
pulmonary inflammation

CLP, cecal ligation and puncture.

oxide levels. Hypercapnia significantly decreased alveolar fluid is central to ARDS resolution [83].
pulmonary vascular resistance and improved right HCA reduces alveolar edema formation by inhibit-
ventricular performance following bleomycin- ing the increase in pulmonary capillary permeability
induced lung injury, and reduced lung macrophage included by free radicals [54], ischemia–reperfusion
recruitment and TNF-a expression [81]. The effect of [61] and high stretch ventilation [45]. In contrast,
HCA on hypoxemic pulmonary vasoconstriction hypercapnia decreases alveolar fluid clearance, a
(HPV) remains unclear. A recent study has shown process dependent on intact Naþ transport across
that CO2 – independently from acidosis – increased the apical surface of alveolar epithelial cells. Hyper-
hypoxemic pulmonary vasoconstriction during sus- capnia – independent of pH – reduces alveolar fluid
tained hypoxemia and increased indices of lung removal through intracellular activation of the
edema possibly through increased inducible nitric protein kinase C z isotype, followed by phosphoryl-
oxide synthase activity [82]. ation and endocytosis of the Naþ/Kþ-ATPase pump
[84]. Hypercapnia also activates ERK1/2, a key regu-
Alveolar fluid dynamics latory molecule in Naþ/Kþ-ATPase endocytosis [85].
&&
The accumulation of pulmonary edema is the hall- Lecuona et al. [86 ] showed that hypercapnia
mark of ARDS, whereas subsequent clearance of increases cAMP levels, activates PKA-Ia that leads

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Table 3. Summary of recent publications on the potential molecular mechanisms of hypercapnia and/or acidosis involving the
NF-kB pathway
Study Model Injury Applied CO2 Effect on NF-kB pathway

Takeshita et al., In-vitro pulmonary Endotoxin 10% Hypercapnia reduced cell injury and
2003 [88] endothelial cells prevented IkB degradation. NF-kB
dependent cytokine (IL-8. ICAM-1)
production was reduced.
O’Toole et al., In-vitro SAEC, HBE, Scratch injury 10, 15% HC reduced the rate of wound closure by
2009 [53] A549 cells (repair) reducing cell migration. HC also inhibited
p65 translocation and IkB degradation.
Helenius et al., Dorsophila and in- Sepsis 13, 20% HC suppressed NF-kB-dependent antimicro-
2009 [89] vitro S2 cells bial protein gene expression and
increased the susceptibility to multiple
bacterial strains and increased mortality.
NF-kB pathway was inhibited by CO2
rather than pH independent of IkB
degradation.
Cummins et al., In-vitro six different Endotoxin stimu- 5, 10% CO2 directly facilitated IKK-a nuclear trans-
2010 [90] cell lines lated port, reduced IkB degradation and
nuclear p65 translocation. Expression of
NF-kB-dependent proinflammatory genes
was blunted (CCL2, ICAM-1, TNF-a)
whereas anti-inflammatory gene (IL-10)
expression was increased.
Wang et al., In-vitro human Endotoxin stimu- 5, 9, 12.5, 20% HC independent of pH inhibited macro-
2010 [91] and mouse lation phage phagocytosis, cytokine release
macrophages (IL-6, TNF-a). CO2 inhibited Il-6 promoter
driven luciferase activity independent of
NF-kB activation.
Contreras et al., In-vivo (rat) and VILI 5, 10% HCA reduced VILI, and BAL cytokines (IL-6,
2012 [49] in-vitro pulmonary TNF-a, CINC-1). Moderate VILI prevented
epithelial cells cytoplasmic IkB degradation and nuclear
p65 translocation. This was confirmed in
in-vitro stretch injury.
Wu et al., 2012 Ex vivo (rat) lung Pulmonary IR 10% HCA reduced inflammation by inhibiting IkB
[62] degradation, p65 translocation and DNA
binding activity, and IKK phosphorylation
in lung tissue.
Wu et al., 2013 Ex-vivo (rat) and Pulmonary IR 5% HCA reduced lung permeability and inflam-
[57 ] in-vitro alveolar mation. HCA also increased HO-1 activity
&&

epithelial cells by inhibition of the IKK-NF-kB pathway.

A549, lung epithelial cell; CCL2, chemokine ligand 2; CINC-1, cytokine-induced neutrophil chemoattractant-1; HBE, human bronchial cells; IkB, inhibitory kappa B;
ICAM-1, intercellular adhesion molecule 1; IKK-a, inhibitory kappa B kinase complex-a; IL-10, interleukin-10; IL-8, interleukin-8; NF-kB, nuclear factor kappa B;
S2, Schneider 2 cells (Drosophila melanogaster cell line); SAEC, small airway epithelial cell.

&&
to the activation of a-adductin – a cytoskeletal injury and repair (Table 3) [49,53,57 ,62,88–91].
protein – mediated endocytosis of the Naþ/Kþ- Takeshita et al. [88] first reported that HCA pre-
ATPase complex (Fig. 1). Others have shown that vented IkB-a degradation in endotoxin-stimulated
increasing levels of CO2 – not acidosis – rapidly pulmonary endothelial cells. Recently, Contreras
activate c-jun N terminal kinase (JNK) resulting in et al. [49] demonstrated that HCA protected against
decreased Naþ/Kþ-ATPase pump activity [84,87]. VILI by inhibiting NF-kB activation. Importantly,
HCA also reduces pulmonary epithelial wound repair
by NF-kB pathway inhibition [53]. Cummins et al.
Hypercapnia and NF-kB pathway [90] proposed the existence of an intracellular CO2
Several beneficial and the deleterious effects of HCA molecular sensor linked to NF-kB pathway as a con-
are mediated by the inhibition of the NF-kB pathway, nection to innate immunity and inflammation.
a pivotal transcriptional activator in inflammation, Others have shown that elevated CO2 suppressed

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 Permissive hypercapnia: what to remember Contreras et al.

host defence by inhibiting NF-kB-dependent antimi- [97,98]. In these studies, arterial CO2 was kept inten-
crobial peptide gene expression in Drosophila result- tionally at moderately elevated levels (63, 68
ing in increased mortality to bacterial infection [89]. mmHg), whereas extremely high arterial CO2 levels
High levels of CO2 have also been shown to inhibit (150–200 mmHg) were also well tolerated in case
IL-6, TNF-a induction and phagocytosis in endo- series involving more severe presentations of
toxin-stimulated macrophages [91]. In the two latter asthma [99]. In spite of lack of RCTs to guide mech-
studies, hypercapnia inhibited the NF-kB pathway anical ventilation in status asthmaticus, PHC has
without affecting IkB-a degradation, suggesting that been frequently used in patients with severe asthma
other pathways or regulatory steps may have been admitted to ICUs both in Europe [100] and in North
involved in mediating the immunosuppressive effect America [101].
of hypercapnia.

Chronic obstructive pulmonary disease

HYPERCAPNIA IN THE CLINICAL Respiratory failure during COPD exacerbations is a
CONTEXT direct result of an acute increase in airway narrow-
Hypercapnia is frequently encountered in the ing, with increased respiratory workload, similarly
setting of acute respiratory failure, both as a con- to acute severe asthma. Although noninvasive
sequence of the disease process and as a result of ventilation is the first-line ventilation strategy in
strategies to minimize the potential of mechanical patients with COPD exacerbations [102], extreme
ventilation to stretch and further injure the lung. respiratory muscle fatigue, CO2 retention-induced
‘coma’ may necessitate invasive ventilation. The
primary aim of mechanical ventilation in this set-
Acute respiratory distress syndrome ting is to reduce over-inflation and prevent VILI by
To date, there have been no clinical trials examining reducing minute ventilation, decreasing inspira-
the direct effect of hypercapnia on patients with tory–expiratory ratio and increasing inspiratory
ARDS. The potential of PHC to improve ARDS flow rate. PHC is a useful approach to achieving
patients’ survival as part of a protective ventilation these goals [103].
strategy was suggested first by Hickling et al. [92,93].
Subsequently, two RCTs comparing ‘traditional’
versus low Vt showed improved survival in patients Neonatal respiratory failure
with ARDS [1,2]. The secondary analysis of the Advances in perinatal medical care and ventilatory
ARMA trial suggested that patients with moderate support have reduced mortality in high-risk new-
HCA on study day 1 had significantly less odds ratio borns [104]. Prolonged mechanical ventilation,
of death at 28 days in the setting of higher – but not however, remains an important cause of pulmonary
lower – Vt [94]. Because the primary aim of these complications, such as bronchopulmonary dysplasia.
trials was to investigate the effect of low stretch Early observational studies suggested that PHC may
ventilation on ARDS, the direct relationship lower the risk for bronchopulmonary dysplasia in
between PHC and lung protection remains to be premature infants. Mariani et al. [105] first reported
determined. In a recent pilot study, a combination that ventilation strategies allowing higher PaCO2
of stepwise recruitment–derecruitment with PHC levels (45–55 versus 35–45 mmHg) in preterm
was compared with lung protective ventilation infants, in the first 96 h of life, result in faster weaning
[95]. This ‘open lung’ strategy resulted in signifi- from mechanical ventilation. Subsequently, a larger
cantly better lung compliance, systemic oxygen- multicenter RCT compared PHC with conventional
ation in a 7-day period. However, arterial CO2 and ventilation with dexamethasone or placebo using a
pH were not different between the two groups, 2  2 factorial design [106]. Although the trial was
suggesting that the achieved benefits were more stopped due to adverse events in the dexamethasone
likely related to better recruitment maneuver in groups, PHC decreased need for assisted ventilation
the open-lung strategy group than to PHC per se. at 36-week gestational age from 16% to just 1%. The
potential of PHC to cause intracranial hemorrhage
and adverse neurological outcomes in premature
Asthma infants is a significant concern. Although an early
The utility of PHC in status asthmaticus was meta-analysis of PHC in newborn infants demon-
reported first by Darioli in 1984 [96]. Subsequent strated some trends toward decreased incidence of
studies also confirmed that lowering minute venti- intracranial hemorrhage in the PHC group [107], in a
lation, in conjunction with longer expiratory recent study higher ranges of hypercapnia (PaCO2:
time, significantly reduces dynamic hyperinflation 55–65 mmHg) were associated with a significant

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Thoracic anesthesia

increase in combined mental impairment and death facilitate even greater reductions in tidal and
in extremely preterm infants [108]. These data minute ventilation is clear, but awaits definitive
indicate that more research is needed to determine studies.
the optimal range of hypercapnia to balance the
benefits and potential harms of PHC in preterm Acknowledgements
infants. None.

Financial support and sponsorship

EXTRA-CORPOREAL CO2 REMOVAL: THE J.G.L. is supported by operating grants from the Cana-
FUTURE? dian Institutes of Health Research and Physicians
In recent years, new-generation extracorporeal CO2 Services Incorporated and by a Merit award from the
removal (ECCO2-R) devices have been developed Department of Anesthesia at the University of Toronto.
that offer lower resistance to blood flow, have small C.M. is funded by a grant from the European Respiratory
priming volumes and have much more effective gas Society.
exchange [109]. These devices may further facilitate
lung protective ventilation by allowing greater Conflicts of interest
reductions in Vt and plateau pressures in patients None.
with severe ARDS, while avoiding the potential for
severe hypercapnia – beyond levels that are gener- REFERENCES AND RECOMMENDED
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34 www.co-anesthesiology.com Volume 28
Number 1
February 2015

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SSI is inversely related to tissue oxygenation. Furthermore, mild hypercapnia has induced lung injury: a pilot study. BMC Anesthesiol 2011; 11:8.
been shown to improve tissue oxygenation in a number of experimental and 49. Contreras M, Ansari B, Curley G, et al. Hypercapnic acidosis attenuates
human studies. The investigators hypothesized that moderate hypercapnia would ventilation-induced lung injury by a nuclear factor-kappaB-dependent me-
reduce SSI compared with normocapnia in patients undergoing elective colon chanism. Crit Care Med 2012; 40:2622–2630.
surgery. Patients were randomly assigned to intraoperative normocapnia 50. Yang WC, Song CY, Wang N, et al. Hypercapnic acidosis confers anti-
(ETCO2: 35 mmHg, n ¼ 623) or hypercapnia (ETCO2: 50 mmHg, n ¼ 592). oxidant and antiapoptosis effects against ventilator-induced lung injury. Lab
The primary outcome was SSI rate within 30 postoperative days. The SSI rate Invest 2013; 93:1339–1349.
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The study was stopped after recruiting 1206 patients due to small treatment && ventilator induced lung injury via a disintegrin and metalloprotease-17.

effect. J Physiol 2014; 592:4507–4521.

28. Brian JE Jr. Carbon dioxide and the cerebral circulation. Anesthesiology The paper demonstrated hypercapnia inhibits stretch-induced injury via a mechan-
1998; 88:1365–1386. ism involving inhibition of the matrix metalloprotease ADAM17, which in turn
29. Reinhard M, Schwarzer G, Briel M, et al. Cerebrovascular reactivity predicts decreases activation of p44/42 MAPK activation that occurs in response to
&& stroke in high-grade carotid artery disease. Neurology 2014; 83:1424– stretch-induced lung injury.
1431. 52. Doerr CH, Gajic O, Berrios JC, et al. Hypercapnic acidosis impairs plasma
This meta-analysis, including nine studies and 754 patients, assessed the membrane wound resealing in ventilator-injured lungs. Am J Respir Crit Care
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patients with symptomatic or asymptomatic severe carotid artery stenosis or 53. O’Toole D, Hassett P, Contreras M, et al. Hypercapnic acidosis attenuates
occlusion. In a multiple regression model, reduced CO2 activity on TCD was pulmonary epithelial wound repair by an NF-kappaB dependent mechanism.
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ratio: 3.69, P < 0.0001). Risk prediction for asymptomatic, as well as sympto- 54. Shibata K, Cregg N, Engelberts D, et al. Hypercapnic acidosis may attenuate
matic carotid stenosis, was significant and associated with a hazard ratio of 1.64 acute lung injury by inhibition of endogenous xanthine oxidase. Am J Respir
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reactivity may represent a simple investigation tool to assess stroke risk in 55. Laffey JG, Tanaka M, Engelberts D, et al. Therapeutic hypercapnia reduces
patients with carotid stenosis. This should be further tested in prospective pulmonary and systemic injury following in vivo lung reperfusion. Am J Respir
studies. Crit Care Med 2000; 162:2287–2294.

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Thoracic anesthesia

56. Gao W, Liu D, Li D, et al. Effects of hypercapnia on T cells in lung ischemia/ 75. Montalto AS, Bitto A, Irrera N, et al. CO2 pneumoperitoneum impact on early
&& reperfusion injury after lung transplantation. Exp Biol Med (Maywood) 2014. liver and lung cytokine expression in a rat model of abdominal sepsis. Surg
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This study aimed to investigate the effects of normocapnia, HCA and buffered 76. Stubs CC, Picker O, Schulz J, et al. Acute, short-term hypercapnia improves
hypercapnia on T-cell function in in-vivo and in-vitro ischemia –reperfusion && microvascular oxygenation of the colon in an animal model of sepsis.

injury following lung transplantation. Hypercapnia decreased CD3þ/CD4þ Microvasc Res 2013; 90:180–186.
T cell ratio, proinflammatory cytokines, whereas it increased anti-inflammatory The aim of this study was to investigate the effects of acute hypercapnia and HCA on
cytokines. Furthermore, CO2 inhibited CD28 and CD2, key molecules of T cell the colonic microcirculation and early cytokine response in colon ascendens stent
activation, whereas acidosis reduced T cell cytokine production. This is the first peritonitis-induced polymicrobial sepsis. Rats were randomized after 24 h sepsis and
study that directly investigated the separate effect of CO2 and pH on T cell ventilated for 120 min with normocapnia (45  5 mmHg) or HCA (75  5 mmHg) or
function. buffered hypercapnia (thromethamine). Colon wall tissue oxygenation, hemody-
57. Wu SY, Li MH, Ko FC, et al. Protective effect of hypercapnic acidosis in namics and cytokine levels were determined. Both hypercapnia and acidosis
&& ischemia-reperfusion lung injury is attributable to upregulation of heme improved tissue oxygenation; however, cytokine levels did not differ among the
oxygenase-1. PLoS One 2013; 8:e74742. groups. This study highlights that the effect of hypercapnia on inflammatory response
&&
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