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Lung-protective ventilation (LPV) has become the cornerstone of management in patients with
ARDS. A subset of patients is unable to tolerate LPV without significant CO2 elevation. In these
patients, permissive hypercapnia is used. Although thought to be benign, it is becoming
increasingly evident that elevated CO2 levels have significant physiological effects. In this
narrative review, we highlight clinically relevant end-organ effects in both animal models and
clinical studies. We also explore the association between elevated CO2, acute cor pulmonale,
and ICU mortality. We conclude with a brief review of alternative therapies for CO2 manage-
ment currently under investigation in patients with moderate to severe ARDS.
CHEST 2018; 154(1):185-195
KEY WORDS: acute cor pulmonale; ARDS; mechanical ventilation; permissive hypercapnia; right
ventricular dysfunction
ABBREVIATIONS: ABG = arterial blood gas; ACP = acute cor pulmo- AFFILIATIONS: From the Department of Critical Care Medicine (Drs
nale; ALI = acute lung injury; CVP = central venous pressure; Barnes and Parhar), University of Calgary, Calgary, AB, Canada; and
ECCO2R = extracorporeal venovenous CO2 removal; ECLS = extra- Department of Critical Care Medicine (Dr Zochios), University Hos-
corporeal life support; Ees:Ea = ratio of elastance of right ventricle to pitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital,
elastance of pulmonary artery system; HA = hypercapnic acidosis; IL- College of Medical and Dental Sciences, University of Birmingham,
8 = interleukin 8; LPV = lung-protective ventilation; mPAP = mean Birmingham, England.
pulmonary arterial pressure; NF-kB = nuclear factor kappa light chain CORRESPONDENCE TO: Ken Parhar, MD, Department of Critical
enhancer of activated B cells; PA = pulmonary artery; PBW = predicted Care Medicine, University of Calgary, ICU Administration, Ground
body weight; PEEP = positive end-expiratory pressure; Ppao = pul- Floor, McCaig Tower, Foothills Medical Center, 3134 Hospital Drive
monary artery occlusion pressure; Pplat = plateau pressure; PVR = NW, Calgary, Alberta, T2N 5A1, Canada; e-mail: ken.parhar@
pulmonary vascular resistance; RV = right ventricle; RVEDA/ albertahealthservices.ca
LVEDA = ratio of right ventricular end-diastolic area to left ventricular Copyright Ó 2017 American College of Chest Physicians. Published by
end-diastolic area; TEE = transesophageal echocardiography; VILI = Elsevier Inc. All rights reserved.
ventilator-induced lung injury
DOI: https://doi.org/10.1016/j.chest.2017.11.010
chestjournal.org 185
systemic cytokine response (biotrauma).4 exposed to hypercapnia develop impaired neutrophil
Unfortunately, mortality in severe ARDS remains function and have higher mortality compared with air-
high—upward of 40%.5 A consequence of low-tidal exposed counterparts.17
volume ventilation is a reduced ability to clear CO2
Additional studies using neutrophil-depletion and
due to reduced minute ventilation. A subset of patients
Escherichia coli-mediated lung injury have found
cannot tolerate LPV without significant PaCO2
hypercapnic acidosis to be beneficial for oxygenation
elevation. In these patients, a higher respiratory rate to
and lung compliance; however, there is no change in
increase minute ventilation and lower PaCO2, or
either lung inflammation or histologic damage between
permissive hypercapnia to facilitate low-tidal volume
hypercapnia and normocapnia.18 Hypercapnia alone
ventilation, is used. Although initially thought to be
significantly enhances inflammatory reactions mediated
benign or even protective, it is becoming increasingly
by nitric oxide and secondary nitrating species in fetal
evident that elevated CO2 levels have significant
rat lung epithelial cells exposed to lipopolysaccharide
physiological effects that may in fact be deleterious.
and inflammatory cytokines.19 The duration of
This review outlines both the physiological and clinical
hypercapnic acidosis may influence its effects, as
sequelae of permissive hypercapnia in ARDS.
attenuation of both histologic and physiological indices
Effects of Hypercapnic Acidosis in Animal of disease severity is observed with hypercapnic acidosis
Models of short duration (< 6 hours)20 and in models of acute
lung injury (ALI) related to systemic sepsis.21
Cytokine Response Conversely, models using pulmonary sepsis-mediated
Normal CO2 arterial tension is generally within the ALI demonstrate no difference in physiological or
range of 35 to 45 mm Hg. Classification of hypercapnia histologic indices of lung injury with hypercapnic
is variably defined but will be referred to in this review acidosis22 or worsened histologic indices and higher
as mild, moderate, and severe according to the ranges of pulmonary bacterial loads in the setting of prolonged
46 to 50, 50 to 75, and > 75 mm Hg, respectively.6 At hypercapnic acidosis (> 48 hours duration) without
the molecular level, hypercapnic acidosis inhibits appropriate antimicrobial therapy.23
production of proinflammatory cytokines and has been
Inhibition of Lung Epithelial Cell Repair and
shown to attenuate inflammation related to ventilator Function
induced lung injury (VILI) by inhibition of nuclear
factor kappa light chain enhancer of activated B cells Hypercapnic acidemia impairs pulmonary epithelial
(NF-kB), and interleukin 8 (IL-8).7,8 Hypercapnic wound healing through two mechanisms.24,25 First, it
acidosis reduces oxidative reactions in the endotoxin- slows epithelial repair of stretch-induced cell membrane
injured rat lung model.9 Hypercapnic acidosis has also injury.24 Second, it inhibits repair of ventilator-induced
been associated with less severe VILI in isolated perfused pulmonary epithelial cell injury, likely through
rabbit lungs ex vivo10 and in vivo.11 It has been inhibition of the NF-kB pathway, by reducing cell
suggested by several groups that therapeutic migration and altering matrix metalloproteinase
hypercapnia might provide benefit in ARDS,12-14 and activity.25 Recent clinical work lends support to these
although decreasing host oxidative injury through findings, as pleural hypercarbia correlates with persistent
hypercapnic acidosis would be of benefit in many cases, alveolar-pleural fistulas post-lung resection.26 Finally,
it may be deleterious when the cause of ARDS is short-term hypercapnia, independent of pH, has been
pulmonary infection, and the free radicals generated shown to impair alveolar epithelial cell function,
may play a role in facilitating bacterial injury and resulting in decreased alveolar fluid resorption.27
death.15 Renal Effects
At the cellular level, hypercapnia alone lowers the release Acute hypercapnic acidosis has been shown to have
of IL-8 from lipopolysaccharide-stimulated several direct effects on renal vasculature in vivo. In
neutrophils,16 whereas hypercapnic acidemia attenuates conscious dogs, it reduces renal plasma flow,28-30
lung neutrophil recruitment and function. This leads to increases renal vascular resistance,30 stimulates robust
a reduced host inflammatory response but at the cost of activation of the renin-angiotensin-aldosterone
impaired immune-mediated bactericidal activity in the system,30,31 contributes to nonosmotic release of
lung.14 The latter is also supported by a study showing vasopressin,29 and diminishes renal free water
that mice with Pseudomonas aeruginosa pneumonia excretion.29 Ischemia-induced apoptosis of rat renal
186 Contemporary Reviews in Critical Care Medicine [ 154#1 CHEST JULY 2018 ]
tubular cells in vitro is observed when hypercapnia and acidosis is directly beneficial in ALI, it does highlight the
hypoxemia are present simultaneously.32 In humans, need for further studies. In addition, a strategy using
hypoxemia and severe hypercapnia have been associated prolonged hypercapnia with untreated pulmonary
with reduced renal function,33 whereas higher plasma infection demonstrates evidence of harm without
norepinephrine levels are correlated with hypercapnia.34 appropriate antimicrobial therapy.23
There is also a potential association with an increased
requirement for hemodialysis in patients using volume-
and pressure-limited ventilation with hypercapnia.35 Clinical Studies of Permissive Hypercapnia
With ARDS
Diaphragmatic and Skeletal Muscle Effects
Cardiopulmonary Effects of Hypercapnia
Hypercapnic acidosis has been shown to modulate rat
diaphragm myogenic response through endothelium- Hypercapnia induces physiological changes in the
mediated alterations to diaphragmatic arteriolar tone. pulmonary and systemic circulations (Fig 1). In
Hypercapnic acidosis with CO2 values < 80 mm Hg healthy subjects, hypercapnic acidosis induces a
elicits enhancement of myogenic tone. Conversely, rightward shift of the oxygen-hemogloblin
hypercapnic acidosis with CO2 values of > 80 mm Hg dissociation curve42 and lowers systemic vascular
inhibits myogenic tone through endothelium-dependent resistance.43 In cardiopulmonary patients who have
inhibitory mechanisms. CO2 values around 100 mm Hg undergone bypass surgery, hypercapnia results in
appear to inhibit myogenic tone by both endothelium- globally reduced myocardial contractility; however,
dependent inhibitory mechanisms and direct effects of sympathetically driven tachycardia serves to maintain
CO2 on arteriolar smooth muscle tone.36 In addition, cardiac output when compensatory reserve exists.44
skeletal muscle atrophy is associated with elevated CO2 Right ventricule (RV) function is particularly affected
both in vitro and in vivo.37 This may have relevance to in the setting of postoperative hypercapnia so that
the subset of patients with ARDS and underlying there is increased right ventricular end-diastolic
chronic pulmonary disease in whom muscle atrophy volume, decreased right ventricular ejection fraction,
correlates with worse clinical outcomes. and a significant increase in right ventricular stroke
work index. These observations are in part due to
Pulmonary Circulation increased PVR owing to the direct vasoconstrictive
Hypercapnic acidosis enhances pulmonary effects of hypercapnic acidosis on pulmonary
vasoconstriction in animals.38,39 In particular, it vasculature and to the accompanying rise in
correlates with significant elevation in mean pulmonary mPAP.45-47 In patients with chronic pulmonary
arterial pressure (mPAP) and pulmonary vascular disease without ARDS, Enson et al48 demonstrated
resistance (PVR) in non-ARDS39 and ARDS porcine that respiratory acidosis, but not hypercapnia alone,
models,38 respectively. causes elevation in PVR and mPAP. In addition, their
study showed that increases in mPAP may be more
Buffered Hypercapnic Acidosis sensitive to hypoxia at lower pH values. Uncertainty
Preclinical studies have investigated whether remains as to the relative contribution of hypercapnia
hypercapnia or the associated respiratory acidemia and respiratory acidosis to increases in PVR and
exerts the physiological effects in models of ALI. Data mPAP in patients with ARDS.
from a rodent model using E coli or endotoxin-induced
Additional insight into the alteration of pulmonary
lung injury exhibited worse lung injury and reduced
hemodynamics in ARDS can be obtained by studies
wound healing in renal buffered hypercapnic acidosis in
examining coupling between the RV and pulmonary
comparison with normocapnic control subjects
arterial circulation. The pulmonary vasculature is
following 6 hours of LPV.40 Additionally, sepsis-induced
characterized by the arterial elastance of the
ALI in rodents demonstrated similar degrees of
pulmonary artery system synonymous with RV
physiological and histologic injury in both bicarbonate-
afterload (Ea), whereas the RV system is characterized
buffered hypercapnic acidosis and nonbuffered
by the RV elastance (Ees).49 The Ees:Ea is the ratio of
normocapnic control animals.41
RV to pulmonary artery (PA) elastance and reflects
Although evidence from preclinical animal studies the mechanoenergetic aspects of RV/PA coupling,
provides little to support the notion that hypercapnic which determines RV stroke volume. When the Ees:Ea
chestjournal.org 187
Figure 1 – Systemic effects of hypercapnia. HR ¼ heart rate; mPAP ¼ mean pulmonary artery pressure; PVR ¼ pulmonary vascular resistance;
RVEF ¼ right ventricular ejection fraction; RVSWI ¼ right ventricular stroke work index; SVR ¼ systemic vascular resistance.
is greater than 1 (normal range 11/2-2), the system is population. It is variably defined using right heart
coupled, providing adequate RV cardiac output at catheterization, pulmonary artery catheterization, and
minimal energy cost.50 In the context of hypercapnia, echocardiography.
pulmonary vasoconstriction and elevated RV
Prior to the advent of LPV, ACP (defined as septal
afterload may lead to an increase in Ea, uncoupling
dyskinesia associated with a right ventricular to left
of the RV/PA system, and subsequent RV
ventricular end-diastolic area ratio [RVEDA/LVEDA] >
dysfunction.50
0.6) was very common and could be observed in more
Cardiopulmonary Effects of Mechanical Ventilation than half of patients examined.55 Not surprisingly, it is
in ARDS positively correlated with increases in plateau pressure
Studies of mechanical ventilation in patients with (Pplat) during mechanical ventilation.56 In a large
ARDS some 40 years ago first identified pulmonary pooled analysis using echocardiographic studies of
capillary lesions leading to pulmonary hypertension, patients with ARDS, the presence of ACP was 13%,
marked RV dysfunction with elevation of right 32%, and 56% when Pplat values ranged between 18 and
ventricular stroke work index, and upward of a 26, 27 and 35, and > 35 cmH2O, respectively. The
threefold increase in PVR.51-54 ACP represents the highest mortality was observed in the two groups with
most severe form of RV dysfunction and has been the highest Pplat values, in whom ACP was most
subject of numerous investigations in the ARDS prevalent.56 However, similar studies using LPV have
188 Contemporary Reviews in Critical Care Medicine [ 154#1 CHEST JULY 2018 ]
described significantly lower rates.57 For example, ventilation on RV function but also has facilitated a
Osman et al58 noted that RV failure (defined as the better understanding of the relationship between
presence of mPAP > 25 mm Hg, central venous mechanical ventilation, permissive hypercapnia, and the
pressure (CVP) greater than pulmonary artery occlusion development of ACP (Table 1). Mekontso Dessap et al65
pressure [Ppao], and stroke volume index < 30 mL/m2) used transesophageal echocardiography (TEE) in
was present in approximately 10% of patients with patients with severe ARDS to demonstrate that
ARDS,58 whereas Boissier et al59 and Lheritier et al60 induction of hypercapnic acidosis with low-tidal volume
noted a prevalence of acute cor pulmonale of 22% and ventilation and increasing PEEP at constant plateau
22.5%, respectively. Driving pressure (defined as the pressure directly impaired RV function independent of
difference between Pplat and total positive the effects of PEEP. Vieillard-Baron et al57 performed a
end-expiratory pressure [PEEP]) is a surrogate of lung multivariate analysis in 75 patients with ARDS studied
stress that has been associated with survival and risk of using TEE. They found that elevated PaCO2 was the sole
cor pulmonale in patients with ARDS, which may individual predictor of ACP. Although the latter had no
suggest that a “low-pressure” ventilatory strategy could influence on mortality, the authors correctly identified
be protective of the right ventricle.61 Lower overall rates ACP early in the study and introduced prone ventilation
of ACP in more recent studies likely relates to a on day 3 in those patients with a PaCO2 /FIO2
combination of right ventricle-protective ventilation < 100 mm Hg. Such adaptions may have mitigated the
strategies, heterogeneity in the definition itself, and mortality associated with ACP.66 Lheritier et al60 used a
therapeutic ventilator adjustments based on its earlier combination of transthoracic echocardiography and
recognition. TEE to study 200 patients with moderate to severe
ARDS < 48 hours after admission. Elevated PaCO2 was
Cardiopulmonary Effects of Permissive significantly associated with ACP, and PaCO2 $ 60 mm Hg
Hypercapnia in ARDS was the only independent factor associated with
Despite these improvements, RV dysfunction remains ACP.60 The study also found that the systolic pressure
prevalent and is linked to worsened outcomes in ARDS. gradient between the right ventricle and right atrium
For example, severe RV dysfunction is shown to be more (DPmax), an indirect measurement of pulmonary
prevalent in nonsurvivors of ARDS.62 RV dysfunction in vascular tone, correlated with PaCO2 and was significantly
early ARDS, as defined by a higher ratio of right atrial higher in patients with a PaCO2 $ 60 mm Hg.60 Despite
pressure to Ppao was independently associated with the study findings, there was no association between
higher mortality.63 The higher mortality exhibited in this ACP at < 48 hours after admission and 28-day
study may in part be explained by the effects of mortality.60 In a recent large prospective observational
mechanical ventilation in the era prior to adoption of study (N ¼ 752), Mekontso Dessap et al67 identified
LPV; however, studies of patients with ARDS in the era hypercapnia (PaCO2 $ 48 mm Hg) as a respiratory
following adoption of LPV also show a correlation variable with a statistically significant correlation with cor
between RV dysfunction and mortality. Boissier et al59 pulmonale (assessed by TEE) in patients with ARDS
found significantly higher 28-day mortality in patients receiving LPV. ACP was found in 22% of the cohort, and
with ARDS and severe RV dysfunction, and Osman severe ACP (defined as RVEDA/LVEDA > 1) was found
et al58 found that elevated mPAP or CVP greater than in 7.2% of patients and was an independent predictor of
Ppao, respectively, was independently associated with mortality.
90-day mortality. In addition, secondary analysis of
Secondary analysis of the ARDS Network study
patients with ARDS from the Fluid and Catheter
published by Kregenow et al68 found that the presence of
Treatment Trial (FACTT) demonstrated that elevation
hypercapnic acidosis at randomization was associated
of transpulmonary gradient (mPAP – Ppao) or elevated
with lower 28-day mortality in the group randomized to
PVR index, conferred a higher risk for 60-day
a tidal volume of 12 mL/kg (but no mortality difference
mortality.64
in patients randomized to 6 mL/kg) (Table 2). This
Notwithstanding LPV, permissive hypercapnia coupled study had several limitations, including being a
with moderate to severe ARDS may exert a synergistic retrospective secondary analysis, defining hypercapnic
effect that can lead to ACP. Widespread use of modern acidosis based on a day 1 blood gas measurement rather
two-dimensional echocardiography not only has than sustained hypercapnic acidosis over time, as well as
improved our understanding of the effects of mechanical having very few patients in the hypercapnic acidosis
chestjournal.org 189
TABLE 1 ] Summary of Clinical Studies Showing Correlation Between Hypercapnia, Severe RV Dysfunction/ACP,
and Mortality in Mechanically Ventilated Patients With ARDS
Study/Year Study Design Results Comments
Vieillard-Baron Prospective single- Multivariate ACP defined as ratio of
et al57/2001 center open design regression analysis: RVEDA/LVEDA
PaCO2 independently > 0.6 by TEE
associated with
ACP; OR, 1.15 (95%
CI, 1.05-1.25);
P ¼ .0001
N ¼ 75 Mortality not MV: Pplat limited
influenced by to # 30 cm H2O,
presence of ACP tidal volume of
6-9 mL/kg (PBW),
PEEP range,
3-15 cm H2O
Lheritier et al60/2013 Prospective Multivariate ACP defined as ratio of
multicenter regression analysis: RVEDA/LVEDA
PaCO2 > 60 mm Hg > 0.6 by TEE
strongly associated
with ACP; OR, 3.70
(95% CI, 1.32-
10.38); P ¼ .01
N ¼ 200 ACP not independently MV: Pplat # 30 cm
associated with H2O, tidal volume
mortality and PEEP according
to expert
recommendations
from the Societe de
Reanimation de
Langue Francaise
Mekontso Dessap Prospective Multivariate ACP and severe ACP
et al67/2016 multicenter regression analysis: defined as ratio of
severe ACP RVEDA/LVEDA
independently > 0.6 and > 1
associated with respectively with
inhospital mortality; presence of septal
OR, 2.00 (95% CI, dyskinesia by TEE
1.03-3.88); P ¼ .04
N ¼ 752 PaCO2 > 48 mm Hg MV: Pplat # 30 cm
associated with H2O, tidal volume of
ACP; OR, 2.39 (95% 6-8 mL/kg (PBW),
CI, 1.62-3.52); PEEP 8 4 cm H2O
P < .01
ACP ¼ acute cor pulmonale; MV ¼ mechanical ventilation; PBW ¼ predicted body weight; PEEP ¼ positive end-expiratory pressure; Pplat ¼ plateau
pressure; RV ¼ right ventricle; RVEDA/LVEDA ¼ ratio of right ventricular end-diastolic area to left ventricular end diastolic area; TEE ¼ transesophageal
echocardiography.
group. As this was a secondary analysis, there was no 24 hours of their ICU admission. It found that
causality proved but only an association inferred. hypercapnic acidosis in the first 24 hours of ICU
admission was associated with higher inhospital
In contrast to the Kregenow et al68 study, two recent mortality compared with compensated hypercapnia or
studies looking at mechanically ventilated patients in the normocapnia69 (Table 2). Interestingly, both patients
ICU have called into question the safety of hypercapnic with compensated hypercapnia and those with
acidosis. The first study was retrospective and included hypercapnic acidosis had higher mortality rates. This
252,812 patients admitted to ICUs with respiratory effect was consistent across all types of ICU admissions.
failure requiring mechanical ventilation during the first This study’s strengths were the large number of patients
190 Contemporary Reviews in Critical Care Medicine [ 154#1 CHEST JULY 2018 ]
TABLE 2 ] Summary of Clinical Studies Showing Effects of Hypercapnia and Hypercapnic Acidosis on Mortality in
Mechanically Ventilated Patients With ARDS
Study/Year Study Design Results Comments
Kregenow Retrospective secondary Multivariate regression analysis HA based on day 1 ABG
et al68/2006 analysis of ARMA trial (ARDS Lower 28-d mortality associated measurement only; too
Network) multicenter RCT with hypercapnic acidosis at few patients with
(2000) 12 mL/kg (PBW); Adjusted OR, sustained HA to analyze
N ¼ 861 0.14 (95% CI, 0.03 -0.70); Significant number of
P ¼ .016 patients missing day 1
No reduction in 28-d mortality ABG measurement
associated with hypercapnic No data collected on IV
acidosis in low-tidal volume bicarbonate infusion use
ventilation group (6 mL/kg PBW)
Tiruvoipati Retrospective multicenter Multivariate regression analysis Strength of this study was
et al69/ 2017 international study Higher hospital mortality for the high number of
N ¼ 252,812 patients with hypercapnic patients included
acidosis, and compensated Used only day 1 ABG data to
hypercapnia, (adjusted for classify
severity of illness); OR, 1.74 No data collected on use of
(95% CI, 1.62-1.88) and 1.18 IV bicarbonate infusion or
(95% CI, 1.10-1.26), extracorporeal life support
respectively, compared with
normocapnia with normal pH;
P < .001
Nin et al70/ Secondary analysis of 3 Multivariate regression analysis Strength is a secondary
2017 prospective noninterventional Significantly higher ICU mortality in analysis of multinational
cohort studies (multicenter/ patients with maximum PaCO2 multicenter cohort from
international) of $ 50 mm Hg (severe ICUs in 40 countries
N ¼ 1,899 hypercapnia) during the first 48 h Used worst PaCO2 from ABGs
of MV; OR, 1.93 (95% CI, 1.32– within 48 h of initiation of
2.81); P ¼ .001 MV
ABG ¼ arterial blood gas; HA ¼ hypercapnic acidosis. See Table 1 legend for expansion of other abbreviations.
included and the longitudinal nature of the data mortality in a population with moderate to severe
collection (data over a 14-year period from 171 ICUs). ARDS70 (Table 2). The authors used propensity
This study classified patients based on a day 1 arterial matching to conduct a sensitivity analysis to
blood gas (ABG) measurement and did not account for demonstrate that hypercapnia independent of acidosis
adjunctive treatments such as bicarbonate infusions and was associated with increased mortality, whereas both
extracorporeal life support (ECLS). had independent additive effects on increasing
mortality. This study included patients from 927 ICUs in
The second study was a secondary analysis of 1,899 40 countries. The investigators used the worst ABG
patients from three prospective noninterventional measurement in the first 48 hours of mechanical
cohort studies on patients with ARDS. It demonstrated ventilation to stratify patients. Some of the weaknesses of
that severe hypercapnia, as defined by a PaCO2 this study included a high number of patients being
$ 50 mm Hg, was associated with higher ICU excluded due to missing ABG data (11.5%) and no data
chestjournal.org 191
collection on the use of adjunctive therapies such as Some studies, however, have suggested that it is the
bicarbonate infusions and ECLS. decrease in PaCO2 associated with a reduction in alveolar
dead space rather than increased PaO2 that might best
Hypercapnia and Organ Dysfunction reflect the degree of functional lung recruited with prone
Not surprisingly, the harmful effects of severe positioning.74,75 Unfortunately, the only prospective
hypercapnia extend beyond the cardiopulmonary randomized controlled trial to demonstrate mortality
system. In the study by Nin et al,70 hypercapnic acidosis benefit with prone positioning (Proning Severe ARDS
was associated with higher ventilator-associated Patients [PROSEVA]) did not directly evaluate alveolar
complication rates (such as barotrauma) and more recruitment with prone positioning.73 In addition, a
organ failure, including renal and cardiovascular retrospective analysis of PROSEVA by Albert et al,76
dysfunction. Further studies will be required to demonstrated that increased survival with prone
externally validate and elucidate the pathophysiological positioning was not predicted by improvement in gas
basis for these findings and whether they share exchange as determined by blood gas analysis.
similarities to those described in animal models. Nonetheless, prone positioning can lower PaCO2 and
unload the right ventricle in selected groups of patients
Strategies of LPV When Severe Hypercapnia Is in the ICU and is an important tool to improve patient
Present outcomes in severe ARDS.77
192 Contemporary Reviews in Critical Care Medicine [ 154#1 CHEST JULY 2018 ]
lower Pplat and driving pressure values) that some have Furthermore, it remains to be determined whether this
speculated would confer survival benefit.82 Although strategy offers additional benefit in either of these
the study by Bein et al78 did not show an overall patient groups compared with LPV with maintenance of
difference in 28- or 60-day ventilator-free days between normocapnia.
groups, a post hoc analysis demonstrated that
patients with severe hypoxemia at randomization (PaO2/
FiO2 < 150 mm Hg) had a significantly shorter Final Thoughts
ventilation period as assessed by higher 60-day Severe hypercapnia has deleterious consequences in
ventilator-free days. Additional studies on this front are patients with moderate to severe “Berlin criteria” ARDS.
under way (A Strategy of Ultraprotective Lung For clinicians managing such patients, we suggest
Ventilation With Extracorporeal CO2 Removal for controlling severe hypercapnia so that PaCO2 is kept
New-Onset Moderate to Severe ARDS [SUPERNOVA] at < 50 mm Hg in line with current evidence.83 In
and Protective Ventilation With Veno-venous Lung addition to examining ultralow-tidal volume ventilation
Assist in Respiratory Failure [REST]). Yet despite these with ECCO2R, it is time to reassess current LPV
trials, it remains unclear whether the “least damaging” strategies in patients with moderate to severe ARDS. A
ventilation approach with ultralow-tidal volume larger adequately powered randomized study using LPV
ventilation and maintenance of normocapnia should be comparing maintenance of normocapnia with ECCO2R
applied to patients with moderate ARDS or severe ARDS vs permissive hypercapnia is warranted.
and whether it confers benefit over current standards of
LPV with maintenance of normocapnia in either of Acknowledgments
Financial/nonfinancial disclosures: None declared.
these groups.
chestjournal.org 193
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