Protective Effects of Hypercapnic Acidosis on
Ventilator-induced Lung Injury
ALAIN F. BROCCARD, JOHN R. HOTCHKISS, CHRISTINE VANNAY, MICHELE MARKERT, ALAIN SAUTY,
FRANÇOIS FEIHL, and MARIE-DENISE SCHALLER
Division of Intensive Care, Department of Internal Medicine and Central Laboratory for Clinical Chemistry, University Hospital (CHUV),
Lausanne, Switzerland
To investigate whether respiratory acidosis modulates ventilator-
induced lung injury (VILI), we perfused (constant flow) 21 isolated
sets of normal rabbit lungs, ventilated them for 20 min (pressure
controlled ventilation [PCV]  15 cm H2O) (Baseline) with an in-
spired CO2 fraction adjusted for the partial pressure of CO2 in the
perfusate (PCO2  40 mm Hg), and then randomized them into
three groups. Group A (control: n  7) was ventilated with PCV 
15 cm H2O for three consecutive 20-min periods (T1, T2, T3). In
Group B (high PCVnormocapnia; n  7), PCV was given at 20
(T1), 25 (T2), and 30 (T3) cm H2O. The targeted PCO2 was 40 mm
Hg in Groups A and B. Group C (high PCVhypercapnia; n  7) was
ventilated in the same way as Group B, but the targeted PCO2 was
 70 to 100 mm Hg. The changes (from Baseline to T3) in weight
gain (WG: g) and in the ultrafiltration coefficient (Kf  grmin
cm H2O100g) and the protein and hemoglobin concentrations in
bronchoalveolar lavage fluid (BALF) were used to assess injury.
Group B experienced a significantly greater WG (14.85  5.49
[mean  SEM] g) and Kf (1.40  0.49 gmincm H2O100 g) than
did either Group A (WG  0.70  0.43; Kf  0.01  0.03) or
Group C (WG  5.27  2.03 g; Kf  0.25  0.12 gmincm H2O
100 g). BALF protein and hemoglobin concentrations (gL) were
higher in Group B (11.98  3.78 gL and 1.82  0.40 gL, respec-
tively) than in Group A (2.92  0.75 gL and 0.38  0.15 gL) or
Group C (5.71  1.88 gL and 1.19  0.32 gL). We conclude that
respiratory acidosis decreases the severity of VILI in this model.
Keywords: respiratory acidosis; hypercapnia; mechanical ventilation;
acute lung injury; rabbits
Recent clinical trials have indicated that ventilatory strategies
aimed at limiting ventilator-induced lung injury (VILI) may
have a positive impact on the outcome of the acute respiratory
distress syndrome (1, 2). These strategies impose limits on tidal
volume (VT) and inflation pressure, and may result in hyper-
capnic acidosis. Until recently, the latter condition was mainly
viewed as a side effect to be either tolerated (permissive hyper-
capnia) or treated by increasing the rate of mechanical breath-
ing or by giving a bicarbonate infusion, or with techniques such
as tracheal gas insufflation or extracorporeal CO2 removal (3).
However, hypercapnia and acidosis have myriads of effects
at the cellular level, several of which might influence the de-
velopment of VILI. First, it is now believed that mechanical
stretch induces lung injury in part by activating various intra-
cellular signaling cascades (4), some of them having demon-
strated a dependence on pH or partial pressure of CO2 (PCO2)
(Received in original form July 13, 2000 and in revised form May 2, 2001)
Supported by the Central Hospitalier Universitarium Vandais. Dr. Hotchkiss was
supported by an American Heart Association Scientist Development Grant, Re-
gions Hospital, St. Paul, Minnesota, and the Centre Hospitalier Universitaire Vau-
dois, Lausanne, Switzerland.
Correspondence and requests for reprints should be addressed to A. Broccard, M.D.,
Division des Soins Intensifs, Départment de Médecine. BH10-982, University Hospital
(CHUV), CH-1011 Lausanne, Switzerland. E-mail: alain.broccard@chuv.hospvd.ch
Am J Respir Crit Care Med Vol 164. pp 802–806, 2001
Internet address: www.atsjournals.org
(5–8). Second, surfactant production or function may be mod-
ulated by acid–base status (9–11). Third, hypercapnia appears
to downregulate the endogenous production of nitric oxide
(NO) in the lung (12), an effect of potential relevance, consid-
ering the dual cytoxoxiccytoprotective potential of NO (13).
Additionally, respiratory acidosis protects rabbit lungs ex vivo
and in vivo against ischemia–reperfusion injury (14, 15). It is
unknown whether such protection would extend to VILI.
With these considerations in mind, we designed the present
study to investigate the possible impact of hypercapnic acido-
sis on the development of VILI in an isolated, perfused rabbit
lung preparation.
METHODS
Care, techniques, and procedures used in the study were approved by
the animal care committee of our institution.
Isolated Perfused Lung Preparation
We used a previously described, isolated, perfused lung preparation
(New Zealand rabbits) (16, 17). No inhibitor of cyclooxygenase was
added to the perfusate. Perfusion was set at a constant flow of 300 ml
min and left atrial pressure (Pla) at 6 mm Hg (referenced to the top of
the lung). Initial ventilation (Veolar ventilator; Hamilton Medical,
Rhazüns, Switzerland) was set in the pressure controlled mode (pressure
controlled ventilation [PCV]), with a positive end-expiratory pressure
(PEEP) of 3 cm H2O, a respiratory rate (RR) of 20 breathsmin, and an
inspiratory time fraction of 0.33. The ventilator was connected to two
gas tanks: the first tank (O2: 40%; CO2: 5%; N2: 55%) was connected to
the air inlet and the second (O2: 40%; CO2: 25%; N2: 35%) to the oxygen
inlet. Thus, adjustment of the ventilator FIO2 knob allowed titration of
the inspired CO2 fraction (FIO2) to the desired perfusate PCO2.
Protocol
The experimental protocol consisted of four successive 20-min peri-
ods. During the first period (Baseline), lungs were ventilated at 15 cm
H2O peak airway pressure (Paw) with normocapnia (perfusate PCO2 
40  5 [mean  SEM] mm Hg). Subsequently, the preparations were
randomized into three groups and studied for three additional periods
(T1, T2, and T3). In the control group (C, n  7), peak Paw and perfu-
sate PCO2 were kept at the Baseline values. In the high-pressure nor-
mocapnic group (HPNC, n  7), peak Paw was raised in increments of
5 cm H2O at the beginning of each new period to a maximum value of
30 cm H2O during T3. The targeted arterial CO2 tension (PaCO2 and
pH were the same as in the C group. In the high-pressure hypercapnic
group (HPHC), n  7], peak Paw was increased as in the HPNC
group, but the targeted PaCO2 was between 70 and 100 mm Hg.
Measurements
Paw, flow, VT, pulmonary artery pressure (Ppa), Pla, and pulmonary
capillary pressure (Pcp) were measured as previously described (16).
Three blood gas analyses were performed during each period. At Base-
line and T3, plasma nitrite  nitrate (NOx) concentrations were as-
sayed (18, 19). Edema formation (weight gain [WG] from the beginning
to the end of each period) was used to calculate changes in WG from
Baseline (WG at T1,T2,T3 as WG[Tx]  WG[Baseline]). The ultrafil-
tration coefficient (Kf) was determined at the end of each period (16),
and changes in Kf from Baseline (Kf at T1,T2,T3) were calculated as
Broccard, Hotchkiss, Vannay, et al.: Lung Injury and Mechanical Ventilation 803

TABLE 1. CHARACTERISTICS OF THE GROUPS AT BASELINE

Control High-Pressure High-Pressure

Normocapnic Normocapnic Hypercapnic
Variables at Baseline Group (C) Group (HPNC) Group (HPHC)

Rabbit weight, kg 2.8  0.1 3.1  0.1 2.9  0.2

Lung weight, gr 16  1 16  1 16  1
Ischemic time, min 23  1 23  2 23  2
Perfusate hematocrit, % 6.1  0.3 6.3  0.2 6.3  0.3
Pla, mm Hg 6.6  0.1 6.5  0.2 6.8  0.2
Ppa, mm Hg 12.7  0.7 11.5  1.2 12.9  1.0
Pcp, mm Hg 9.1  0.6 8.7  0.5 8.4  0.4
Pulmonary vascular resistance, dynes  sec1  cm5 1,284  173 1,219  326 1,298  284
Lung compliance, ml/cm H2O 4.3  0.2 4.5  0.4 5.1  0.5
PaO2, mm Hg 233  4 220  6 228  6
PaCO2, mm Hg 42  5 36  6 35  5
pH 7.26  0.03 7.35  0.05 7.32  0.05
W, g 1.35  0.3 0.55  0.2 1.37  0.7
Kf, g/min/cm H2O/100g 0.18  0.03* 0.11  0.02 0.08  0.02

Definition of abbreviations: W  weight gain; Kf  ultrafiltration coefficient; PaCO2  arterial carbon dioxide tension; PaO2  arterial ox-
ygen tension; Pcp  pulmonary capillary pressure; Pla  left atrial pressure; Ppa  pulmonary artery pressure.
* p  0.04 Control group versus HPHC group.

Kf (Tx)  Kf (Baseline) (17). When these other measurements were Statistics

completed, recovered fluid from a bronchoalveolar lavage (BAL) of
the left lung was divided into two aliquots to measure the BAL hemo-
globin level (HbBAL)(20), and, after centrifugation, the supernatant
protein (bicinchonic acid assay, [BCA]; Pierce, Rockford, IL) and NOx
concentrations (18, 19). NOx was used to track lung NO production.
The lung wet weight (WWL)dry weight (DWL) ratio was measured with
lung tissue pieces sampled from each of the right lung lobes.
The mean values of variables measured only once were compared
among groups with the Kruskal–Wallis analysis of variance (ANOVA)
on ranks; the Student–Newman–Keuls’ adjustment was performed for
multiple comparisons. Variables for which one measurement was
made in each experimental period were analyzed with a repeated
measures ANOVA. Correlations were examined through linear re-

TABLE 2. CHARACTERISTICS OF STUDY GROUPS AFTER RANDOMIZATION AT THE BEGINNING OF EACH

PERIOD OF VENTILATION

Control High-Pressure High-Pressure

Normocapnic Normocapnic Hypercapnic
Time Variables Group Group Group

T1 Peak alveolar pressure, cm H2O 15.1  0.3 20.2  0.2* 20.7  0.2*
Total PEEP, cm H2O 2.4  0.2 2.4  0.2 2.7  0.2
VT, ml 52  4 75  13* 73  8*
Pla, mm Hg 6.9  0.2 6.4  0.3 6.8  0.2
Ppa , mm Hg 12.7  0.7 12.5  1.1 12.8  0.9
Ppa-Pla, mm Hg 3.9  0.7 4.6  0.3 3.9  1.0
PaO2, (mm Hg) 230  3 229  4 240  3
PaCO2, mm Hg 28  0.6† 36  4.7† 64  6.5
pH 7.38  0.01† 7.32  0.04† 7.12  0.04
T2 Peak alveolar pressure, cm H2O 15.1 0.2 25.2  0.2* 25.1  0.2*
Total PEEP, cm H2O 2.4  0.3 2.4  0.2 2.7  0.3
VT, ml 54  3 80  9* 83  8*
Pla, mm Hg 6.9  0.1 6.6  0.4 6.9  0.3
Ppa , mm Hg 11.8  1 14.1  1 13.5  1
Ppa-Pla, mm Hg 4.0  0.6 5.9  1.7 4.0  0.9
PaO2, mm Hg 229  5 233  6 244  4
PaCO2, mm Hg 40  3† 34  3† 93  7
pH 7.3  0.02† 7.3  0.03† 6.98  0.02
T3 Peak alveolar pressure (cm H2O) 15.1  0.2 30.1  0.1* 30.0  0.2*
Total PEEP, cm H2O 2.2  0.2 2.4  0.2 2.7  0.2
VT, ml 52  2 84  10* 100  10*
Pla, mm Hg 6.9  0.1 6.5  0.3 6.9  0.3
Ppa , mm Hg 11.9  0.7 16.7  1.4* 15.7  0.8*
Ppa-Pla, mm Hg 4.9  0.7 9.5  1.2‡ 6.1  0.9
PaO2, mm Hg 234  5 230  7 247  3
PaCO2, mm Hg 37  3† 45  6† 105  6
pH 7.29  0.02† 7.29  0.04† 6.93  0.02

Definition of abbreviations: PaCO2  arterial carbon dioxide tension; PaO2  arterial oxygen tension; PEEP  positive end-expiratory pres-
sure; Pla  left artrial pressure; Ppa  pulmonary artery pressure; Ppa-Pla  pulmonary artery pressure minus left atrial pressure measured
with continuous positive airway pressure.
* p 0.05 versus Control group.
†
p 0.05 versus High-Pressure Hypercapnic group.
‡
versus the two other groups.
804 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
gression analysis. The level of
was set at 0.05. In the RESULTS sec- T1 to T3 (p  0.04 and p  0.25, respectively). In the HPNC
tion, all data are summarized as mean  SEM.
RESULTS
The three study groups had similar characteristics at Baseline,
as summarized in Table 1. In particular, the initial WG did not
differ among the groups. The Baseline Kf was higher in the C
group than in the HPHC group (Table 1), but this difference
was small, and values in all three groups were well within the
normal range for rabbit lungs (21). The ischemic time (21  1
[mean  SEM] min), the initial hematocrit (6.2  0.1%), the
initial perfusate pH (7.30  0.03), and the perfusate tempera-
ture (36.5  0.1 C) did not differ among the groups. After
randomization, the controlled variables for the three groups
differed at each stage of the study, as intended (Table 2).
Indices of Lung Injury
Neither edema formation (WG: Figure 1a) nor permeability
VOL 164 2001
Figure 1. Indices of lung injury. *p
0.05 within-group comparison (T3 versus
T1), p 0.05 for between-group compar-
ison at the same time; † versus C group.
‡
versus C group and HPHC group.
group, both WG (p  0.01) and Kf (p  0.005) increased
significantly over time. At the end of the protocol (T3), WG
and Kf were significantly greater in the HPNC than in the
HPHC or C groups (Figures 1a and 1b; WG: p 0.001; Kf
p  0.01). The HPHC group differed significantly from the C
group for WG (p  0.03) but not for Kf (p  0.27).
At the end of the experimental period, the WWLDWL ratio
was higher in the HPNC than in the HPHC or C groups (p
0.005; HPNC group  8.33  0.25; HPHC group  7.19  0.18; C
group  6.85  0.34). The BALF protein concentration was
higher in the HPNC group than in the C group (p 0.05) (Figure
1c), whereas BALF hemoglobin levels were higher in the two ac-
tive treatment groups than in the C group (p 0.05) (Figure 1d).
The BALF protein concentration was higher in the HPNC than
in the HPHC group (p 0.05), with a similar but statistically in-
significant trend noted for BALF hemoglobin (p  0.24).
NOx in BALF and Perfusate
(Kf: Figure 1b) increased significantly over time in the C The overall mean circulating NOx was 41.2  3.1 ml/L at Base-
group. In the HPHC group, WG but not Kf increased from line and 58.8  3.3 ml/L at T3 (p 0.01). The level of NOx in

Figure 2. NOx concentration (a) change over time in per-

fusate and (b) at the end in BALF. *p 0.05 versus C and
HPHC groups, † p 0.05 versus C group.
Broccard, Hotchkiss, Vannay, et al.: Lung Injury and Mechanical Ventilation
the perfusate increased over time in all groups. This change
was less marked in the HPHC group than in the other two
groups, a difference that did not reach statistical significance
(Figure 2a). The level of NOx in the BALF, measured at the
end of the experimental period, was highest in the HPNC
group, intermediate in the HPHC group, and lowest in the C
group (Figure 2b, p 0.05 for all comparisons). BALF NOx
correlated significantly with all indices of injury: Kf (r  0.65,
p 0.001); BALF hemoglobin (r  0.62, p 0.01); and BALF
protein (r  0.7, p 0.001).
Hemodynamic Data
At Baseline, there were no significant differences in vascular
pressures among the study groups (Table 1). Throughout the
experiment, Pla was adequately controlled at values around
the targeted value (Table 2). After randomization, the mean
pulmonary artery pressure (Ppa) measured during tidal venti-
lation remained close to the Baseline value and similar in all
groups until T2. At the beginning of T3, it became higher in the
HPNC and HPHC groups than in the C group (Table 2). Mean
Ppa differed among all groups only at the end of T3 and was
highest in the HPNC, intermediate in the HPHC, and lowest in
the C group (data not shown, p 0.05 for all comparisons).
Pcp measured under apneic conditions with a continuous posi-
tive airway pressure (CPAP) of 5 cm H2O was similar among
groups from Baseline (Table 1) to the end of the study [9.2 
0.2 cm H2O (C group); 9.8  0.4 cm H2O (HPNC group); 8.5 
0.5 cm H2O (HPHC group); p  0.1]. Pulmonary vascular re-
sistance (as reflected by Ppa minus Pla under conditions of
constant lung perfusion, interrupted ventilation, and a CPAP
of 5 cm H2O), remained practically stable and comparable
among groups until the end of T2 (Table 2). At the end of T3,
by contrast, this variable was significantly higher in the HPNC
group than in the other two groups (Table 2) (p 0.05). At
this time, pulmonary vascular resistance correlated with WG
(r  0.58, p  0.005) and Kf (r  0.5, p  0.02).
DISCUSSION
Our main finding was that respiratory acidosis decreased the
severity of VILI in this model. Hemodynamic effects of the
acid–base status were unlikely to account for this observation,
because they were modest and only apparent after significant
lung injury developed. Our data raise the hypothesis that re-
spiratory acidosis could reduce VILI by attenuating the in-
creased NO production arising from high-pressure mechanical
ventilation.
Adequacy of the Experimental Model
The validity of the present experiments depends crucially on
the actual induction of VILI in the group of isolated lungs
ventilated with high pressure in normocapnia (HPNC). Injury
was assessed by measurement of edema formation (WG)
and altered lung permeability to markers covering a wide
range of sizes (i.e., water [Kf], protein [BALF protein con-
centration], and red blood cells [BALF hemoglobin concen-
tration]). Each of these measurements taken in isolation has
limitations for assessing injury. However, all of them signifi-
cantly differed in the HPNC and the C groups at the end of
the experiment (Figure 1). In our previous study of the same
model, injurious ventilatory patterns induced these same mul-
tiple abnormalities, which correlated closely with histologic
scores of both alveolar and extraalveolar hemorrhage (17). To
the extent that extravasation of red blood cells is indicative of
either anatomic or severe functional disruption of lung struc-
805
tures, we are confident that the mechanical stress imposed on
the lungs ventilated with high pressures was sufficient to pro-
duce injury, at least in normocapnia.
Possible Mechanisms of Protection Against VILI Afforded by
Respiratory Acidosis
The study data clearly indicate a protective effect of hypercap-
nic acidosis against VILI in this model. Indeed, with the possi-
ble exception of BALF hemoglobin, all markers of lung injury
that were noted to be increased in the HPNC group were
blunted in the HPHC group (Figure 1). The study was prima-
rily conducted to establish this fact. It was not designed to sort
out the relative contributions of PCO2 and pH. Nor did it spe-
cifically address the possible mechanisms of protection, for
which, nevertheless, a few clues exist in the data.
Hemodynamic factors. In the course of experimentation,
the Ppa and vascular resistance increased less in the HPHC
than in the HPNC group (Table 2). This difference might have
been due to hypercapnia per se, which is a known vasodilator
in the pulmonary circulation (22). In the presence of lung in-
jury, differences in Ppa may have a significant impact on
edema formation and possibly on injury. Nevertheless, several
arguments run against a fundamental role of hemodynamic
factors in the lung-protective effects of respiratory acidosis.
First, although hypercapnia largely blunted the formation of
edema (Figure 1a), it had no influence on capillary pressure
throughout the experiment. Second, the hemodynamic differ-
ence between the HPNC and HPHC groups was present only
after significant injury developed (end of T3) and was limited
to a modestly higher Ppa in the HPNC group (19.6  1.1 mm
Hg compared with 16.5  0.8 mm Hg; p 0.05). Respiratory
acidosis per se had no discernible effect on the vascular tone
prior to injury, probably because the CO2-mediated vasodila-
tion in this condition is offset by acidosis-mediated vasocon-
striction (22) (i.e., at T1 and T2; Table 2). These consider-
ations converge to indicate that pulmonary hypertension was
most likely a marker rather than a cause of VILI in this model,
as also documented by other investigators (23).
Possible role of NO. We found that circulating NOx tended
to increase less from T1 to T3 in the HPHC group than in the
other two study groups (Figure 2a). In addition, BALF NOx
at the end of the experimental period was lower in the HPHC
group than in the HPNC group (Figure 2b), and correlated
with all indices of injury. Since BAL and circulating NOx
track the formation of NO within the lung (24), our results
suggest that the latter may have been blunted by respiratory
acidosis. Indeed, depressed NO production by high airway
concentrations of CO2 has been reported by other investiga-
tors, both in vivo and in isolated perfused rabbit lungs (12).
That BALF NOx was higher in the HPNC than in the C group
would be consistent with recent data indicating that lung
stretch may stimulate the production of NO by the airway mu-
cosa (25, 26). At the cellular level, NO may be both protective
and cytotoxic, the net result being highly dependent on the
particular pathophysiologic state (13). Reflecting this com-
plexity, inhalation of NO was protective in a model of oxidant-
induced lung injury (27), whereas the endogenous production
of NO was deleterious to the lung in experimental endotox-
emia (28).
If the cytotoxic potential of NO predominated under the
conditions of the present study, our results might fit into the
following scenario: (1) stretch-induced overproduction of NO
contributed to VILI; and (2) hypercapnic acidosis was protec-
tive by interfering with this mechanism. Further experiments
will be required to test this hypothesis.
806 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Limitations of the Study
The model used in the study has important limitations that are
discussed elsewhere (16), and characteristics that may prevent
direct extrapolation of our results to the intact animal, and
certainly to patients. For instance, we kept blood flow con-
stant. In the intact animal, respiratory acidosis enhances both
sympathetic activity and catecholamine secretion, which tend
to increase cardiac output and pulmonary vascular resistance
and pressure (3). This could partly offset the beneficial effect
of hypercapnia on VILI. In addition, assuming that reduced
NO production is an important mechanism by which respira-
tory acidosis ameliorates VILI, the net result may be either
beneficial or detrimental according to the underlying type of
lung insult requiring mechanical ventilation. Although hyper-
capnia has been reported to be associated with an improved
outcome (1, 29, 30) and to cause no serious complications, the
improved outcome could be entirely due to other aspects of
the ventilatory strategy used in the studies in which this was
found, and not to hypercapnia per se. Moreover, whether hy-
percapnia resulting from hypoventilation and hypercapnia re-
sulting from inhaled CO2 may provide equivalent lung protec-
tion is still unknown.
Conclusions
Two recent studies by Kavanagh and colleagues demonstrated
the lung-protective potential of hypercapnic acidosis in an is-
chemia–reperfusion model of lung injury (14, 31). Our results
show that the protection afforded by hypercapnic acidosis is
not limited to ischemia–reperfusion injury, but also applies to
VILI. This is of great interest, since lung-protective ventila-
tory strategies tend to induce respiratory acidosis. Respiratory
acidosis may worsen gas exchange in patients with acute respi-
ratory distress syndrome (32) and may have undesirable ef-
fects on organs other than the lungs, as reviewed elsewhere
(3). If confirmed in intact animals, our results would, however,
indicate that hypercapnic acidosis should not necessarily be
viewed as an undesirable side effect to be tolerated, but rather
as a potentially useful adjunct to current strategies for lung
protection during mechanical ventilation. Our results also re-
inforce the concept that medical interventions designed to re-
store normal physiologic parameters may be counterproduc-
tive in critically ill patients, at least under certain clinical
circumstances.
Acknowledgment : The authors thank Camille Anglada, technician in the
Division of Pathophysiology, Department of Internal Medicine, University
Hospital, Lausanne, Switzerland, for the time and technical assistance he
provided to us. They are grateful to Terramed, Inc. and Hamilton Medical,
Rhazüns, Switzerland, for lending us a Veolar ventilator for this study.
References
1. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP,
Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R,
et al. Effect of a protective-ventilation strategy on mortality in the
acute respiratory distress syndrome. N Engl J Med 1998;338:347–354.
2. The Acute Respiratory Distress Syndrome Network. Ventilation with
lower tidal volumes as compared with traditional tidal volumes for
acute lung injury and the acute respiratory distress syndrome. N Engl
J Med 2000;342:1301–1308.
3. Feihl F, Perret C. Permissive hypercapnia: how permissive should we
be? Am J Respir Crit Care Med 1994;150:1722–1737.
4. Dos Santos CC, Slutsky AS. Invited review: mechanisms of ventilator-
induced lung injury: a perspective. J Appl Physiol 2000;89:1645–1655.
5. Miura M, Takayama K, Okada J. Neuronal expression of Fos protein in the
rat brain after baroreceptor stimulation. J Auton Nerv Syst 1994; 50:31–43.
6. Kuo NT, Agani FH, Haxhiu MA, Chang CH. A possible role for protein
kinase C in CO2H-induced c-fos mRNA expression in PC12 cells.
Respir Physiol 1998;111:127–135.
7. Takeshita K, Suzuki Y, Nishio K, Aoki T, Takeuchi O, Toda K, Sato N,
VOL 164 2001
Naoki K, Kudo H, Yamaguchi K. Hyperoxia and hypercapnic acidosis
differentially alter nuclear factor-kappa B activation in human pulmo-
nary artery endothelial cells. Adv Exp Med Biol 1999;471:265–270.
8. Xu L, Fidler IJ. Acidic pH-induced elevation in interleukin 8 expression
by human ovarian carcinoma cells. Cancer Res 2000;60:4610–4616.
9. Shepard JW Jr., Dolan GF, Yu SY. Factors regulating lamellar body vol-
ume density of type II pneumocytes in excised dog lungs. J Appl Phys-
iol 1982;53:555–562.
10. Chander A. Regulation of lung surfactant secretion by intracellular pH.
Am J Physiol 1989;257:L354–L360.
11. Zhu S, Basiouny KF, Crow JP, Matalon S. Carbon dioxide enhances ni-
tration of surfactant protein A by activated alveolar macrophages.
Am J Physiol (Lung Cell Mol Physiol) 2000;278:L1025–L1031.
12. Adding LC, Agvald P, Persson MG, Gustafsson LE. Regulation of pul-
monary nitric oxide by carbon dioxide is intrinsic to the lung. Acta
Physiol Scand 1999;167:167–174.
13. Liaudet L, Soriano FG, Szabo C. Biology of nitric oxide signaling. Crit
Care Med 2000;28:N37–N52.
14. Shibata K, Cregg N, Engelberts D, Takeuchi A, Fedorko L, Kavanagh
BP. Hypercapnic acidosis may attenuate acute lung injury by inhibition
of endogenous xanthine oxidase. Am J Respir Crit Care Med 1998;158:
1578–1584.
15. Laffey JG, Tanaka M, Engelberts D, Luo X, Yuan S, Keith TA, Post M,
Lindsay T, Kavanagh BP. Therapeutic hypercapnia reduces pulmo-
nary and systemic injury following in vivo lung reperfusion. Am J
Respir Crit Care Med 2000;162:2287–2294.
16. Broccard AF, Hotchkiss JR, Suzuki S, Olson D, Marini JJ. Effects of
mean airway pressure and tidal excursion on lung injury induced by
mechanical ventilation in an isolated perfused rabbit lung model. Crit
Care Med 1999;27:1533–1541.
17. Broccard AF, Hotchkiss JR, Kuwayama N, Olson DA, Jamal S, Wangens-
teen DO, Marini JJ. Consequences of vascular flow on lung injury induced
by mechanical ventilation. Am J Respir Crit Care Med 1998;157:1935–1942.
18. Liaudet L, Fishman D, Markert M, Perret C, Feihl F. L-canavanine im-
proves organ function and tissue adenosine triphosphate levels in ro-
dent endotoxemia. Am J Respir Crit Care Med 1997;155:1643–1648.
19. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannen-
baum SR. Analysis of nitrate, nitrite, and [15N]nitrate in biological flu-
ids. Anal Biochem 1982;126:131–138.
20. Kenneth A, Tait Malloy E, Tait Malloy H. Microdetermination of oxy-
hemoglobin, methemoglobin, and sulfhemoglobin in a single sample
of blood. J Biol Chem 2000;126:665–672.
21. Hernandez LA, Peevy KJ, Moise AA, Parker JC. Chest wall restriction
limits high airway pressure-induced lung injury in young rabbits. J
Appl Physiol 1989;66:2364–2368.
22. Brimioulle S, Lejeune P, Vachiery JL, Leeman M, Melot C, Naeije R.
Effects of acidosis and alkalosis on hypoxic pulmonary vasoconstric-
tion in dogs. Am J Physiol 1990;258:H347–H353.
23. Parker JC, Gillespie MN, Taylor AE, Martin SL. Capillary filtration co-
efficient, vascular resistance, and compliance in isolated mouse lungs.
J Appl Physiol 1999;87:1421–1427.
24. Su WY, Day BJ, Kang BH, Crapo JD, Huang YC, Chang LY. Lung epi-
thelial cell-released nitric oxide protects against PMN-mediated cell
injury. Am J Physiol 1996;271:L581–L586.
25. Carlin RE, Ferrario L, Boyd JT, Camporesi EM, McGraw DJ, Hakim
TS. Determinants of nitric oxide in exhaled gas in the isolated rabbit
lung. Am J Respir Crit Care Med 1997;155:922–927.
26. Adding LC, Bannenberg GL, Gustafsson LE. Gadolinium chloride inhi-
bition of pulmonary nitric oxide production and effects on pulmonary
circulation in the rabbit. Pharmacol Toxicol 1998;83:8–15.
27. Kavanagh BP, Mouchawar A, Goldsmith J, Pearl RG. Effects of inhaled
NO and inhibition of endogenous NO synthesis in oxidant-induced
acute lung injury. J Appl Physiol 1994;76:1324–1329.
28. Matsuo N. The role of intrapulmonary nitric oxide generation in the de-
velopment of adult respiratory distress syndrome. Surg Today 1999;29:
1068–1074.
29. Darioli R, Perret C. Mechanical controlled hypoventilation in status
asthmaticus. Am Rev Respir Dis 1984;129:385–387.
30. Hickling KG, Henderson SJ, Jackson R. Low mortality associated with low-
volume, pressure limited ventilation with permissive hypercapnia in severe
adult respiratory distress syndrome. Intensive Care. Med 1990;16:372–377.
31. Laffey JG, Engelberts D, Kavanagh BP. Buffering hypercapnic acidosis
worsens acute lung injury. Am J Respir Crit Care Med 2000;161:141–146.
32. Feihl F, Eckert P, Brimioulle S, Jacobs O, Schaller MD, Melot C, Naeije
R. Permissive hypercapnia impairs pulmonary gas exchange in the
acute respiratory distress syndrome. Am J Respir Crit Care Med 2000;
162:209–215.