Reduced tidal volumes and lung protective ventilatory
strategies: where do we go from here?
Luciano Gattinoni, MD, Davide Chiumello, MD, and Riccarda Russo, MD
Three major determinants of lung injury associated
with mechanical ventilation have been clearly identified:
high pressure/high volume, the shear forces caused
by intratidal collapse and decollapse leading to
barotrauma/volotrauma/biotrauma. The lung protective
strategy aims to reduce the impact of all three determinants.
A groundbreaking study showed that reduced tidal volume is
less dangerous than high tidal volume, but the researchers did
not apply “full” lung protective strategy and did not take into
account the shear forces. “Full” protective lung strategy was
tested in only one study and in a limited number of patients.
Several physiologic studies strongly suggest the advantages
of the lung protective strategy. Curr Opin Crit Care 2002, 8:45–50
© 2002 Lippincott Williams & Wilkins, Inc.
Istituto di Anestesia e Rianimazione, Universita’ degli Studi di Milano, Ospedale
Policlinico-IRCCS, Milano, Italy.
Correspondence to Luciano Gattinoni, Istituto di Anestesia e Rianimazione,
Ospedale Maggiore Policlinico-IRCCS, via Francesco Sforza, 35, 20122 Milano,
Italy; e-mail: gattinon@polic.cilea.it
Current Opinion in Critical Care 2002, 8:45–50
Abbreviations
ALI acute lung injury
ARDS acute respiratory distress syndrome
PEEP positive end-expiratory pressure
ISSN 1070–5295 © 2002 Lippincott Williams & Wilkins, Inc.
Mechanical determinants of lung injury
High pressure/high volume
Thirty years ago it was stated: “Extensive clinical expe-
rience in conscious patients indicates that tidal volumes
of 7 mL/kg, even with half-hourly manually applied
deep breathing provided around the clock, are poorly
tolerated. Patients experience dyspnea and inadequate
chest expansion even though arterial oxygenation and
carbon dioxide are normal. Consequently, larger tidal
volumes (10 to 15 mL/kg) are preferable, having been
used in several thousand ventilated patients without evi-
dence of the development of pulmonary damage” [1].
In 30 years these concepts have been completely re-
versed [2••]. Given that mechanical ventilation is still
essential in the treatment of acute lung injury (ALI) and
acute respiratory distress syndrome (ARDS), its potential
for damage has been recognized in hundred of articles
[3,4]. High airway pressure was first considered as the
major determinant of lung injury, causing the passage of
alveolar air to the extraalveolar space [5]. The conse-
quent damage was called barotrauma, which includes in-
terstitial emphysema [6], pneumomediastinum [6],
pneumothorax [5], and gas embolism [7]. In the late
stages of ALI/ARDS, the use of high airway pressure
treatment was associated with the appearance of lesions
resembling emphysema [8–10,11•].
However, the concept of barotrauma was challenged by
Dreyfuss et al. [12], who underlined the importance of
high volume (ie, volotrauma) instead of high pressure in
inducing lung injury. In an animal model, high tidal vol-
ume caused severe lung edema, not observed in animals
ventilated with the same high airway pressure but a
lower tidal volume. Previous work also showed that the
use of high volumes caused an increase in lung perme-
ability [13] and lung edema [14].
In our opinion, barotrauma and volotrauma are two as-
pects of the same phenomenon: the abnormal increase of
transpulmonary pressure, which is the distending force
of the lung. High airway pressure per se does not cause
barotrauma if the transpulmonary pressure is normal, be-
cause chest wall elastance increases. In fact, Dreyfuss
et al. [12] found that the pleural pressure was likely to be
increased by the chest wall binding. The high volume
does not necessarily induce lung damage when the trans-
pulmonary pressure is in the normal range as when ven-
45
46 Respiratory system
tilating with large tidal volume lungs with an elevated
functional residual capacity.
Intratidal collapse and decollapse
More recently, several articles have reported lung dam-
age resulting from continuous collapse and decollapse of
some lung regions throughout the ventilatory cycle. Dur-
ing inspiration, most lung regions open up because in-
spiratory pressure is sufficient to overcome the regional
opening pressure. During expiration, if positive end-
expiratory pressure (PEEP) is inadequate, part of the
lung (usually the dependent regions) undergoes collapse
[15]. The damaging effect of the shear forces generated
by the cycling collapse and decollapse has been theoret-
ically quantified by Mead et al. [16] and subse-
quently demonstrated in experimental [17] and clinical
settings [18].
Consequences of mechanical lung injury
Besides the macroscopic effects of high-volume/high-
pressure ventilation (volotrauma and barotrauma), an in-
jurious form of mechanical ventilation resulted in an in-
flammatory response (biotrauma) [19]. This was shown
first in an ex vivo lung model [20] and subsequently in a
vivo model [21]. The release of inflammatory mediators
may lead to distal organ damage [22••,23••] and predis-
pose the patient to multiorgan failure [3]. In addition to
this experimental evidence, it has been shown in a clini-
cal setting that an injurious form of mechanical venti-
lation leads to the release of local and systemic cyto-
kines [18].
However, Ricard et al. [24••], by using mechanical venti-
lation with high tidal volume in healthy rats, were unable
to detect any tumor necrosis factor-␣ and only trivial
amounts of interleukin-1B in the lung or in the blood.
Similar results were obtained in patients without previ-
ous lung injury, in whom high tidal volumes for 1 hour
did not cause consistent changes of a variety of inflam-
matory mediators in the blood [25••]. Thus, the role of
proinflammatory cytokines in the pathogenesis of venti-
lator-induced lung injury is still questionable [26•].
Lung protective strategy
The lung protective strategy refers to a ventilatory strat-
egy intended to avoid alveolar collapse and overdisten-
sion, without taking into account arterial carbon dioxide,
and to maintain an “open lung” independently of hemo-
dynamic conditions [27]. Because the major mechanical
determinants of lung injury are high pressure/high vol-
ume and intratidal collapse and decollapse, a “full” lung
protective strategy should include the control of all these
determinants [28]. Unfortunately, most of the available
studies deal only with the reduction of tidal volume,
which is just one aspect of the “full” lung protective
strategy, not taking into account the possible intratidal
collapse and decollapse.
Reduced tidal volume
Hickling et al. [29] first focused on the potential benefit
of tidal volume reduction, disregarding the consequent
hypercapnia (ie, hypercapnia permissive), and showed a
considerable decrease retrospectively in mortality rela-
tive to the expected mortality in 50 patients with ARDS.
However, hypercapnia may be a problem in intracranial
pathology [30], severe pulmonary hypertension [31], and
congestive heart failure [32].
In 1998, it was suggested on the basis of expert opinion
to limit the airway plateau pressure to 30 to 40 cm H2O
or the transpulmonary pressure to below 25 to 30 cm
H2O [33], but three randomized controlled trials did not
find any benefit in the clinical outcome when tidal vol-
umes ranging between 7 and 10.7 mL/kg were compared
[34–36]. However, in early 2000, the ARDS Network
[37••] showed a 22% decrease in mortality when patients
with ALI/ARDS were ventilated with 6 mL/kg com-
pared with 12 mL/Kg. Several explanations have been
proposed to explain the difference in outcome obtained
in these different trials. Among them were the tidal vol-
ume differences tested, the study power, the treatment
of respiratory acidosis, and the presence of intrinsic
PEEP. Eisner et al. [38••] in the ARDS Network data-
base found that 6 mL/kg tidal volume ventilation was
equally effective in subgroups of patients with different
risk factors for ARDS. On the basis of these results, it has
been recommended that 6 mL/kg tidal volume ventila-
tion should be broadly applied to patients with ARDS
[39•,40••]. Its actual implementation in the routine
management of ARDS is under investigation in the cen-
ters that participated in the study.
However, the mandatory use of 6 mL/kg of tidal volume
is, in our opinion, questionable. In fact, although it is
known that 12 mL/kg tidal volume, compared with
6 mL/kg, increases mortality, the effects of interme-
diate tidal volume ventilation (ie, 8 to 10 mL/kg) are still
not known. Interestingly, in a post hoc analysis of a ran-
domized clinical trial in ALI/ARDS, we found that mor-
tality was similar at any tidal volume below 12 mL/kg,
whereas mortality sharply increased with tidal volumes
ⱖ12 mL/kg [41••].
The safe use of intermediate tidal volume instead of
6 mL/kg is not clinically irrelevant, because 6 mL/kg
implies an increased use of sedative or muscle relaxant
agents to adapt the patient to the ventilator and carries
potential harmful effects, such as progressive atelectasis
and derecruitment [42••]. Indeed, in our opinion,
whereas mechanical ventilation with high tidal volume
must be avoided, intermediate ventilation (ie, 8 to
10 mL/kg of tidal volume) should be reconsidered. If, in
 Reduced tidal volumes and lung protective ventilatory strategies Gattinoni et al. 47
a given patient, 8 to 10 mL/kg ventilation results in trans-
pulmonary pressure or airway pressure within the safe
range, we do not see any demonstrated reason for which
6 mL/kg ventilation, with its potential for complications,
should be used.
Collapse and decollapse
Recruitment
Besides avoidance of high-volume and high-pressure
ventilation, the other cornerstone of the lung protective
strategy is the prevention of intratidal collapse and de-
collapse [43••]. Lachmann [44] emphasized the impor-
tance of opening the lung (recruiting the lung) and
keeping it open (avoiding derecruitment). For years, un-
fortunately, recruitment was mainly attributed to PEEP,
which actually only prevents derecruitment. For PEEP
selection, the pressure volume curve has been widely
used since the 1970s [45,46]. The traditional view sug-
gests that the pressure volume curve, in its inspiratory
limb, is the expression of three phenomena: (1) the lower
part up to the inflection point reflects the recruitment
zone, (2) the straight line reflects the normal inflation
zone, and (3) the upper inflection point reflects the over-
distension zone [47]. According to this model, Amato
et al. [27], in a randomized clinical trial, set the PEEP
2 cm H2O above the lower inflection point and limited
the airway plateau pressure to 40 cm H2O and found a
significant increase in survival at 28 days compared with
a control group. Ranieri et al. [18], by using the same
technique for PEEP selection, were able to decrease a
variety of proinflammatory mediators in patients with
ARDS.
However, the use of the inspiratory limb of the pressure
volume curve for PEEP selection appears at least ques-
tionable. Venegas et al. [48], with a theoretical back-
ground, and Hickling [49,50], with a mathematical
model, suggested that recruitment occurs throughout the
entire inspiratory limb of the pressure volume curve. In
a CT analysis of the pressure volume curve, differences
in recruitment across the lower inflection point could be
found [47], and more recently it was found both in ani-
mals [51••] and in humans with ARDS [52••] that re-
cruitment is an inspiratory phenomenon occurring along
the entire inspiratory limb of the pressure volume curve,
well above the lower inflection point. Indeed, most data
suggest that setting the PEEP (controlling the derecruit-
ment) according to the inspiratory limb of the pressure
volume curve does not have a solid physiologic basis.
The positive results obtained by Amato et al. [27] and
Ranieri et al. [18] from setting the PEEP above the in-
flection point may be simply explained by the higher
PEEP applied in the treatment group than in the control
group.
Derecruitment
Using CT analysis of the regional expiratory limb of
the pressure volume curve, we found that the upper
lung regions are always open, whereas the middle and
lower lung regions present a progressively higher closing
pressure [53].
Several mechanisms are responsible for lung collapse: (1)
the superimposed pressure caused by the gravitational
forces in an edematous “heavy” lung [54], (2) the weight
of the heart [55,56•], (3) the possible increase in the
abdominal pressure [57], and (4) the possible deficit of
surfactant [58•]. Consequently, to keep the lung open,
PEEP equal or greater than the compressive forces must
be used. Because the compressive forces are not equally
distributed throughout the lung parenchyma, and they
increase along the sternovertebral [54] and cephalocau-
dal gradients [59], the PEEP adequate to keep open the
dependent/caudal zone unavoidably causes overdisten-
tion of the lung region less subject to the compressive
forces (nondependent/apical zone) [15].
Prevention of collapse and decollapse
There is a large consensus that “opening the lung and
keeping the lung open” is an essential part of the lung
protective strategy. Several approaches have been used
to perform the recruitment maneuver, such as the appli-
cation of continuous positive airway pressure of 35 to
40 cm H2O for 40 seconds [27], intermittent higher tidal
volumes [60], intermittent higher PEEP [61•], and ex-
tended sigh [62•].
In our opinion, an adequate recruitment maneuver de-
pends on the patient’s characteristics, and a few rules
should be observed. First, we should consider that the
potential for recruitment is low in primary ARDS and
high in secondary ARDS [63]. Second, it must be kept in
mind that the actual opening pressure is the transpulmo-
nary pressure, which depends strictly on the elastance of
the lung and chest wall.
In fact, TP = Paw*[EL/(EL+EW)], in which TP is the
transpulmonary pressure, Paw is the applied airway pres-
sure, EL is the elastance of the lung, and EW is the
elastance of the chest wall. In a normal condition, EL
equals EW, and TP would be approximately 50% of the
applied pressure to the airways. In primary ARDS, EL is
greater than EW, and in secondary ARDS the reverse is
true [63]. Thus, a higher Paw is necessary in secondary
ARDS to reach the same transpulmonary pressure. In-
deed, for the same applied airway pressure, the potential
risks of the recruitment maneuver would be barotrauma
in primary ARDS (high transpulmonary pressure) and
hemodynamic derangement in secondary ARDS (high
pleural pressure).
48 Respiratory system
Keeping the lung open
The rules for selecting adequate PEEP have not yet
been defined. The use of the inspiratory limb of the PV
curve, as previously discussed, is inappropriate because
PEEP deals with the expiratory limb of the PV curve.
PEEP should be higher than the compressive forces,
which cannot exceed the sternovertebral height (10 to
20 cm H2O). This has been shown experimentally [51••]
but has not been tested in clinical practice. A PEEP trial
has been suggested to select a PEEP sufficient to pre-
vent lung collapse [45]; however, direct evidence of the
adequacy of this approach is still lacking.
An alternative mode for monitoring the presence of col-
lapse and decollapse was suggested by Ranieri et al.
[64••] using the pressure time curve during constant
flow ventilation and analyzing the shape of the curve.
This interesting approach, however, has yet not been
validated in a clinical setting. New forms of continuous
monitoring of collapse and decollapse, as with electrical
impedance tomography, are still in the experimental
stage [65•].
Application of the full lung
protective strategy
Most studies dealing with the lung protective strategy
are physiologic. The only outcome study so far to test the
“full” lung protective strategy is that conducted by
Amato et al. [27], who introduced the concept. Tidal
volume reduction is just one aspect of the lung protec-
tive strategy, and the outcome studies performed so far
did not take into account the collapse and decollapse. It
is not clear at present whether the lung protective strat-
egy is actually applied in daily practice.
It is also important to consider that whereas there is
strong evidence that high-volume/high-pressure ventila-
tion and collapse and decollapse are deleterious, there is
not strong evidence that low tidal volume (6 mL/kg)
should be applied when transpulmonary pressure and
airway pressure are within the safe limits with interme-
diate tidal ventilation. Moreover, it is also possible that
keeping the lung “closed,” avoiding recruitment (as in
lobar pneumonia) is not dangerous and may be benefi-
cial. Experimental studies showed that keeping part of
the lung closed resulted in a decrease of lung damage in
comparison with a control group [66,67]. In our opinion,
we should be ready to consider and study also this pos-
sibility, and in this view, extracorporeal assist should be
reconsidered [68].
Where do we go from here?
Although the physiologic basis for the lung protective
strategy has been well established, several questions are
still open. Because the tidal volume is harmful, we may
expect a decrease in lung injury with the use of high-
frequency oscillation or high-frequency ventilation. It
has been shown that high-frequency ventilation com-
pared with conventional mechanical ventilation resulted
in lower production of inflammatory mediators [69]. Un-
fortunately, these kinds of ventilations did not show any
benefit in clinical practice [70]. However, the PEEP lev-
els used in these studies were likely inadequate. To
define the role of high-frequency ventilation and high-
frequency oscillation in the lung protective strategy, ap-
propriate trials are needed [71••].
Another possible improvement would be the intermit-
tent use of a higher tidal volume (“sigh” ventilation).
When airway pressure is intermittently increased to
45 cm H2O, maintaining the tidal volume in the safe
range, two possible advantages have been demonstrated.
First, the “sigh” ventilation may prevent the develop-
ment of reabsorption atelectasis, supplying fresh gas to
lung regions with low ventilation/perfusion ratios. Sec-
ond, if atelectasis develops, the “sigh” may act as a
recruitment maneuver [60]. Similar results may be ob-
tained by intermittently raising the PEEP while main-
taining a constant tidal volume [61•].
Further progress in preventing lung damage may be ob-
tained by the prone position. In experimental works it
has been shown that the prone position, compared with
the supine position, leads to less lung damage [72••]. In
a recent trial of the effectiveness of the prone position,
we found (although in a post hoc analysis) that the mor-
tality rate in patients treated with 12 mL/kg tidal volume
or higher in the prone position was half that in patients
treated with similar tidal volumes in the supine position
[41••].
Conclusions
Mechanical ventilation in ALI/ARDS has a long story.
From high-volume/high-pressure ventilation we have
progressively shifted to “more gentle” ventilation, aim-
ing for relative lung rest [73••]. Furthermore, the role of
PEEP has been redefined to include not only gas ex-
change but also to prevent collapse and decollapse.
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have been highlighted as:
• Of special interest
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50 Respiratory system
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••
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47 Gattinoni L, Pesenti A, Avalli L, et al.: Pressure volume curve of total respira-
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48 Venegas JG, Harris RS, Simon BA: A comprehensive equation for the pulmo-
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49 Hickling KG: The pressure volume curve is greatly modified by recruitment: a
mathematical model of ARDS lungs. Am J Respir Crit Care Med 1998,
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50 Hickling KG: Best compliance during a decremental but not incremental posi-
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51 Pelosi P, Golden A, Mckihbemn A, et al.: Recruitment and derecruitment dur-
•• ing acute respiratory failure: an experimental study. Am J Respir Crit Care
2001, 164:122–130.
An animal study that points out the mechanism of recruitment and derecruitment.
52 Crotti S, Mascheroni D, Caironi P: Recruitment and derecruitment during
•• acute respiratory failure: a clinical study. Am J Respir Crit Care Med 2001,
164:131–140.
A clinical study in which the same findings obtained in Pelosi et al.’s [51] animal
study were seen in humans. In the era of “open the lung and keep it open,” both this
study and that of Pelosi et al. clarify the underlying physiologic mechanisms.
53 Gattinoni L, D’Andrea L, Pelosi P, et al.: Regional effects and mechanism of
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56 Malbouisson LM, Brush CJ, Puybasset L, et al.: Role of the heart in the loss of
• aeration characterizing lower lobes in acute respiratory distress syndrome.
Am J Respir Crit Care Med 2000, 161:2005–2012.
Another interesting study dealing with the physiopathologic mechanism of recruit-
ment and derecruitment.
57 Froese AB, Bryan AC: Effects of anesthesia and paralysis on diaphragmatic
mechanics in man. Anesthesiology 1976, 41:242–254.
58 Vazquez de Anda GF, Lachmann RA, Gommers D, et al.: Treatment of venti-
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2001, 3: 559–565.
Another interesting study dealing with the physiopathologic mechanism of recruit-
ment and derecruitment.
59 Puybasset L, Curiel P, Chao N, et al.: A computed tomography scan assess-
ment of regional lung volume in acute lung injury. Am J Respir Crit Care Med
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60 Pelosi P, Cadringher P, Bottino N et al. Sigh in acute respiratory distress
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61 Foti G, Cereda M, Sparacino ME, et al.: Effects of periodic lung recruitment
• maneuvres on gas exchange and respiratory mechanics in mechanically ven-
tilated acute respiratory distress syndrome (ARDS) patients. Intensive Care
Med 2000, 26:501–507.
This study presents a different perspective on the recruitment maneuver. Others
are likely to follow soon.
62 Lim CM, Koh Y, Park W, et al.: Mechanistic scheme and effect of “extended
• sigh” as a recruitment maneuver in patients with acute respiratory distress
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See [61•].
63 Gattinoni L, Pelosi P, Suter PM, et al.: Acute respiratory distress syndrome
caused by pulmonary and extrapulmonary disease: different syndromes? Am
J Respir Crit Care Med 1998, 158:3–11.
64 Ranieri VM, Zhang H, Mascia L, et al.: Pressure time curve predicts minimally
injurious ventilatory strategy in an isolated rat lung model. Anesthesiology
••
2000, 93:1320–1328.
Although experimental, this study may introduce the breath-by-breath monitoring of
the recruitment and derecruitment phenomenon. Clinical data are needed, how-
ever.
65 Kunst PWA, Bohm SH, Vazquez G, et al.: Regional pressure volume curves
• by electrical impedance tomography in a model of acute lung injury. Crit Care
Med 2000, 28:178–183.
Although experimental, this new technique, in our view, has spectacular clinical
potential. The reader should be aware of this new technology.
66 Rossi N, Kolobow T, Aprigliano M, et al.: Intratracheal pulmonary ventilation at
low airway pressures in ventilator-induced model of acute respiratory failure
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67 Hickling KG, Timothy W, Laubscher K, et al.: Extreme hypoventilation reduces
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term infants. N Engl J Med 1989, 320:88–93.
71 Krishnan JA, Brower RG: High frequency ventilation for acute lung injury and
•• ARDS. Chest 2000, 118:795–807.
In the era of lung protective strategy, this review, which underscores the potential
advantages, aims to rediscover the role of high-frequency ventilation.
72 Broccard A, Shapiro RS, Schmitz LL, et al.: Prone positioning attenuates and
•• redistributes ventilator induced lung injury in dogs. Crit Care Med 2000,
28:295–303.
An interesting paper that stresses the potential benefit of the prone position in
reducing ventilator-induced lung injury.
73 Slutsky AS: The acute respiratory distress syndrome, mechanical ventilation,
•• and the prone position. N Engl J Med 2001, 345:610–612.
A sound clinical approach to evaluating therapies in the era of evidence-based
medicine that reevaluates the old, good common clinical sense.