Clin Physiol Funct Imaging (2007) 27, pp67–90 doi: 10.1111/j.1475-097X.2007.00722.

REVIEW ARTICLE

Lung protective ventilatory strategies in acute lung injury

and acute respiratory distress syndrome: from experimental
findings to clinical application
Serge J. C. Verbrugge1, Burkhard Lachmann2 and Jozef Kesecioglu1
1
Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, and 2Department of Anesthesiology, Erasmus Medical Center, Dr. Molewaterplein
50, Rotterdam, The Netherlands

Summary

Correspondence
Dr S.J.C. Verbrugge, Laan van Moerkerken 20,
3271 AK Mijnsheerenland, The Netherlands
E-mail: serge.verbrugge@12move.nl
Accepted for publication
Received 4 November 2006;
accepted 20 November 2006
Key words
haemodynamics, mechanical ventilation, open lung
strategy, positive end-expiratory pressure, tidal
volume, ventilator-induced lung injury.
This review addresses the physiological background and the current status of
evidence regarding ventilator-induced lung injury and lung protective strategies.
Lung protective ventilatory strategies have been shown to reduce mortality from
adult respiratory distress syndrome (ARDS). We review the latest knowledge on the
progression of lung injury by mechanical ventilation and correlate the findings of
experimental work with results from clinical studies. We describe the experimental
and clinical evidence of the effect of lung protective ventilatory strategies and open
lung strategies on the progression of lung injury and current controversies
surrounding these subjects. We describe a rational strategy, the open lung strategy,
to accomplish an open lung, which may further prevent injury caused by mechanical
ventilation. Finally, the clinician is offered directions on lung protective ventilation
in the early phase of ARDS which can be applied on the intensive care unit.

severe hypoxaemia, reduced lung compliance and diffuse

Introduction
In Greek mythology, Scylla, once a beautiful nymph, was turned
into a dangerous six-dog-headed sea monster with 12 paws and
a fish-tail by Circe, the daughter of the sun god, out of jealousy.
Charybdis, once a sea nymph, was turned into a sea monster by
Zeus after flooding her father’s kingdom. She soaked up and
spitted out enormous amounts of sea water three times a day
causing enormous vortexes in the sea. These two creatures
where housing on both sides of a narrow sea strait. Six sailors
from Ulysses’ boat, caught between Scylla and Charybdis, are
amongst the most famous victims of Scylla. However, Captain
Jason and his Argonauts led by Thetis could pass this strait and
survive by sailing as much into the middle of these two evils as
possible. As has been described before, intensivists wishing to
oxygenate and ventilate patients with adult respiratory distress
syndrome (ARDS) and acute lung injury (ALI) have become the
argonauts of modern intensive care medicine (Dreyfuss &
Saumon, 1994). They have to navigate between the danger of
overdistension of relatively healthy non-dependent lung regions
and repeated alveolar collapse and re-expansion of basal
consolidated lung regions (Froese, 1997). With this article,
we hope to be of some help like Thetis was for Jason.
Acute respiratory distress syndrome and ALI are clinical
syndromes characterized by inflammatory pulmonary oedema,
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Journal compilation  2007 Blackwell Publishing Ltd • Clinical Physiology and Functional Imaging 27, 2, 67–90
endothelial and epithelial lung injury (Ashbaugh et al., 1967;
Ware & Matthay, 2000). The criteria for ALI are an acute onset,
a P/F ratio (PaO2/FiO2) < 300 mmHg (40 kPa), bilateral
pulmonary infiltrates on a chest X-ray and a pulmonary wedge
pressure 618 mmHg if known or no clinical signs of increased
left atrial pressures. For ARDS the criteria are the same except
for the P/F ratio which is <200 mmHg (26Æ7 kPa) (Bernard
et al., 1994). Regarding these criteria the following remarks can
be made. The PaO2 in ARDS and ALI patients and thus the P/F
ratio is directly dependent on the level of positive end-
expiratory pressure (PEEP) used for mechanical ventilation. A
recent study by Ferguson et al. (2004) in intubated and
ventilated patients meeting ARDS criteria demonstrated that a
standard ventilator setting with standardized PEEP (FiO2 ¼
100%; PEEP ¼ 10 cmH2O; tidal volume 7–8 ml kg)1) for
30 min had impact on the P/F ratio and therefore the ARDS
prevalence. Of the 41 patients enrolled, 24 patients primarily
classified as ARDS did not meet ARDS criteria after ventilation
with standardized PEEP for 30 min (Ferguson et al., 2004). This
demonstrates the relative uselessness of the American-European
Consensus conference (AECC) definitions for ARDS and shows
the need for the inclusion of standardly applied ventilator
settings in defining the disease state of the lung and in the
definition of ARDS.
67
68 Lung protective ventilatory strategies, S. J. C. Verbrugge et al.
Irrespective of these facts mortality from ARDS varies from
30% to 70% (Vincent et al., 2003; MacCallum & Evans, 2005;
Perkins et al., 2006). However, mortality from primary
respiratory insufficiency is <20%; the highest mortality is
caused by dysfunction of other organ systems (Ferring &
Vincent, 1997; Esteban et al., 2002; Vincent et al., 2003;
MacCallum & Evans, 2005). In the last 30 years it has become
more and more established that mechanical ventilation itself
can induce and worsen pulmonary pathological changes that
cannot be discerned from the pathophysiological changes in
ARDS (Dreyfuss & Saumon, 1998; Anonymous, 1999). As we
will see, such ventilation-induced changes do not remain
confined to the lung itself. Harmful forms of mechanical
ventilation can induce, e.g. changes in pulmonary and
systemic inflammatory mediators (Dreyfuss & Saumon,
1998; Slutsky & Tremblay, 1998; Haitsma et al., 2003),
bacteraemia and endotoxaemia (Nahum et al., 1997; Verb-
rugge et al., 1998a,b,c; Murphy et al., 2000) and cell apoptosis
in other organ systems (Imai et al., 2003). Protective forms of
mechanical ventilation may result in lower serum cytokine
concentrations (Ranieri et al., 1999; Anonymous, 2000), a
reduction in organ dysfunction (Ranieri et al., 2000) and a
reduction of mortality in patients with ARDS (Amato et al.,
1998; Anonymous, 2000). As a consequence, in recent years
there has been a shift in the goal of mechanical ventilation in
ALI/ARDS patients from maintaining a normal gas exchange
to protection of the lung against ventilation-induced lung
injury (VILI) by protective ventilatory strategies (Fan et al.,
2005). We will now first discuss the experimental data on the
physiological changes induced by mechanical ventilation.
What did we learn from animal experiments on
ventilator-induced lung injury?
Basic physiology of the alveolus-capillary membrane:
pulmonary surfactant
Historic considerations
Laplace, a French mathematician (1749–1827), was the first to
draw attention to surface-active forces in general and described
the relationship between force, surface tension, and radius of an
air–liquid interface of a bubble: P ¼ 2c/r (P ¼ pressure to
stabilize a bubble; c ¼ surface tension at air–liquid interface;
and r ¼ radius of a bubble). Almost one century later, von
Neergaard (1929) applied this law to pulmonary alveoli by
demonstrating that the pressures required to expand an air-filled
lung were almost three times that required to distend a lung
filled with fluid. In this way, the surface tension effect at the air–
liquid boundary was eliminated (Fig. 1). From the findings, he
concluded that: (i) two-thirds of the retractive forces in the lung
are due to surface tension phenomenon which act at the air–
liquid interface of the alveoli, and (ii) the surface tension at the
air–liquid interface must be reduced by the presence of a
surface-active material with a low surface tension to allow
normal breathing (von Neergaard, 1929).
Journal compilation  2007 Blackwell Publishing Ltd • Clinical Physiology and Functional Imaging 27, 2, 67–90
Figure 1 P–V diagram of a normal airfilled lung and an adult respiratory
distress syndrome (ARDS) lung. von Neergaard (1929) showed that
much larger pressures are required to expand an air-filled lung than a
lung filled with fluid. In RDS even higher pressures are required to
expand the lung, due to the high surface tension at the air–liquid
interface in the alveoli caused by a diminished surfactant system.
It was not until 1959 that von Neergaard’s findings became
clinically relevant, when Avery & Mead (1959) published
direct evidence linking absence of the surface-active material
to the appearance of stiff lungs in newly born premature
babies with RDS. This surface-active material is called
pulmonary surfactant. Surfactant is synthesized by the alveolar
type II cells and secreted into alveolar spaces (Van Golde et al.,
1988). The pulmonary surfactant system can be divided into
active and non-active subfractions by differential centrifuga-
tion (Veldhuizen et al., 1993). The active subfractions, which
represent tubular-myelin-like forms of surfactant, are the
metabolic precursors of the non-active components which
represent small vesicular structures (Magoon et al., 1983).
Conversion of active to non-active surfactant subfractions is
dependent on cyclic changes in surface area (Gross & Narine,
1989).
Adult respiratory distress syndrome was mentioned in an
historic article by Ashbaugh et al. (1967). They described 12
patients with severe dyspnoea, tachypnea, cyanosis, loss of
compliance and diffuse alveolar infiltration seen on the X-ray.
They observed and reported several clinical and pathological
similarities with neonates with respiratory distress syndrome,
notably surfactant dysfunction (Ashbaugh et al., 1967).
Mechanical stabilization of lung alveoli
The integrity of the surfactant system of the lung is a
prerequisite for normal breathing with the least possible
effort. The surfactant system acts by decreasing surface
tension of the interface between alveoli and air. This provides
an explanation as to why we have to generate a ‘negative’
pressure by muscular effort of only 3–8 cmH2O during each
inspiration; in the absence of surfactant the surface tension at
the air–liquid interface would be that of plasma and the
pressure needed to maintain lung aeration would be 25–
40 cmH2O (depending on the radius of the alveoli) for
which much more muscular effort would be necessary. This
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is a well-known problem in patients with respiratory failure
(Ashbaugh et al., 1967).
In alveoli with different radii an equal lowering of surface
tension would not, however, produce stabilization of the
alveolar system. It would instead, according to the Law of
Laplace, lead to the collapse of the smaller bubbles or alveoli,
and to their emptying into the larger bubbles/alveoli. As alveoli
in vivo do not exhibit such behaviour, one can conclude that the
second quality of the alveolar lining layer is that it can change
the surface tension in a manner related to the size of the alveoli
(Lachmann et al., 1972) (Fig. 2). It will prevent end-expiratory
collapse by reducing the surface tension to almost zero at small
alveolar sizes. By prevention end-expiratory alveolar collapse
surfactant will prevent the development of shear forces between
open and closed alveoli due to pulmonary interdependence
between alveolar units (see also section ‘Surfactant changes as an
explanation for…’ below).
Protection against lung oedema
Another function of the pulmonary surfactant system is
stabilization of the fluid balance in the lung, and protection
against oedema (Fig. 3) (Guyton et al., 1984). The normal
plasma oncotic pressure of 37 cmH2O is opposed by the oncotic
pressure of interstitial proteins of 18 cmH2O, the capillary
Figure 2 The surface tension behaviour of lung surfactant, serum,
perflubron and water. Lung surfactant shows dynamic surface tension
behaviour, with low surface tension for lower surface areas and higher
surface tension for higher surface areas. In adult respiratory distress
syndrome, the lung surfactant at the air–liquid interface is replaced with
serum, which displays much higher surface tensions for each surface
area when compared with lung surfactant. Water does not display
dynamic surface tension behaviour and neither does perflubron. They
both show a constant surface tension for different surface areas, which
will predispose the lung alveoli to end-expiratory collapse and peak
inspiratory overstretching.
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Lung protective ventilatory strategies, S. J. C. Verbrugge et al. 69
Figure 3 Simplified schematic diagram representing the factors influ-
encing fluid balance in the lung. See text for details.
hydrostatic pressure of 15 cmH2O, and by the surface tension-
conditioned suctioning of 4 cmH2O (Fig. 3).
In general, alveolar flooding will not occur as long as the
suction force in the pulmonary interstitium exceeds the pressure
gradient generated by the surface tension in the alveolar air–
liquid interface. As this pressure gradient is inversely related to
the radius of the alveolar curvature there is, for each
combination of the interstitial resorptive force and average
surface tension, a critical value for surface tension and for
alveolar radius, below which alveolar flooding occurs (Fig. 3)
(Guyton et al., 1984).
Functional changes due to a disturbed surfactant system
Disturbance of the surfactant system can result from different
factors. Damage to the alveolar-capillary membrane leads to
high-permeability oedema with wash-out or dilution of the
surfactant and/or inactivation of the surfactant by plasma
components, such as fibrin(ogen), albumin, globulin and
transferrin, haemoglobin and cell membrane lipids (Seeger
et al., 1993; Lachmann et al., 1994). These components are
known to inhibit pulmonary surfactant function in a dose-
dependent way (Lachmann et al., 1994). Furthermore, the
pulmonary surfactant may also be disturbed by the following
mechanisms: breakdown of surfactant by lipases and proteases;
phospholipid peroxidation by free radicals; loss of surfactant
from the airways caused by mechanical ventilation with large
tidal volumes and disturbed synthesis, storage, or release of
surfactant secondary to direct injury to type II cells (Stinson
et al., 1976; Seeger et al., 1993; Verbrugge et al., 1998a,b,c).
Diminished pulmonary surfactant has far-reaching conse-
quences for lung function. Independent of the cause, decreased
surfactant function will directly or indirectly lead to decreased
pulmonary compliance, decreased functional residual capacity
(FRC), atelectasis and enlargement of the functional right-to-left
shunt, decreased gas exchange and respiratory acidosis, hypo-
xaemia with anaerobic metabolism and metabolic acidosis, and
pulmonary oedema with further inactivation of surfactant by
plasma constituents (Lachmann, 1987).
70 Lung protective ventilatory strategies, S. J. C. Verbrugge et al.

Ventilation-induced lung injury (VILI) (a)

Surfactant changes caused by mechanical ventilation
Pioneering work of Mead & Collier (1959) showed that
mechanically ventilated dogs had a progressive fall in pulmonary
compliance (Mead & Collier, 1959); such mechanical changes
were related to the pulmonary surfactant system as shown by
Greenfield et al. (1964) who demonstrated increased surface
(b)
tensions of lung extracts in dogs ventilated at peak inspiratory
pressures of 28–32 cmH2O for 1–2 h. A subsequent report by
Sladen et al. (1968) showed that also patients ventilated for long
periods suffered from an increased alveolar-arterial oxygen
gradient, and a fall in respiratory system compliance (Sladen
et al., 1968).
Early studies by Benzer (1968) demonstrated that rabbits
ventilated with an open thorax at a peak inspiratory pressure of (c)
30 cmH2O with 5 cmH2O of PEEP or with a closed thorax
without PEEP had a better preserved surfactant system at the end
of a 75-min ventilation period than animals ventilated with an
open thorax without PEEP; these observations were extended in
a subsequent report by Woo & Hedley-Whyte (1972) who
observed pulmonary oedema foam in the airways of open-chest
dogs ventilated with large tidal volumes, whereas the same Figure 4 (a) Balance between synthesis, release and consumption of
surfactant in the healthy lung. The pressure values given represent the
ventilator settings in closed-chest animals induced no such
intrapulmonary pressure needed to open up the alveolus. At the surface
abnormalities. and the hypophase (micelles), there are sufficient molecules of
Two primary mechanisms of surfactant inactivation by surfactant. These micelles deliver the surfactant necessary to replace the
mechanical ventilation have been described. First, mechanical molecules squeezed out during expiration. (b) Imbalance between
ventilation was shown to enhance surfactant release from the synthesis, release and consumption of surfactant caused by artificial
ventilation. At the beginning of inspiration, there is an apparent
pneumocyte type II into the alveolus (Faridy et al., 1966;
deficiency of surfactant molecules but there is a respreading of molecules
Forrest, 1967; McClenahan & Urtnowski, 1967; Massaro & stored in the hypophase of the surfactant layer. At the end of inspiration
Massaro, 1983). This material is subsequently lost into the small there is, in principle, enough surfactant on the surface. (c) With the next
airways as a result of compression of the surfactant film when expiration, surface-active molecules are squeezed out and no surface-
the surface of the alveolus becomes smaller than the surface active molecules are left in the hypophase for respreading, creating the
situation where a serious surfactant deficiency follows.
occupied by the surfactant molecules (Wyszogrodski et al.,
1975; Faridy, 1976) (Fig. 4). A second mechanism to describe
the surfactant changes associated with mechanical ventilation is
based on the observation that the alveolar surface area changes
associated with mechanical ventilation, result in the conversion
of surface-active large surfactant aggregates into non-surface
active small surfactant aggregates (Veldhuizen et al., 1996,
2001; Ito et al., 1997; Verbrugge et al., 1998a,b,c) (Fig. 5).
Surfactant changes caused by mechanical ventilation are
reversible as a result of a metabolically active process, involving
de novo production of surfactant (McClenahan & Urtnowski,
1967). It probably involves a balance between secretion and
production of large aggregates, and uptake clearance and Control 7/0 45/10 45/0
reconversion of small aggregates in the pneumocyte type II Figure 5 Ratio of non-active to active phosphorus (P) (non-active to
(Magoon et al., 1983). active surfactant) in rats ventilated for 20 min with peak inspiratory
pressures/positive end-expiratory pressures of: 45/0; 45/10; 7/0 and
non-ventilated controls. Group 45/0 had a significant conversion of
Consequences of surfactant changes for fluid balance and active to non-active total phosphorus during the ventilation period
compared with controls.
solute permeability of the alveolo-capillary barrier
The hypothesis proposed by Pattle (1955) and Clements (1961) by demonstrating increased transmural filtration pressure, in
that loss of active surfactant with an increase in alveolar surface experiments in which surfactant impairment was induced by
tension results in a decrease in pericapillary pressure was proved cooling the lung and ventilation with large tidal volume (Albert
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Journal compilation  2007 Blackwell Publishing Ltd • Clinical Physiology and Functional Imaging 27, 2, 67–90

et al., 1979) or by aerosolation of detergent (Bredenberg et al.,
1986).
However, surfactant dysfunction has also been shown to
increase the permeability of the alveolo-capillary barrier to small
solutes, e.g. technetium-99m-labelled diethylene triamine
pentaacetic acid (99mTc-DTPA) in the absence of other substan-
tial changes in the function of the alveolocapillary unit (Evander
et al., 1988), and increased surfactant content in healthy
ventilated rabbits was shown to reduce the permeability for
the same molecule (Bos et al., 1992). Surfactant is not only rate
limiting for the transfer of small solutes; studies in both
premature animals (Jobe et al., 1983) and adult surfactant-
depleted animals (Robertson et al., 1985) have shown that
surfactant treatment before starting mechanical ventilation
substantially reduces the transfer of albumin over the alveolo-
capillary barrier.
These studies indicate that surfactant has a primary role in the
regulation of the permeability of the alveolo-capillary barrier to
small solutes and protein. This may be due to both a direct
action of surfactant on the alveolo-capillary barrier and a
reduction of the structural damage caused by mechanical
ventilation due to the presence of surfactant.
Disturbed fluid balance over the capillary barrier caused by
mechanical ventilation
Functional integrity of both the endothelium and epithelium is a
prerequisite for maintaining a normal fluid balance at the
alveolo-capillary membrane. Both increased capillary filtration
pressure and altered microvascular protein permeability have
been shown to contribute to pulmonary oedema after lung
overinflation. Studies in open-chest large animals, which
indirectly calculated the capillary filtration pressure from
measurements of mean pulmonary artery and left atrial
pressures after lung overinflation at peak inspiratory pressures
of around 60 cmH2O, demonstrated a mild increase in mean
transmural microvascular pressure as a result of overinflation
when compared with normal conditions (Carlton et al., 1990;
Parker et al., 1990). However, any increase in transmural
microvscular pressure will have a dramatic effect on oedema
formation when the microvascular barrier has altered sieving
properties (Huchon et al., 1981). The three basic forces acting
on the capillary wall which can eventually result in loss of its
functional integrity have been reviewed by West & Mathieu-
Costello (1992).
1 An increase in the circumferential tension (which is directly
proportional to the transcapillary wall pressure and the capillary
radius, and inversely proportional to the wall thickness). It may
be speculated that ventilation-induced surfactant impairment
with alveolar collapse, hypoxic vasoconstriction and redistribu-
tion of blood flow to selected capillaries, may increase
transcapillary wall pressure and thus circumferential tension in
those capillaries. In principal, this will result in hydrostatic
oedema, but it may be speculated that it becomes of the
permeability type if transcapillary pressure reaches 40 mmHg or
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Lung protective ventilatory strategies, S. J. C. Verbrugge et al. 71
above. Injury at such pressures is not limited to the endothelial
cells but also causes breaks in type I cells (Tsukimoto et al.,
1991).
2 Surfactant inactivation caused by mechanical ventilation
results in loss of the supportive ‘hoop’ function by surfactant
on the capillary wall. An increase in surface tension therefore
causes a reduction in perivascular pressure, with an increase in
distending pressure on the capillary. Nieman et al. (1981)
showed that the number of alveoli with continuous blood flow
(zone III conditions) increases after lung lavage with a detergent
solution elevating surface tension.
3 Longitudinal tension on the capillary due to lung overin-
flation. Fu et al. (1992) have shown that increasing lung
volume by increasing transpulmonary pressure from 5 to
20 cmH2O at a constant capillary pressure of 32 cmH2O
resulted in a significant increase in the number of endothelial
and epithelial type I breaks. The increase in the number of
endothelial breaks produced by equivalent increases in
transpulmonary pressure and capillary transmural pressure
was similar. Thus, vascular pressures too low to affect
microvascular permeability at low lung volume may increase
microvascular permeability when the lung volume is suffi-
ciently increased.
Surfactant changes affect endothelial susceptibility to
breaks by mechanical ventilation
Many studies in open and closed chest animals using different
approaches have shown that lung overinflation is associated
with changes in microvascular permeability (Webb & Tierney,
1974; Dreyfuss et al., 1985, 1988; Hernandez et al., 1989;
Carlton et al., 1990; Parker et al., 1990). The existence of a
pressure threshold above which microvascular permeability
changes occur has been suggested (Parker et al., 1984),
although others suggested the absence of a well-delimited
pressure or volume threshold (Tsuno et al., 1990). Independ-
ent of this, it has become clear that microvascular injury
secondary to ventilation occurs at much lower airway
pressures and volumes in isolated perfused lungs with
inactivated surfactant, when compared with ventilation of
healthy lungs (Coker et al., 1992). These studies suggest that
lungs with an impaired surfactant system are more susceptible
to overinflation than healthy lungs and that minor surfactant
alterations, such as those produced by spontaneous ventilation
during prolonged anaesthesia (Huang et al., 1988; Ward &
Nicholas, 1992) are sufficient to synergistically increase the
harmful effects of overinflation on permeability of the
endothelial barrier (Dreyfuss et al., 1995).
Similarly, whereas either oleic acid or mechanical ventilation
in isolated lungs did not significantly affect capillary permeab-
ility, the combination of the two did (Hernandez et al., 1990).
Similarly studies in intact animals suggested a synergism rather
than additivity between lung injury induced by mechanical
ventilation and chemical substances (Dreyfuss et al., 1995) in
inducing endothelial permeability.
72 Lung protective ventilatory strategies, S. J. C. Verbrugge et al.

Disturbed fluid balance over the epithelial barrier caused by

mechanical ventilation
It is known that the epithelium is more rate limiting for solute
and fluid movement between blood and alveolus than the
endothelium or interstitial spaces (Gorin & Stewart, 1979; Effros
et al., 1986). Effects of overinflation on epithelial permeability
have been studied in fluid-filled in situ lobes, to exclude the effect
of surface tension. As the epithelium is progressively stretched
during static inflation there is a non-reversible opening of
water-filled channels between alveolar cells resulting in free
diffusion of small solutes and even albumin across the epithelial
barrier (Egan et al., 1976; Kim & Crandall, 1982; Ramanathan
et al., 1990). Such changes were shown to occur only at high
distending pressures and have been attributed to peak inspir-
atory epithelial overstretching which occurs as a result of
inflation in the supra-physiological range only (Kim & Crandall,
1982). Experimental studies with small solutes like 99mTc-DTPA
have shown that the rate of clearance of this tracer from the
alveolar space increases with increases in lung volume, whether
caused by large tidal volume ventilation (Evander et al., 1990) or
PEEP (O’Brodovich et al., 1986).
As a result of damage of both the epithelial and endothelial
barrier, surfactant components may be lost into the blood-
stream (Winsel et al., 1976; Doyle et al., 1995; Robertson
et al., 1995). More importantly, protein will accumulate intra- Figure 6 Shear forces are caused between open and closed alveoli due
alveolarly which results in dose-dependent inhibition of to pulmonary interdependence of alveoli. This figure shows the
surfactant (Said et al., 1965; Seeger et al., 1985; Kobayashi difference between mechanical ventilation of normal alveoli (upper
et al., 1991; Lachmann et al., 1994). As surfactant is rate panel) and mechanical ventilation of the same alveolar unit after
limiting for the transfer of proteins over the alveolo-capillary surfactant inactivation (lower panel), which results in end-expiratory
collapse. In the normal situation the tissue between equally expanded
barrier, loss of surfactant function will lead to further protein alveoli (upper panel) will be much less stretched than in a situation in
infiltration. This may result in a self-triggering mechanism of which alveoli are not equally expanded (lower panel).
surfactant inactivation.
Important evidence for this mechanism comes from the
Surfactant changes as an explanation for epithelial breaks findings that ventilation at low lung volumes can also augment
caused by mechanical ventilation: repeated alveolar lung injury in lungs with an impaired surfactant system
collapse and re-expansion (Robertson, 1984; Muscedere et al., 1994). A study in a model
of subtle surfactant perturbation showed that surfactant changes
As discussed above, endothelial and epithelial overstretching
make the lung vulnerable to lung parenchymal injury by
with widening of intracellular junctions is considered the basic
mechanical ventilation (Taskar et al., 1997). These studies
mechanism for loss of alveolo-capillary barrier function.
confirm earlier work of Nilsson et al. (1980) in ventilated
However, one idea of VILI and epithelial stretching goes back
premature newborn rabbits with a primary surfactant deficiency.
to the pioneering work of Mead who demonstrated that because
Foetuses treated with surfactant before receiving mechanical
of pulmonary interdependence of alveoli (Fig. 6) the forces
ventilation had less bronchiolar epithelial lesions in comparison
acting on the fragile lung tissue in non-uniformly expanded
with nonsurfactant-treated controls.
lungs are not only the applied transpulmonary pressures, but
rather the shear forces that are present in the interstitium
between open and closed alveoli (Mead et al., 1970). An alveolus Positive end-expiratory pressure (PEEP)
with surfactant impairment would be predisposed to end-
Effect of PEEP on ventilation induced lung injury
expiratory alveolar collapse and prone to be affected by such
‘shear forces’. Shear forces, rather than end-inspiratory over- Initial studies have investigated the effect of increasing levels of
stretching, may well be the major reason for epithelial PEEP at constant tidal volume ventilation, which resulted in
disrupture and loss of barrier function of the alveolar epithelium higher end-inspiratory pressures and volumes. Such studies
and considerable increases in regional microvascular transmural found that increasing levels of PEEP reduced shunt (Caldini et al.,
pressure. 1975; Toung et al., 1977) and improved oxygenation and lung
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mechanics (Hopewell & Murray, 1976) which was attributed to
reopening of flooded alveoli with redistribution of oedema fluid
from flooded alveoli into the interstitial spaces (Permutt, 1979;
Pare et al., 1983; Malo et al., 1984). Such studies, however, also
demonstrated that the use of high PEEP levels did not reduce
(Caldini et al., 1975; Hopewell & Murray, 1976; Hopewell,
1979) or even increase oedema formation (Toung et al., 1977;
Demling, 1993). These findings have been reported in both
isolated perfused lungs (Caldini et al., 1975) and in closed-chest
healthy animals (Hopewell & Murray, 1976) and closed-chest
animals with different forms of lung injury (Toung et al., 1977;
Hopewell, 1979; Luce et al., 1983) or hydrostatic oedema
caused by lobar venous occlusion (Demling et al., 1975).
Overinflation caused by PEEP is probably the explanation for
the lack of reduction or even worsening of oedema reported
with PEEP during such experiments (Bshouty et al., 1988).
However, it has now been unequivocally demonstrated in
different animal models that ventilation with PEEP at lower tidal
volumes results in less oedema than ventilation without PEEP
and a higher tidal volume for the same peak or mean airway
pressure (Webb & Tierney, 1974; Bshouty et al., 1988; Dreyfuss
et al., 1988; Corbridge et al., 1990) and that, more specifically,
PEEP prevents alveolar flooding (Webb & Tierney, 1974;
Verbrugge et al., 1998a,b,c).
Studies by Dreyfuss et al. (1988) in rats ventilated at peak
inspiratory pressure of 45 cmH2O have shown that damage
caused by mechanical ventilation begins at the endothelial side
after 5 min and rapidly progresses to the epithelium after
20 min (Dreyfuss et al., 1988). A subsequent study showed a
reduction of endothelial injury and the preservation of the
structure of the alveolar epithelium by use of 10 cmH2O of
PEEP, which was accompanied by a lack of alveolar flooding
(Dreyfuss et al., 1985).
Reduced microvascular filtration due to capillary
compression by PEEP
Several experiments in closed-chest animals have suggested that
PEEP reduces microvascular filtration pressure due to a decrease
in cardiac output (Caldini et al., 1975; Hopewell, 1979;
Colmenero-Ruiz et al., 1997). It was shown in rats ventilated
at peak inspiratory pressure of 45 cmH2O that the main
determinant of lung oedema formation is the end-inspiratory
lung volume independent of the level of PEEP (Dreyfuss &
Saumon, 1993). Infusion of dopamine to correct the drop in
systemic arterial pressure that occurs with PEEP was shown to
partially abolish the reduction in pulmonary oedema by PEEP
(Dreyfuss & Saumon, 1993). The effect of PEEP in reducing
protein infiltration and permeability of the alveolo-capillary
barrier was attributed to a decrease in lung capillary hydrostatic
pressure and, therefore, filtration pressure (Dreyfuss & Saumon,
1993). Such a mechanism occurs at supraphysiological PEEP
levels, higher than the level necessary to compensate for the
retractive forces of the alveolus, and is attributable to compres-
sion of the capillary by adjacent alveoli. However, pulmonary
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Lung protective ventilatory strategies, S. J. C. Verbrugge et al. 73
artery pressure or cardiac output was not recorded in that study
(Dreyfuss & Saumon, 1993) and loss of the endothelial and
epithelial barrier function was not differentiated. Moreover,
despite similar arterial pressures, the animals ventilated with
PEEP that received dopamine had less oedema than animals
ventilated without PEEP, suggesting that reduced filtration by
capillary compression is not the only reason for the reduction in
oedema by PEEP and that other mechanisms are acting. These are
discussed below.
PEEP and the surfactant system: reduced filtration due to
surfactant preservation
Experiments in the same rat model of overinflation have shown
a significant conversion of active into non-active surfactant
aggregates compared with non-ventilated controls after lung
overinflation; 10 cmH2O PEEP was shown to prevent a
significant conversion of large aggregates into small aggregates
compared with non-ventilated controls (Verbrugge et al.,
1998a,b,c). This latter study suggests that the beneficial effect
of PEEP in reducing protein infiltration after overinflation at
peak inspiratory pressure of 45 cmH2O without PEEP in rats is
partially attributable to a reduced filtration by surfactant
preservation (Verbrugge et al., 1998a,b,c).
Two basic mechanisms have been described in literature
which explain the surfactant-preserving effect of PEEP during
mechanical ventilation. Wyszogrodski et al. (1975) have shown
that PEEP prevents a decrease in lung compliance and surface
activity of lung extracts, indicating a prevention of loss of
alveolar surfactant function during lung overinflation (Verb-
rugge et al., 1998a,b,c). It was suggested that PEEP prevents
alveolar collapse and thus keeps the end-expiratory volume of
alveoli at a higher level, thereby preventing excessive loss of
surfactant in the small airways by a squeeze-out mechanism
during expiration (Fig. 4) (Tyler, 1983; Houmes et al., 1992).
Successive studies by Veldhuizen and colleagues have shown
that the rate of conversion of surfactant large into small
aggregates is dependent on tidal volume and on time (Veldhu-
izen et al., 1996); changing the respiratory rate (Veldhuizen
et al., 1996) or the level of PEEP (Verbrugge et al., 1998a,b,c)
did not affect surfactant conversion. These studies suggest that
the preservation of the surfactant system by PEEP comes from
the reduction in cyclic changes in surface area by PEEP (Fig. 5).
It should be noted, however, that at a higher FRC, comparable
changes in tidal volume are accompanied by smaller surface area
changes compared with the same volume changes at lower FRC.
Another study further tested the hypothesis that reduced
filtration as a result of surfactant preservation is responsible for
the reduction of oedema by PEEP. In this study, a high peak
inspiratory pressure ventilation without PEEP was preceded by
administration of high amounts of exogenous surfactant
(Verbrugge et al., 1998a,b,c). Surfactant-preserved oxygenation
and lung mechanics after 20 min of overinflation at peak
inspiratory pressures of 45 cmH2O without PEEP and reduced
intra-alveolar accumulation of Evans blue dye (Verbrugge et al.,
74 Lung protective ventilatory strategies, S. J. C. Verbrugge et al.
Control 45/0 S100 S200 S400
Figure 7 This figure shows Evans blue dye recovery after 20 min from
the broncho-alveolar lavage fluid after intravenous injection of
30 mg kg)1 Evans blue in non-ventilated control rats (control), and rats
ventilated with peak pressure/PEEP of 45/0 which received
100 mg kg)1 (S100), 200 mg kg)1 (S200), 400 mg kg)1 (S400) or no
intratracheal surfactant (45/0) prior to mechanical ventilation.
1998a,b,c), have been shown to have a good correlation with
extravasation of 125I-albumin (Rogers et al., 1989) (Fig. 7).
These data provide strong evidence that besides peak inspiratory
overstretching after lung overinflation, surfactant inactivation
plays a key role in ventilation-induced intra-alveolar oedema
formation and that the effect of PEEP in reducing lung
permeability to protein is at least partially attributable to its
effect on preservation of the surfactant system. In a subsequent
study, it was also demonstrated that exogenous surfactant can be
used to treat VILI once it is established (Vazquez de Anda et al.,
2001).
Splinting open alveolar lung units with an increased
collapse tendency by PEEP
The utilization of PEEP to splint open the airways and alveoli at
end-expiration in surfactant-deficient lungs may markedly
reduce lung injury (Fig. 6). Studies in both saline-lavaged
isolated perfused rat lungs (Muscedere et al., 1994) and saline-
lavaged intact animals (Argiras et al., 1987; Sandhar et al., 1988)
have shown that ventilation strategies which keep the alveoli
open throughout the respiratory cycle by sufficiently high levels
of PEEP induce significantly less morphological injury (Lach-
mann et al., 1982a,b) with better preservation of pulmonary
compliance than strategies in which alveolar collapse is allowed
at end-expiration. Although healthy lungs do not seem to be
damaged when terminal units are repeatedly opened or closed
for short periods by negative end-expiratory pressure [which
nevertheless reduces compliance and alters gas exchange (Taskar
et al., 1997)], it does become clear from what is discussed
above, that early surfactant changes, which may be induced by
mechanical ventilation itself, predispose lungs for VILI by
repeated opening and closure of alveolar units (Taskar et al.,
1997). In a rat model of surfactant deficiency, a recent study by
Tsuchida et al. (2006) showed that distal airway injury caused
by injurious mechanical ventilation using low PEEP does not
remain confined to atelectatic lung areas but instead is
generalized to both atelectatic and non-atelectatic regions.
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Alveolar injury caused by mechanical ventilation associated
with atelectasis occurred in remote non-atelectatic lung areas
and not in atelectatic areas. Non-injurious ventilation using high
PEEP prevented both alveolar and distal airway injury (Tsuchida
et al., 2006).
Inflammatory mediator release due to mechanical
ventilation
Tremblay et al. (1997) demonstrated that injurious ventilation
strategies could induce cytokine release. Using an isolated non-
perfused rat lung model they demonstrated that ventilation with
high volumes (40 ml kg)1 body weight, BW) and no PEEP
resulted in increased levels of tumour necrosis factor (TNF)-a,
interleukin (IL)-1b, IL-6, macrophage inflammatory protein
(MIP)-2, interferon (IFN)-c and IL-10, both in the presence of
an inflammatory stimulus (lipopolysaccharide induced) or in a
non-stimulated lung (Tremblay et al., 1997). Ventilation with a
lower volume (15 ml kg)1 BW) without PEEP, resulted in only
a significant effect on the above-mentioned cytokines in the
preinflamed lung (Tremblay et al., 1997). Addition of PEEP of
10 cmH2O almost prevented this increase of cytokine release.
The observation that ventilation-induced cytokine release is
dependent on the level of ‘priming’ of the inflammatory milieu
is corroborated by other studies (Verbrugge et al., 1999; Ricard
et al., 2001). Ricard et al. (2001) (in a similar set of experi-
ments) failed to show any effect of ventilation on cytokine
releases without a prestimulus. Similarly release of any TNF-a
during different ventilation strategies could not be demonstrated
in vivo in healthy lungs (Verbrugge et al., 1999). In contrast,
ventilation of an ‘inflamed’ lung has been shown to result in
release of cytokines (Tremblay et al., 1997; Chiumello et al.,
1999; Ricard et al., 2001). One of the proposed mechanisms for
increased mediator levels found in injuriously ventilated lungs
or in the serum of these animals is the loss of compartmen-
talization (Nelson et al., 1989; Haitsma et al., 2000, 2002). The
concept of compartmentalization states that the inflammatory
response remains compartmentalized in the area of the body
where it is produced, i.e. in the alveolar space or in the systemic
circulation (Nelson et al., 1989; Haitsma et al., 2000, 2002).
Compartmentalization of TNF-a (a proinflammatory cytokine)
is lost after ventilator-induced lung injury (Haitsma et al., 2000).
This loss of compartmentalization is dependent on the amount
of active surfactant present at the alveolar-capillary membrane
(Haitsma et al., 2002). Preserving the endogenous surfactant
system with PEEP will (further) reduce this loss of compart-
mentalization (Haitsma et al., 2002).
Imai et al. (2003) in a rabbit acid-aspiration lung injury
model demonstrated that ventilation without PEEP and high
tidal volume resulted in increased levels of end-organ epithelial
cell apoptosis (injurious ventilation 10Æ9%; non-injurious
1Æ86%). Kidneys are amongst the first organs to fail during
multi-organ failure (Wardle, 1994). In the study of Imai et al.
(2003) especially renal tubular epithelial cells showed increased
levels of apoptosis linking injurious ventilation with possible
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Figure 8 Organ–organ interaction, which can perpetuate the secondary
multiple organ failure. The inflammatory lung as seen with adult
respiratory distress syndrome is the initiating focus, which may be a
source of inflammatory mediators, endotoxaemia and bacteria. GI,
gastrointestinal.
organ failure as observed in many patients with ARDS. Plasma
obtained from the rabbits that underwent the injurious
ventilation strategy induced higher levels of apoptosis in
cultured renal cells in vitro, suggesting that circulating soluble
factors associated with the injurious mechanical ventilation
might be involved in this process (Imai et al., 2003). Fas:Ig, a
fusion protein that blocks soluble Fas ligand (a pro-apoptotic
molecule), attenuated this induction of apoptosis in vitro. In
plasma samples from patients included in a previous random-
ized controlled trial (Ranieri et al., 1999, 2000) lower levels of
soluble Fas ligand were found in the group ventilated with a
lung protective ventilation compared with the conventionally
ventilated group (Imai et al., 2003). These data link together
distant organ changes/failure and mechanical ventilation.
Injurious ventilation strategies besides inducing an inflamma-
tory response in the lung, also downregulate the peripheral
immune response (Vreugdenhil et al., 2004). Vreugdenhil et al.
(2004) observed a decrease in MIP-2 and IL-10 production,
splenocyte proliferation, splenic natural killer cell activity and
IFN-c production during injurious ventilation (Vreugdenhil
et al., 2004). Again demonstrating that besides a local effect on
the lung itself, injurious ventilation also affects other cells and
organs (Vreugdenhil et al., 2004) (Fig. 8).
Endotoxaemia and ventilation-induced bacterial
translocation from the lung
Based on the observation that mechanically ventilated ARDS
patients often develop pneumonia (Fabregas et al., 1996) and
septicaemia the question may be raised whether damaging
mechanical ventilation can promote bacteraemia and/or sepsis
(Fig. 8). It is conceivable that bacteria more readily gain access
to the circulation from damaged lung parenchyma than from
previously normal lung tissue (Johanson et al., 1985; Seidenfeld
et al., 1986). It has been established that preserving end-
expiratory lung volume with PEEP has a beneficial effect on the
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Lung protective ventilatory strategies, S. J. C. Verbrugge et al. 75
course of infection in terms of reducing bacterial counts
recovered from the lung tissue after prolonged mechanical
ventilation of lungs inoculated with bacteria (Tilson et al.,
1977). Moreover, avoiding high peak transpulmonary pressures
and preserving end-expiratory lung volume with PEEP has been
shown to reduce translocation of Pseudomonas aeruginosa (Tilson
et al., 1977), Escherichia coli (Nahum et al., 1997) and Klebsiella
pneumoniae (Verbrugge et al., 1998a,b,c) from the lung into the
bloodstream. In addition, reducing the degree of atelectasis by
naturally modified surfactant and/or open lung ventilation, has
been shown to decrease bacterial growth and translocation in a
piglet model of group B streptococcal pneumonia (van Kaam
et al., 2004). Exogenous surfactant before instillation of strepto-
cocci attenuated both bacterial growth and translocation, and
prevented clinical deterioration. This goal was also achieved by
reversing atelectasis in lavaged animals via open lung ventilation
(see below). Combining both exogenous surfactant and open
lung ventilation prevented bacterial translocation completely,
comparable with group B streptococci instillation into healthy
animals (van Kaam et al., 2004). These experiments showed that
a reduction in atelectasis, thus preventing repeated opening and
collapse of atelectatic lung units (atelectrauma) during mechan-
ical ventilation, is at least partially responsible for the decrease in
bacterial growth and translocation (van Kaam et al., 2004). We
have to keep in mind that ventilation should be set to the
individual need of the lung. Ventilation with end-expiratory
pressures higher than required for optimal gas exchange also
promotes bacterial translocation in terms of time to bacteraemia
and absolute numbers of colony forming unit (CFUs) found in
arterial blood (R. Lachmann, unpublished data).
The same principle of translocation applies to endotoxin
derived from the lung, which may translocate as a result of
detrimental forms of mechanical ventilation (Murphy et al.,
2000). These data suggest that ventilation-induced changes in
the barrier function of the lung epithelium and/or endothelium
to bacteria may, to a certain extent, contribute to the
development of bacteraemia and endotoxaemia as it is seen in
multiple organ failure.
Lung protective ventilation in ARDS: the open
lung strategy
Lung protective ventilation
Introduction
In an ARDS lung or a lung that is susceptible to develop ARDS a
higher level of inflammation is present. Although ARDS is
characterized by a P/F ratio in the AECC on ARDS (Bernard et al.,
1994), patients do not die from hypoxaemia but rather die from
multi-organ failure (Ferring & Vincent, 1997; Esteban et al.,
2002). Increased levels of inflammatory mediators correlate
with the development of ARDS (Donnelly et al., 1993) and high
bronchoalveolar lavage (BAL) levels of these mediators in ARDS
lungs have been described extensively (Chollet-Martin et al.,
1993; Goodman et al., 1996; Park et al., 2001). Furthermore,
76 Lung protective ventilatory strategies, S. J. C. Verbrugge et al.
persistent high levels of inflammatory mediators in the lung
over time correlate with poor outcome (Meduri et al., 1995).
Similarly, plasma levels of inflammatory mediators correlate
with severity of ARDS and subsequent outcome (Meduri et al.,
1995; Headley et al., 1997). Headly investigated the role of
inflammatory plasma cytokines during infections and systemic
inflammation, and the subsequent development and progression
of ARDS (Headley et al., 1997). The final outcome of ARDS
patients correlated with the magnitude and duration of the host
inflammatory response in the serum and was independent of the
precipitating cause of ARDS or the occurrence of infections.
Similar observations were made in multiple trauma patients in
which high concentrations of cytokines correlated with the
development of ARDS and finally multi-organ failure (Roumen
et al., 1993). In healthy patients no effect on plasma levels of
mediators were observed during 1 h of mechanical ventilation;
even ventilation with high tidal volumes on zero end-expiratory
pressure did not result in higher cytokine levels compared with
lung protective ventilatory strategies (Wrigge et al., 2000).
Previous lung damage seems to be mandatory to cause an
increase in plasma cytokines after 1 h of high tidal volume
ventilation (Wrigge et al., 2000). In addition, Ranieri et al.
(1999, 2000) linked increased levels of serum inflammatory
mediators to organ failure in patients suffering from ARDS.
These increased serum levels of inflammatory mediators were
observed in patients ventilated with conventional ventilation; in
contrast, a lung protective ventilatory strategy (high PEEP, low
tidal volume) minimized the inflammatory response and
subsequently had a lower incidence of organ failure (Ranieri
et al., 1999, 2000; Stuber et al., 2002).
The concept of loss of compartmentilization of cytokines
from the lung was also demonstrated in patients with ALI by
Stuber et al. (2002). In their study, plasma and BAL cytokines
were measured in patients initially during lung protective
mechanical ventilation (PEEP of 15 cmH2O; tidal volume
5 ml kg)1). Thereafter, ventilation was changed to a more
conventional ventilatory setting (5 cmH2O PEEP and a tidal
volume of 12 ml kg)1) for 6 h and switched back to protective
ventilation again. It was demonstrated that plasma cytokines
increased when switching from protective to conventional
ventilation and decreased again after switching back
to protective ventilation. In contrast, BAL cytokines continued
to increase even when mechanical ventilation was switched back
to protective ventilation again. Thus, in patients with ALI
initiation of low PEEP high tidal volume ventilation is associated
with cytokine release into the circulation and this loss of
compartmentalization of cytokines can be reversed by protective
ventilation with high PEEP despite further increased production
of cytokines in the lung (Stuber et al., 2002).
These facts demonstrate that when lungs of ARDS patients are
mechanically ventilated, ventilation that will increase the
inflammation response should be minimized and the barrier
function of the lung should be preserved. Using a lung
protective ventilation, the outcome of these patients can be
improved. So what guidelines or rules should we use in lung
Journal compilation  2007 Blackwell Publishing Ltd • Clinical Physiology and Functional Imaging 27, 2, 67–90
protective ventilation? Especially ventilation with large tidal
volumes combined with end-expiratory alveolar collapse and
the subsequent appearance of shear forces should be minimized.
However, additional guidelines could help to reduce mortality
even further. In 1982 and 1992 Lachmann suggested such a
ventilation strategy (Lachmann et al., 1982a,b; Lachmann,
1992). In the 1992 editorial entitled ‘Open up the lung and
keep the lung open’ he explained his lung protective guidelines.
There are three steps to open the lung as described by
Lachmann:
1 a critical opening pressure must be overcome during
inspiration;
2 this opening pressure must be maintained for a sufficiently
long period of time;
3 during expiration, no critical time that would allow closure of
lung units should pass, by using intrinsic PEEP or applying
sufficiently high PEEP levels which prevent alveolar collapse.
What is an open lung and why should it be opened?
When a lung is ‘open’ it is characterized by an optimal gas
exchange (Lachmann, 1992) and a low rate of intrapulmonary
shunting (ideally <10%) corresponding with a PaO2 of more
than 450 mmHg (60 kPa) on pure oxygen (Kesecioglu et al.,
1994a). At the same time, airway pressures are at the minimum
that ensure the required gas exchange; haemodynamic side-
effects are thus minimized (Lachmann, 1992). All alveoli are
almost equally expanded, minimizing shear forces reducing any
further damage or progression of lung injury. An open lung
corresponds with the ‘normal state of a healthy lung’. All alveoli
are expanded and although they change size during respiration
no alveoli collapse. Ashbaugh et al. (1967) already described the
consequences of closed lung units: hypoxaemia, intrapulmonary
shunt and atelectasis, with a high risk of infection, multi-organ
failure and finally death. Thus an open lung has no (or minimal
numbers of) collapsed alveoli. In ARDS/ALI atelectasis is a
hallmark of the disease (Bernard et al., 1994), so the first step in
an open lung is to open up the atelectatic areas.
Recruiting the lung
To recruit the collapsed alveoli to improve gas exchange a high
opening pressure is needed. The rationale behind the high
opening pressure to recruit the lung and the need for lower
pressures to keep the alveoli open can be deduced from the P–V
curve of an individual alveolus (Fig. 9). The behaviour of an
alveolus is quantal in nature; it is either open or closed (Bond &
Froese, 1993). A critical opening pressure has to be reached
before previously collapsed alveoli can be opened. Once open,
alveoli remain open until the pressure drops below a critical
level and immediate collapse occurs. Re-opening again requires
the high recruiting pressure. Any state between open and closed
is unstable and impossible to maintain. After opening of the
alveoli, they should be kept open by using a ventilator setting
which will keep the pressure above the critical closing pressure
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Figure 9 Physiological behaviour of the alveolus. The pressure–volume
(P–V) relationship is shown on the xy axes. On the right side, the
status of the broncho-alveolar unit; its radius (r) reflects the P–V
relationship (I–IV). Surface tension in pathological (T1) and normal
conditions (T2) is shown. The arrows indicate the direction from closed
(bottom) to open (top) states and vice versa.
of the alveolus, i.e. with a sufficient high PEEP level. Because the
alveoli are open during the whole ventilation period no collapse
of alveoli occurs, reducing shear forces to a minimal level.
Open lung strategy
The open lung strategy describes the steps and methods used to
safely open the lung and how to keep it open. Figure 10 shows the
predetermined sequence of therapeutic phases, each with its
specific treatment objective (Lachmann, 1992; Bond & Froese,
1993). As shown in Fig. 10, the goal of the initial increase in
inspiratory pressure is to recruit collapsed alveoli and to determine
the critical opening pressure. Then, the minimum pressures that
prevent the lung from collapse are determined. Finally, after an
active re-opening strategy sufficient pressure is applied to keep the
lung open. After opening the lung and finding the lowest pressure
to keep it open, the resulting pressure amplitude is minimized and
at the same time pulmonary gas exchange is maximized. A
reduction of the total level of support is generally possible after a
successful alveolar recruitment (Boehm & Lachmann, 1996).
Should a renewed collapse of alveoli occur, often caused by
intrapulmonary suction or disconnection, a fall in PaO2 indicates
that a re-opening strategy has to be performed in the same way as
previously described.
Figure 10 Schematic representation of the opening procedure for
collapsed lungs. Note: The imperatives (!) mark the treatment goal of each
specific intervention. The bold words mark the achieved state of the lung.
At the beginning the precise amount of collapsed lung tissue is not known.
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Lung protective ventilatory strategies, S. J. C. Verbrugge et al. 77
Monitoring
Monitoring an open lung: visual imaging techniques
A cumbersome technique to define the state of openness of the
lung is the use of computer tomography (CT) or magnetic
resonance imaging. These techniques allow optimal visualization
of individual lung areas and can even produce almost movie-like
images of the lung in motion during ventilation (Gattinoni et al.,
1994). However, both these techniques are not readily available
on the intensive care ward and demand transportation of the
patient to other wards resulting in a less convenient and expensive
technique to find out whether a lung is open.
A relatively new technique which can be used at the bedside of
patients to visualize the aeration of lung is electrical impedance
tomography (Kunst et al., 2000). In this technique changes in
impedance caused by lung volume changes in a 2D image plane
are registered and plotted against time. Using this technique the
lower inflection point and upper deflection point can be
determined which correspond with traditional P–V curve points
which help determine the total amount of lung recruited (i.e.
open) (Kunst et al., 2000). Although this latter technique shows
great promise as a bedside tool to characterize an open lung, it is
now only used experimentally and needs further development and
validation to obtain its rightful place as a bedside tool. A similar
technique is the use of optoelectric plethysmography; in this
technique thorax volume changes are recorded by reflective
markers positioned on the body and recorded through cameras on
an automatic motion analyser (Aliverti et al., 2000). This
technique has shown to accurately register volume changes
during respiration. However, markers are placed on the body
requiring accurate positioning and the line of site of these markers
and the registration cameras should not be interrupted (by sheets
or other registration devices, etc.) (Aliverti et al., 2000). Besides
the direct methods, a number of indirect methods exist which can
help determine the state of the openness of the lung.
Monitoring an open lung: non-visual imaging techniques
In strain gauge plethysmography, a mercury strain senses
changes in lung volume indirectly by measuring changes in
chest circumference through a change in electric resistance
(Sumner, 1985). After calibration with a known volume with
the gauge in situ, changes in lung volume can be measured as
accurately as in millilitres (Sumner, 1985). This technique can
be used to determine the upper and lower inflection point of the
P–V curve of the lung (Kunst et al., 2000), but this technique
cannot define the state of openness of the lung.
Arterial oxygen tension is a traditional tool used to obtain
indirect information on the lung function. When using 100%
oxygen an arterial oxygen tension above 450 mmHg (60 kPa)
characterizes an open lung. The registration of PaO2 by
continuous online intra-arterial measurements facilitates this
process (Fig. 11). Because direct intra-arterial measurements
quickly respond (seconds) to changes in oxygenation, this
allows rapid adjustment of ventilation. Furthermore, when
78 Lung protective ventilatory strategies, S. J. C. Verbrugge et al.
recruitable lung areas are still available a further recruitment
procedure will result in an additional rise of PaO2 (Fig. 11).
When the maximal recruitment has been reached a further
increase of inspiratory pressures will not lead to a further rise in
arterial oxygenation, indicating that the lung is open. When the
inspiratory pressures are increased even further this will lead to a
decrease in PaO2 because of V/Q mismatching. With this very
sensitive technique even small areas of atelectasis can be actively
recruited. When searching for the minimal pressure needed to
maintain an open lung, a decrease in pressures below the critical
closing level will result in an immediate decrease in arterial
oxygenation (Fig. 11).
In principal one can use any FiO2 that one deems safe, but
especially in critically ill patients (ARDS) this could lead to a
(temporary) period of severe hypoxia, when searching for the
closing pressure. Furthermore at a high FiO2 level it is easier to
recognize small atelectasis which could be missed at lower FiO2
levels due to the inherent margin of error of every machine. To
avoid such complications, one could use an FiO2 of 100%. The
use of this technique is easier with an intra-arterial oxygen
Figure 11 Original registration of on-line blood gases of an experi-
mental animal model of acute respiratory failure. The lungs of a pig were
lavaged and ventilated in a volume controlled mode with positive end-
expiratory pressure (PEEP) of 5 cmH2O, tidal volume of 15 ml kg)1 BW
and a respiratory rate of 15 bpm, obtaining a PaO2 < 50 mmHg
(6Æ7 kPa) at an FiO2 ¼ 1Æ0. Thereafter, the lung was opened by a peak
airway pressure of 40, 50 and 60 cmH2O successively, which resulted in
a PaO2 above 500 mmHg (66Æ7 kPa) (1). After this opening-up
procedure, the lungs could be kept open at a peak airway pressure of
31 cmH2O with a total PEEP of 18 cmH2O (1). The animal was than
disconnected and the alveoli were left to collapse. Peak inspiratory
pressures of 40–60 cmH2O were now insufficient to re-open the alveoli
(2). During period (3) several attempts were made to treat the sick lung
with more conventional ways of mechanical ventilation, which all failed
to restore arterial oxygenation. Thereafter, an increase up to 75 cmH2O
peak inspiratory pressure, followed by a peak inspiratory pressure of
65 cmH2O with total PEEP levels of 15–20 cmH2O, was not able to
restore arterial oxygenation to >500 mmHg (66Æ7 kPa) at an FiO2 ¼
1Æ0 (4). During period (5) the lung was step-wise recruited by
increasing peak inspiratory pressure up to 100 cmH2O. A
PaO2 > 500 mmHg (66Æ7 kPa) was achieved with full lung recruitment.
The animal was than disconnected again from the ventilator. In period
(6), The lung was recruited with a peak airway pressure of 100 cmH2O
with a total PEEP of 24 cmH2O, and the lung could be kept open with a
peak inspiratory pressure of 48 cmH2O and a total PEEP of 21 cmH2O
thereafter. The animal was disconnected again, fully recruited at a peak
pressure of 100 cmH2O, but peak pressure was than reduced to
40 cmH2O, which was insufficient to keep the lung open. Period (8)
indicates the start of a new recruitment manoeuvre after the last
disconnection. Note: Repeated disconnection of a sick lung results in a more severe stage
of respiratory failure which requires higher opening pressures [compare period (1) with
periods (6–7)].
Journal compilation  2007 Blackwell Publishing Ltd • Clinical Physiology and Functional Imaging 27, 2, 67–90
sensor, but transcutaneous saturation sensors messengers can
serve as a non-optimal online alternative.
If offline arterial blood gases are used, this will require
frequent sampling during the establishment of an ‘open lung’. It
is also mandatory that arterial blood gas sample handling should
be strictly adhered to prevent any air bubbles in the sample.
Because high oxygen values will rapidly equilibrate to the partial
oxygen tension of the room, this leads to misinterpretation of
results, and thus unnecessary adjustments of the ventilation.
Besides arterial oxygenation the determination of the FRC can
help establish how ‘open’ a lung is. The interpretation of this
measurement should not be made without a corresponding
arterial blood gas measurement. Because an increase of FRC will
not always be due to an increase of recruitable lung area (e.g.
atelectasis), it can also be due to overinflation of a still reduced
FRC. The corresponding PaO2 will immediately differentiate
between recruitment or overinflation. The PaO2 would immedi-
ately increase during recruitment but not during overinflation.
Another simple method, which is very effective in opening larger
atelectatic areas, is the use of the physician’s best friend ‘the
stethoscope’. When listening to the lung the presence of crackles
and crepitant rales indicates that during ventilation alveoli are still
collapsing and actively reopening in the subsequent inspiratory
phase (Ploysongsang et al., 1989). It does not tell if the lung is
open or not. If one would hear crepitant rales however, it will
indicate that fluid moves into the airways, which means that the
applied PEEP is too low. In an ‘open lung’ these sounds will not be
present. These crackles can best be heard in the dependent lung
areas; it can however be difficult to distinguish the crackles in a
mechanically ventilated patient from other sounds.
P-V curves
As mentioned before, the behavior of an individual alveolus is
quantal in nature, either open or closed. The P–V curve of a lung is
the accumulation of millions of these alveoli. Looking at a P–V
curve a distinct inflation and deflation curve can be seen.
Figure 12 shows the pressure–volume (P–V) relationship of the
lung, representing the cumulative behaviour of all alveoli. When a
lung is collapsed the remaining volume will be almost zero and
increasing the pressure will lead to a rise in volume. The inflation
limb of the P–V curve shows the changes in lung volume during
incremental airway pressures and usually contains a so-called
lower inflection point. Above this point lung volume suddenly
increases. As lung volume approaches total lung capacity (TLC)
the inflation limb flattens off. The deflation limb represents the
changes in lung volume during decremental airway pressures
starting at TLC. Lung volume is initially maintained (increased
radius) as pressures are lowered but eventually decreases due to
progressive alveolar collapse.
Thus, when a P–V curve is obtained during ventilation
(most common) a period of active recruitment of collapsed
alveoli will lead to an increase in volume as can be observed
by an increased slope of the inflation limb. Finally the slope
of the inflation limb will flatten which can be interpreted as
 2007 The Authors

Figure 12 Pressure–volume relationship of the lung showing the
inflation (solid line) and deflation limb (dashed line). Note the clear
difference in lung volume between both limbs at identical pressures.
maximal recruitment, and subsequent deflation will lead to
the characteristic deflation curve. As shown in Fig. 12,
however, it is possible that not all recruitable lung tissue
has been recruited at the pressure used at the lower inflection
point, and a further increment of the pressure could result in
an additional increase of arterial oxygenation and a recruit-
ment of still collapsed alveoli. Translating this to the P–V
curve means that increasing the pressure on this lung even
further would lead to an additional increase in volume (e.g.
recruitment). Thus, there is still ongoing recruitment above
the lower inflection point. If this second recruitment
procedure with higher pressures had not been performed,
the original P–V curve would be considered as the represen-
tative curve of this lung, without obtaining the P–V curve
corresponding with an ‘open lung’.
Mathematical models and animal experiments have shown that
adequate recruitment of collapsed alveoli followed by optimal
stabilization with adequate levels of PEEP, will place ventilation on
the more steeply sloped deflation limb of the P–V curve
(Rimensberger et al., 1999; Hickling, 2001). By only using the
P–V curve though, it may be difficult to differentiate between
alveolar collapse or a general decrease of lung volume. These two
phenomena will be differentiated by measuring the PaO2.
What did we learn from human studies on
mechanical ventilation?
Limiting peak inspiratory pressures/volumes
Clinical studies
Hickling et al. (1990) demonstrated that limiting peak
inspiratory pressures to <30–40 cmH2O during mechanical
ventilation of ARDS patients by reducing tidal volumes and
allowing permissive hypercapnia [up to a arterial CO2 of
70 mmHg (9Æ3 kPa)] could reduce mortality from ARDS
(Hickling et al., 1990). However, three subsequent controlled
trials using permissive hypercapnia could not demonstrate an
improved patient outcome (Brochard et al., 1998; Stewart
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Lung protective ventilatory strategies, S. J. C. Verbrugge et al. 79
et al., 1998; Brower et al., 1999). These studies used tidal
volumes of 7 ml kg)1 in the low tidal volume study groups
and tidal volumes of 10 ml kg)1 in the control groups. A
study by the ARDS network group using a tidal volume of
6 ml kg)1 lean body weight and a peak inspiratory pressure
<30 cmH2O in a protective ventilation group and a tidal
volume of 12 ml kg)1 BW and a maximum peak inspiratory
pressure of 50 cmH2O in a control group, showed a reduced
mortality (Anonymous, 2000). Explanations given for the
difference in outcome between this trial and the other three
trials included the larger difference in tidal volume between
the study groups in this trial, the power of the study (the
ARDS Network used 861 patients, while the other studies
used a maximum of 120 patients) and the aggressive
treatment/prevention of acidose in the ARDS Network study.
Furthermore, in the ARDS Network study only 12% of the
screened patients were randomized while the mortality in the
excluded group was higher than those included in the trial
(Suchyta et al., 2001; Esteban et al., 2002). Increased levels of
IL-6 proinflammatory cytokine in the serum were observed
after 3 days of ventilation in the control arm of the study
when compared with the reduced tidal volume group.
Another randomized controlled study by Amato et al.
(1998) showed a reduced mortality in 53 patients by using
a lung protective ventilation strategy. Their study used a tidal
volume of 12 ml kg)1 BW in a control group and a tidal
volume of 6 ml kg)1 BW in a study group with permissive
hypercapnia up to a pH of 7Æ2. In the study group, a low
tidal volume was combined with a high PEEP level, a
recruitment manoeuvre and maximum pressure amplitudes
above the PEEP level of 20 cmH2O. A more recent similar
study was conducted by Villar et al. (2006) in 103 patient
with demonstrated persistent ARDS 24 h after initially
meeting ARDs criteria while on standard ventilator settings
(Villar et al., 2006). Their study used a tidal volume of 9–
11 ml kg)1 predicted body weight in a control group and a
tidal volume of 5–8 ml kg)1 predicted bodyweight in a study
group. In both groups ventilatory frequency was adjusted to
maintain pCO2 between 35 and 50 mmHg (4Æ7–6Æ7 kPa).
When compared with conventional ventilation, the protective
strategy was associated with improved ICU mortality (32%
versus 53Æ3%), improved hospital mortality (34% versus
55Æ5%) and a higher number of ventilator-free days at
28 days (6Æ02 versus 10Æ9). The mean difference in the
number of additional organ failures postrandomization was
higher in the control group (Villar et al., 2006).
Ranieri et al. (1999, 2000) showed a correlation between an
increased concentration of inflammatory mediators in the serum
of ARDS patients and non-pulmonary organ or system failure
(circulatory, coagulation and renal). The increase in serum levels
of inflammatory mediators was found in patients ventilated with
high tidal volumes (average of 11Æ1 ml kg)1 BW). Patients
ventilated with protective forms of mechanical ventilation with
low tidal volumes (average of 7Æ6 ml kg)1) and maximal peak
inspiratory pressures of 35 cmH2O had lower concentrations of
80 Lung protective ventilatory strategies, S. J. C. Verbrugge et al.
serum and BAL inflammatory mediators. The decrease in
concentration of inflammatory cytokines was correlated with an
decrease in multisystem organ failure (MSOF) especially in the
number of patients with renal failure.
Limitations and controversies
An increase in arterial CO2 concentration during permissive
hypercapnia can induce vasodilatation, an increase in pulse
frequency, blood pressure and cardiac output (Sevransky et al.,
2004) and a decrease in renal blood flow (Kuiper et al., 2005). The
use of permissive hypercapnia is limited in patients with pre-
existing metabolic acidosis and contraindicated in patients with
increased intracranial pressures (ICPs) (Tasker & Peters, 1998).
Considering hypercapnia and lung function, it has been suggested
that hypercapnia by itself may have protective effects (Kavanagh &
Laffey, 2006) which are not related to reductions in lung stretch.
However, in mechanically ventilated animals hypercapnia, as
opposed to eucapnia, was shown to aggrevate the amount of
protein infiltration across the alveolo-capillary membrane and
increase the lung tissue wet/dry ratio in response to lipopoly-
saccharide exposure (Lang et al., 2005). We have to realize that the
incidence of ventilator-associated pneumonia may be as high as
71% and that, thus, hypercapnia may aggrevate the disease state of
the lung in a majority of ventilated patients with ARDS (Chastre &
Fagon, 2002). Further, considering hypercapnia and/or hypoxia,
even small and short-lasting disturbances of PaCO2 and PaO2 may
lead to impairment of cognitive function in ICU patients such as
delirium (Truman & Ely, 2003) which has been shown to be a
predictor of mortality in mechanically ventilated ICU patients (Ely
et al., 2004).
Protective ventilatory strategies that lead to hypercapnia may
be clinically acceptable, provided the clinician is primarily
targeting reduced tidal stretch (Laffey et al., 2004). There are no
clinical data that support the practice of buffering hypercapnic
acidosis (Laffey et al., 2004). Clinical trials using lung protective
ventilatory strategies have accepted pH limits of up to 7Æ2
(Amato et al., 1998).
Recommendations
There is clinical evidence that during mechanical ventilation in
ARDS patients tidal volumes should be limited to <6 ml kg)1 if
possible. Peak inspiratory pressures should be limited to 30–
35 cmH2O or the pressure amplitudes above PEEP should not be
higher than 15–20 cmH2O and hypercapnia could be prevented
by higher respiratory rates.
Using PEEP in ARDS patients
Clinical studies
Kirby et al. (1975) already used total PEEP levels of 30 cmH2O
in 28 patients with ARDS and demonstrated an overall survival
rate of 61% in this group of ventilated ARDS patients. Similarly,
Journal compilation  2007 Blackwell Publishing Ltd • Clinical Physiology and Functional Imaging 27, 2, 67–90
Lachmann et al. (1982a,b) applied total PEEP levels of
20 cmH2O in six patients with ARDS and demonstrated
markedly improved oxygenation ratios and optimalized carbon
dioxide removal using more intrinsic PEEP, which generally
allows better control of CO2 removal when compared with static
PEEP. In sharp contrast to these two studies, a recently published
multicentre European study reported survival rates of only 32%
in patients with ARDS and found that ARDS patients initially
received PEEP levels of only 8 cmH2O (Brun-Buisson et al.,
2004). Thus, the initial proof of the beneficial effects of high
PEEP levels in patients with ARDS of the earlier days of
ventilatory research unfortunately seems to have been left again
in the years thereafter. In recent years, there has been a renewed
interest in the concept of higher levels of PEEP in ARDS. The
studies by Amato et al. (1998) and by Villar et al. (2006) showed
a significantly lower mortality in ARDS patients when combi-
ning low tidal volume ventilation with high levels of PEEP (17
and 13Æ4 cmH2O respectively) using PEEP levels of 1–2 cmH2O
above the lower inflection point of a static P–V curve when
compared with mechanical ventilation with high tidal volumes
and lower PEEP levels (8 and 9Æ8 cmH2O respectively). When
compared with three negative studies using low tidal volumes
(Brochard et al., 1998; Stewart et al., 1998; Brower et al., 1999)
the level of PEEP in Amato’s study and Villar’s study was higher
(Fig. 13).
In the ARDS Network trial the low tidal volume group had a
slightly higher set PEEP of 9 cmH2O compared with a set PEEP
of 8 cmH2O in the control group (Anonymous, 2000).
However, the increased respiratory rate (to help prevent
acidosis) used in the low tidal volume group may have resulted
in intrinsic PEEP which contributed to a higher total PEEP
(16 cmH2O) in this group (Lee et al., 2001; de Durante et al.,
2002) compared with the 12 cmH2O in the traditional tidal
volume group. This higher total PEEP could help explain the
decrease in mortality observed in this group (Fig. 13).
PEEP (cmH2O)
18
16
14
12
10
8
6
4
2
0
Brochard Brower Stewart Amato ARDSNet Villar
Figure 13 Total positive end-expiratory pressure (PEEP) levels applied
in studies on protective mechanical ventilation. Studies used are by
Brochard et al. (1998), Brower et al. (1999), Stewart et al. (1998), Amato
et al. (1998), the ARDSnet with intrinsic PEEP modification from de
Durante et al. (2002) and Villar et al. (2006). Gray bars represent the
PEEP levels in the lung protective strategies and the white bars represent
the PEEP levels in the control arms of the corresponding studies.
 2007 The Authors

In 2004, the ARDS Network published a follow-up study,
investigating whether increased PEEP levels combined with low
tidal volume ventilation affects outcome compared with the low
tidal volume ventilation used in their previous study (Brower
et al., 2004). The data and safety monitoring board stopped the
trial at the second interim analysis, after 549 patients had been
enrolled, on the basis of the specified futility stopping rule.
Although in this study no benefit in outcome was observed
between the patient groups, the mortality rate in both study
arms was reduced [24Æ9% lower PEEP (average 8Æ3 cmH2O) and
27Æ5% higher PEEP (average 13Æ2 cmH2O)], again confirming
that adjusting the ventilatory settings decreases mortality in
ARDS/ALI patients. Unfortunately, patients randomized to the
higher PEEP group also had at baseline more characteristics that
predict a higher mortality; adjustments for these differences in
baseline covariates did not alter the final outcome but did favour
the higher PEEP group (Levy, 2004). A follow-up study by
Grasso et al. (2005) concluded that the PEEP protocol used in
this ARDSNet study lacked a solid physiological basis and did
not frequently result in alveolar recruitment in ARDS. Moreover,
the study group with low PEEP settings in the ARDSNet study is
likely to have had a higher level of intrinsic PEEP and thus the
difference in the total level of PEEP may have been much lower
than the difference of 5 cmH2O reported (Anonymous, 2000).
Therefore, the study may have been underpowered to demon-
strate a significant difference in mortality.
In the studies by Ranieri et al. (1999, 2000), a protectively
ventilated patient group received higher levels of PEEP when
compared with a control group (14Æ8 cmH2O versus
6Æ5 cmH2O). This resulted, in combination with lower tidal
volumes, in reduced serum concentrations of inflammatory
cytokines and a lower MSOF score.
Limitations and controversies
It has been suggested that too high levels of PEEP could possibly
induce overdistension of relatively healthy lung units in ARDS/
ALI (Levy, 2004; Gattinoni et al., 2006). As previously des-
cribed, there is evidence from animal studies, however, that
high levels of PEEP may serve to prevent the conversion of active
forms of pulmonary surfactant into non-active forms by
preventing cyclic surface area changes. Such studies would
suggest that PEEP would serve to preserve normal function of
the alveolar-capillary membrane in relatively healthy lung units
during the use of high peak inspiratory pressures (Verbrugge
et al., 1998a,b,c).
Positive end-expiratory pressure levels currently employed in
intensive care units around the world are below 6 cmH2O in
78% of the patients receiving mechanical ventilation (Esteban
et al., 2000). Considering the fact that patients with healthy
lungs receiving general anaesthesia in the operating room
already need PEEP pressures in the order of 5–10 cmH2O to
prevent alveolar collapse (Neumann et al., 1999), the applied
pressures were certainly too low for ARDS patients. Even more
disturbing is that in the same study only three patients of the
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Lung protective ventilatory strategies, S. J. C. Verbrugge et al. 81
1638 ventilated ICU patients studied had a PEEP level above
15 cmH2O. It is known that high PEEP levels in the range of
15 cmH2O and above are necessary to prevent repetitive
collapse of alveoli and thus reduce shear forces in ARDS patients
(Gattinoni et al., 1995). Furthermore, only studies using PEEP
levels above 13Æ5 cmH2O in their protective arm have demon-
strated a reduction in mortality (Amato et al., 1998; Ranieri
et al., 1999; Anonymous, 2000; de Durante et al., 2002; Villar
et al., 2006) (Fig. 13).
Recommendations
There are profound clinical grounds that suggest that higher
levels of PEEP should be used in ARDS/ALI. An initial PEEP level
in patients with ARDS for lung protection could be in the range
of 15 cmH2O (Fig. 13). One should realize that it is not the
absolute level of PEEP that is important. It is the effect of PEEP
that counts: an adequate level of PEEP results in a permanent P/F
ratio above 450 mmHg (60 kPa).
The use of recruitment strategies in ARDS patients
Clinical studies
The use of PEEP can prevent collapse of open and perfused
alveoli but PEEP itself does not recruit collapsed alveoli because
recruitment is an inspiratory phenomenon (Lim et al., 2003).
However, PEEP can indirectly create a higher end-inspiratory
pressure in volume-controlled mechanical ventilation. By
creating a higher end-inspiratory pressure, PEEP can indirectly
reopen collapsed lung areas and reduce the amount of
intrapulmonary shunting and improve oxygenation (Richard
et al., 2003).
There are only limited data available on open lung ventilation
in patients. Amato et al. (1998) reported on a trial using a setting
similar to the open lung concept (OLC). Patients (53 with early
ARDS) were randomly assigned to conventional or protective
mechanical ventilation. Protective ventilation involved a recruit-
ment strategy, end-expiratory pressures above the lower
inflection point on the static P–V curve, a tidal volume of
<6 ml kg)1, driving pressures of <20 cmH2O above the PEEP
value, permissive hypercapnia, and preferential use of pressure-
limited ventilatory modes (Amato et al., 1998). When compared
with conventional ventilation, the protective strategy was
associated with improved survival at 28 days (38% versus
71%), a higher rate of weaning from mechanical ventilation
(66% versus 29%), and a lower rate of barotrauma (7% versus
42%), in patients with ARDS (Amato et al., 1998). Although
several guidelines of the open lung strategy were followed,
lungs of the patients were not totally recruited (as indicated by
the P/F ratio) this is in part due to the uniformly applied
recruitment pressure of 35–40 cmH2O of continuous positive
airway pressures for 40 s, which is insufficient for more severe
atelectatic areas to open (Schreiter et al., 2004). Moreover, this
study used the lower inflection point of the P–V curve where
alveolar decruitment is shown to occur (Maggiore et al., 2001).
82 Lung protective ventilatory strategies, S. J. C. Verbrugge et al.
A recent study by the same group showed that higher
recruitment pressures of up to 60 cmH2O could permanently
recruit 95% of atelectatic lung tissue as measured by arterial
oxygenation and CT scans in almost all (26/28) studied patients
with early ARDS (Borges et al. 2006).
In a recent retrospective analysis of patients with ARDS due to
pulmonary contusion Schreiter et al. (2004) showed that
mechanical ventilation according to the open lung strategy
dramatically improved oxygenation and lung aeration. This
results in low tidal volumes of 3Æ5 ml kg)1 BW (Schreiter et al.,
2002). Schreiter et al. carefully monitored lung recruitment by
both arterial oxygenation and thoracic helical CT scans before
and after ventilation according to the open lung strategy. The
recruitment reduced atelectatic areas from 604 to 106 ml and
increased the normally aerated volume from 1742 to 2971 ml
(Schreiter et al., 2004). Furthermore, arterial oxygenation levels
were stable after the recruitment procedure thus minimizing the
cyclic opening and collapse which augments cytokine release
(Muscedere et al., 1994; Tremblay et al., 1997; Tremblay &
Slutsky, 1998). The severity of the injury in the patients studied
by Schreiter et al. is illustrated by the Acute Physiology and
Chronic Health Evaluation II (APACHE II) of 23 (range 11–26)
points. The predicted mortality of the APACHE II score was
49Æ7%, and the adjusted APACHE II had a predicted mortality of
22Æ4%. These rates correspond with the respective mortality rate
observed in ARDS patients (42%) and in ARDS due to
pulmonary contusion (20%). However, all patients in the study
by Schreiter et al. (2004) survived and were alive up to 14–
60 months after treatment for ALI/ARDS. The same group
recently published a case report describing protective mechan-
ical ventilation using low tidal volume ventilation and high PEEP
in a 17-year-old trauma patient with pulmonary contusion and
substantial bilateral atelectasis (Reske et al., 2006). Protective
mechanical ventilation alone (low tidal volume, high PEEP) did
not improve oxygenation and pulmonary mechanics, whereas
these parameters did improve after alveolar recruitment.
Aeration of the entire lung after recruitment was confirmed
by CT (Reske et al., 2006). These findings underscore the
importance of the use of recruitment manoeuvres next to low
tidal volume and high PEEP in the concept of protective
mechanical ventilation.
Limitations and controversies
One of the limitations of recruitment strategies may be
increases in ICPs. Wolf et al. (2002) applied an open lung
strategy in 11 patients with known intracranial pathology and
concomitant ARDS. The P/F ratio in these patients was
markedly improved and mean PEEP levels as high as
15 cmH2O were applied. In contrast to the general idea that
PEEP increases ICP, these authors found that the ICP even
declined non-significantly after a recruitment manoeuvre
when compared with the ICP values before recruitment, this
despite a moderate increase in PaCO2 (Wolf et al., 2002).
Such findings were confirmed by data in patients with severe
Journal compilation  2007 Blackwell Publishing Ltd • Clinical Physiology and Functional Imaging 27, 2, 67–90
traumatic brain injury. Increasing PEEP levels from levels
below 5 cmH2O to levels as high as 15 cmH2O led to
decreases in ICP and improvements of cranial perfusion
pressure (CPP) (Huynh et al., 2002). Similarly, Georgiadis
et al. (2001) found that an increase in PEEP level of up to
12 cmH2O did not significantly influence ICP in 20 ventilated
patients with acute stroke. The observed changes in CPP
induced by PEEP in this study were mediated through
changes in mean arterial pressure (MAP). Thus, PEEP
application should be safe, provided that the MAP is
maintained. It is our opinion that an open lung strategy to
improve oxygenation is safe in patients with intracranial
pathology and cerebral complications should not be used as
an excuse not to apply an open lung strategy in patients on
mechanical ventilation.
Another possible side-effect of lung recruitment and open
lung ventilation could be cardiac impairment by high mean
airway pressures and redistribution of blood flow (Villagra et al.,
2002). As the open lung strategy is a method of ventilation
intended to maintain end-expiratory lung volume by increased
airway pressure, this could increase right ventricular afterload.
An open lung strategy is accompanied by elevated intrathoracic
pressures and since the work of Cournand et al. (1948), elevated
intrathoracic pressures are associated with a decrease in cardiac
output. This idea could not be confirmed in experimental work
in animals applying an open lung strategy (Kesecioglu et al.,
1994b). Reis Miranda et al. (2004) recently studied the effect of
the open lung strategy on right ventricular afterload in patients
after cardiac surgery. Patients were randomly assigned to OLC or
volume-controlled ventilation with a PEEP of 5 cmH2O. To
achieve an open lung, recruitment attempts were performed
with a peak pressure of 45Æ5 cmH2O. To keep the lung open, a
PEEP of 17 cmH2O was required. Compared with baseline,
pulmonary vascular resistance and right ventricular ejection
fraction did not change significantly during the observation
period in either group. No evidence was found that ventilation
according to the OLC affects right ventricular afterload in
normovolemic patients. These studies demonstrate that applying
open lung ventilation is feasible in cardiac patients (Reis
Miranda et al., 2004). Findings from other authors confirm that
recruitment strategies do not result in important haemodynamic
disturbances (Lim et al., 2001; Dyhr et al., 2002; van den Berg
et al., 2002; Johannigman et al., 2003). An increase of right
ventricular afterload, however, can be compensated by an
increase of contractility without affecting cardiac output.
Indeed, an increase of airway pressure was associated with an
increment of right ventricular afterload and a decrease in RV
ejection fraction in other studies (Biondi et al., 1988; Dambrosio
et al., 1996; Spackman et al., 1999; Schmitt et al., 2001). It has
been demonstrated that it is not PEEP but high tidal volume that
is the main factor in increasing right ventricular afterload
(Poelaert et al., 1994; Vieillard-Baron et al., 1999, 2001).
Thus, a large amount of investigations have been conducted
on the effect of PEEP on haemodynamics but most of these do
not exactly describe their methodology (Pinsky, 2005).
 2007 The Authors

Although positive results of manipulation of the Startling
equation have been suggested (Lewis & Martin, 2004), many
negative effects of striving for a negative fluid balance in ARDS
patients have been described (Schuster, 1993). In contrast,
studies that reported adequate fluid management prior to lung
recruitment did not report any deterioration with PEEP levels of
10–15 cmH2O (Miranda et al., 2003, 2005). Adequate fluid
loading and haemodynamic stabilization is thus a prerequisite
for conducting an open lung strategy. Some reservedness might
be in place though in performing recruitment manoeuvres in
patients with severe cardiac compromise or with a depleted
circulatory volume.
Recruitment pressures in clinical studies have been limited to a
maximum of 40–45 cmH2O (Amato et al., 1996, 1998; Lim et al.,
2001; Villagra et al., 2002; Brower et al., 2003; Johannigman et al.,
2003; Oczenski et al., 2004). This is most likely caused by a fear of
peak inspiratory overstretching with the risk of causing harm to
relatively healthy lung units. Recently, high inspiratory pressures
(Boussarsar et al., 2002) and elevated PEEP (Eisner et al., 2002)
levels were correlated with an increased rate of pneumothorax,
although Boussarsar studied high inspiratory pressures applied for
a prolonged period. In contrast, Weg et al. (1998) in a large
prospective study in 725 patients suffering from ARDS found no
significant correlation between high ventilatory pressures and the
development of pneumothorax or other leaks. Schreiter found no
increase in pneumothoraces in patients with severe chest trauma
ventilated with an open lung strategy (Schreiter et al., 2002) using
mean peak inspiratory pressures of 65 cmH2O (up to 80 cmH2O)
during recruitment. Re-expansion of atelectasis during general
anaesthesia in patients with healthy lungs already requires peak
inspiratory pressures of 40 cmH2O to fully reexpand atelectatic
lung tissue (Rothen et al., 1993). Limiting peak inspiratory
pressures in patients with ARDS will certainly prevent recruitment
of the most severely affected alveoli and therefore may result in
ongoing shear stress from repeated alveolar collapse and
reexpansion. Gattinoni et al. (2006) conducted a CT-controlled
study on alveolar recruitment in ARDS patients using maximum
recruitment pressures of 45 cmH2O. From their findings they
concluded that 24% of lung tissue in ARDS cannot be recruited.
However, it is likely that such alveoli are recruitable but that the
used recruitment pressures of 45 cmH2O may have been to low to
open them up (Slutsky & Hudson, 2006). Similar to the findings
described by Schreiter et al. (2004) using recruitment pressures up
to 80 cmH2O, a more recent study by the Amato group using
multislice CT and continuous blood-gas monitoring to confirm
recruitment, demonstrated that recruitment pressures of up to
60 cmH2O could permanently reverse hypoxia and collapse in
more than 95% of the lung units in 24 of 26 patients with early
ARDS (Borges et al., 2006). The findings of Schreiter and Amato’s
group confirm that peak recruitment pressures higher than
40–45 cmH2O are necessary to fully recruit the lungs of ARDS
patients.
Recruitment strategies in a late phase of the disease process,
when collapsed alveoli are being organized and infiltrated with
fibroblasts are usually not possible and increase the risk of injury
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Lung protective ventilatory strategies, S. J. C. Verbrugge et al. 83
(Grasso et al., 2005). Moreover, lung recruitment may be more
efficient in secondary ARDS (of extrapulmonary origin) in
which a great part of collapsed lung is due to compression
atelectasis; in primary ARDS (of pulmonary origin) in which an
important reason for lung collapse in intrapulmonary oedema
and inflammation, recruitment can be more difficult (Gattinoni
et al., 1998; Pelosi et al., 1999; Lim et al., 2003). However, this
distinction in response between primary and secondary ARDS
could not be demonstrated in a recent paper by the Amato
group (Borges et al., 2006). Patient categories in which a lung
recruitment strategy should probably be conducted with great
reserve include patients with severe airway obstruction/chronic
obstructive pulmonary disease and patients with large pulmon-
ary infiltrates of lung abscesses.
Recommendations
Data from animals and limited data in humans demonstrate that
applying open lung ventilation is feasible in patients. Recruit-
ment pressures should probably be in the high range and may
well be above those of maximally 50 cmH2O currently
employed in most clinical studies. The safe use of recruitment
pressures of up to 80 cmH2O has been reported and has resulted
in a lower than predicted mortality from APACHE II scores
(Schreiter et al., 2004). If one performs a recruitment man-
oeuvre, to prevent possible complications recruitment should
not last longer than 2–3 respiratory cycles or 5–15 s.
Clinical guidelines for lung protective ventilation in early
phase ARDS
From the findings of the clinical studies described above, we
would like to suggest the following guidelines for lung
protective ventilation in early phase ARDS. A standard procedure
ventilatory protocol (FiO2 ¼ 100%; PEEP ¼ 10–12 cmH2O;
target tidal volume 5–7 ml kg)1; respiratory rate 25–30 per
minute using pressure controlled ventilation) is set and
sufficient haemodynamic stabilization is provided (both fluid
loading and initiation of inotropic support). If, after application
of the standard ventilation protocol for 30 min, the P/F ratio is
>200 mmHg (26Æ7 kPa), PEEP is set at 15 cmH2O; if the P/F
ratio <200 mmHg (26Æ7 kPa); PEEP is set at 20 cmH2O.
Thereafter, PEEP is titrated on the basis of the P/F ratio
[>450 mmHg (60 kPa)]. Tidal volumes should be 6 ml kg)1 or
preferably lower. If possible a pressure amplitude <15 cmH2O
above PEEP should be applied. Permissive hypercapnia has been
accepted in clinic, but considering our previous discussion, it
should be accepted with great reluctance. If hypercapnia is
present the respiratory frequency should simply be increased
(Schreiter et al., 2002). In the haemodynamically stable patient,
a recruitment pressure of 50 cmH2O should be applied for three
breaths or 5–15 s at maximum. After this recruitment man-
oeuvre the maximum airway pressure should go down to 30–
35 cmH2O. If the latter procedure results in P/F ratios above
450 mmHg (60 kPa) and remains stable for at least 10–15 min,
84 Lung protective ventilatory strategies, S. J. C. Verbrugge et al.
we would call this an open lung. If the P/F ratio would not be
stable, one should consider to increase the PEEP further by
1–2 cmH2O. If the P/F ratio <450 mmHg (60 kPa), apply
another recruitment manoeuvre increasing the recruitment
pressure by 10 cmH2O (in this case to 60 cmH2O). This cycle
should be repeated until the P/F ratio is >450 mmHg (60 kPa).
Recently, the relationship of oxygen saturation to the inspiratory
fraction of oxygen (SaO2/FiO2) was described for using
recruitment procedures in infants (De Jaegere et al., 2006).
Although not yet published in adults, a similar procedure can
also be adapted for use in the adult population.
Conclusions
The role of the pulmonary surfactant system was first described
in 1929 and became clinically relevant when infant and acute
(adult) respiratory distress syndrome were first described in the
1950s and 1960s. Experimental studies have showed us that
modes of mechanical ventilation which use high peak inspir-
atory pressures/volumes and which do not use positive end-
expiratory pressure can lead to changes within the alveolar-
capillary membrane including the surfactant system of the lung
which mimic those seen in ALI/ARDS. Such detrimental forms
of mechanical ventilation were related to distant organ failure
(e.g. kidney failure) by the release of inflammatory mediators
and bacteria/endotoxins from the lung. In ARDS a majority of
patients die from dysfunction of organ systems other than the
lung and recent clinical evidence suggests that protective modes
of mechanical ventilation may reduce mortality from patients
with ARDS.
Considering the fact that each lung has a collapse tendency
(even healthy ones) each patient should be ventilated with
sufficient PEEP levels and with a ventilation protocol that applies
a recruitment manoeuvre. The use of the P/F ratio at present is
the method that best combines practicality with sensitivity in
defining the state of openness of a lung.
There is clinical evidence that during mechanical ventilation
in ARDS patients tidal volumes should be limited to <6 ml kg)1
if possible. PEEP can prevent collapse of open and perfused
alveoli but PEEP itself does not recruit collapsed alveoli because
recruitment is an inspiratory phenomenon. PEEP levels currently
employed worldwide are too low and clinical evidence suggests
that higher levels of PEEP should be used in ARDS/ALI. Data
from animals and limited data in humans demonstrate that
recruitment pressures should probably be in the high range and
should well be above those of maximally 50 cmH2O currently
employed in most clinical studies.
As stated in the introduction of the article, we aimed this
article to be a guide in the Scylla and Charybdis of ventilatory
management of ARDS patients. Lung protective ventilation
strategies in ARDS patients have already showed an improved
survival when compared with traditional forms of mechanical
ventilation. Ventilatory management does not involve having to
face Scylla and Charybdis like Ulysses. In this regard, adequately
performed recruitment strategies may further help the
Journal compilation  2007 Blackwell Publishing Ltd • Clinical Physiology and Functional Imaging 27, 2, 67–90
intensivist and reduce mortality caused by mechanical ventila-
tion from ARDS just like Thetis helped Jason and his Argonauts.
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