Réanimation 15 (2006) 14–20
http://france.elsevier.com/direct/REAURG/
Mise au point
Goal oriented ventilation in acute respiratory distress syndrome:
a concept for optimal gas exchange at lung protective ventilation
Ventilation adaptée au cours du Syndrome de détresse respiratoire aiguë :
comment combiner échanges gazeux et protection pulmonaire ?
B. Jonson
Department of Clinical Physiology, University Hospital of Lund, S-221 85 Lund, Sweden
Abstract
The strategy goal oriented ventilation means that mechanical ventilation should aim at clearly defined immediate physiological objectives
based upon the actual status of the individual patient. The immediate goals, which ultimately should lead to an optimal outcome, comprise
normocapnia, oxygenation and lung protection. Obstacles of physiological nature on the way towards the goals are briefly discussed, as are
strategies to overcome each of them. The challenge is to optimise all aspects of mechanical ventilation in order to reach all goals. For that
purpose a holistic approach must be taken in which comprehensive information about patient status is taken into account. Shortcomings of
available monitoring systems are underlined. On the basis of improved monitoring it should be possible to use computer simulation in order to
come closer to the goals of mechanical ventilation, than what is possible on the basis of presently practised clinical routines.
© 2006 Société de réanimation de langue française. Published by Elsevier SAS. All rights reserved.
Résumé
Une stratégie de ventilation « ajustée » selon les échanges gazeux et la mécanique respiratoire doit tenir compte d’objectifs physiologiques
adaptés à chaque malade. Ces objectifs reposent sur un contrôle optimal de la capnie et de l’oxygénation qui doivent êtres associés à la protection
pulmonaire. Les limites et les solutions physiologiques d’une telle stratégie sont discutées. Le « challenge » est de réussir à combiner ces
différents objectifs en ajustant individuellement les réglages du ventilateur. Pour se faire, une approche « holistique » fondée sur des informations
physiologiques fiables et relevantes peut être proposée. Les limites liées aux outils de mesures physiologiques disponibles sont exposées. Des
mesures physiologiques fiables permettent de simuler et donc de prédire les effets des différents réglages du ventilateur. Cette stratégie de
ventilation « ajustée » pourrait permettre de s’approcher d’avantage des objectifs physiologiques de ce qui est actuellement réalisé dans notre
pratique clinique.
© 2006 Société de réanimation de langue française. Published by Elsevier SAS. All rights reserved.
Keywords: Ventilator induced lung injury; Computer simulation; Acute respiratory distress syndrome
Mots clés : Lésions induites par la ventilation ; Syndrome de détresse respiratoire aiguë modélisation
Goal oriented ventilation stands for the approach that mode
and setting of a ventilator aims at clearly defined objectives
based upon the actual status of the individual patient. Objec-
E-mail address: [email protected] (B. Jonson).
tives may be immediate or ultimate. The immediate objectives
can be described in physiological terms. The secondary or ultimate objectives refer to outcome. In the acute respiratory distress syndrome (ARDS), survival with preserved organ function is the ultimate objective, the achievement of which
depends on adequate ventilation that does not cause ventilator
induced lung injury (VILI).
1624-0693 /$ - see front matter © 2006 Société de réanimation de langue française. Published by Elsevier SAS. All rights reserved.
doi:10.1016/j.reaurg.2005.12.004
B. Jonson / Réanimation 15 (2006) 14–20
Obviously, optimal ventilation is only one of several features of intensive care necessary to save the ARDS patient. In
1967 Ashbaug et al. [1] stated: ‘The use of positive end-expiratory pressure (PEEP) merely buys time: unless the underlying
process can be successfully treated or reversed the prognosis is
grave’ [1]. This statement is still valid but may be expanded to
other aspects of mechanical ventilation which may ‘buy time’.
An important new and complementary aspect is that VILI may
induce multiorgan failure leading to death [2]. This aspect links
the immediate and ultimate goals of ventilation.
Already in 1970, the group of Falke (Kumar et al. [3]) verified the usefulness of PEEP. The research groups referred to
above, showed an insight into the pathophysiology remarkable
for its time, quote from Ashbaug et al. [1]: ‘If surfactant is
diminished, alveoli should collapse on expiration when the
end-expiratory pressure is at atmospheric levels.’
The immediate goal of mechanical ventilation is: Adequate
gas exchange with respect to CO2 and O2 achieved with lung
protective ventilation (LPV). In the present review problems to
reach this and its partitions will be discussed in relation to the
compromised physiology in ARDS.
1. The goal of normocapnia
Apnoeic oxygenation by extracorporeal CO2 elimination illustrates that ventilation is not essential for blood oxygenation
and O2 exchange [4]. Ventilation is, however, a prerequisite for
CO2 exchange, if this is not achieved with extracorporeal CO2
elimination. Accordingly, ventilation serves the purpose to
control the arterial partial pressure of CO2, PaCO2. Factors determining PaCO2 are metabolic CO2 production, V′CO2, and
alveolar ventilation, V′A:
Pa CO2 ¼ V 0 CO2 =V 0 A × Pbarometric
Accordingly, in order to reach a target PaCO2, V′A, must
balance V′CO2.
What the target PaCO2 might be has been a matter of intensive debate during the last years. In order to minimize tidal
volumes, permissive hypercapnia has been tried. From physiological aspects, acidosis associated with hypercapnia has many
potentially dangerous consequences. It offsets efficient enzyme
functions, cell membrane functions, sympathetic and other receptor functions. These are just examples of basic physiological pH dependent functions, which may be disturbed at hypercapnia and lead to negative effects on physiology [5,6]. Not
surprisingly, some studies permitting hypercapnia do not show
improved outcome [7,8]. Notably, up to moderate variation in
PaCO2 is well tolerated by the organism. It is rather pH that
needs to be controlled by maintaining a target value of PaCO2.
A primary goal suggested is to achieve a PaCO2 that does not
lead to respiratory acidosis. A matter outside the scope of this
review is that metabolic acidosis should also be avoided. Hyperventilation to compensate for metabolic acidosis leads to
deleteriously high tidal volumes and other negative consequences. In conclusion, a primary goal of ventilation in ARDS
is to maintain normocapnia. The precise definition of normo-
15
capnia may still be debated. Most reasonable seems to have a
goal in the upper normal range around 6–7 kPa or 45–
50 mmHg.
Surprisingly, little emphasis has been laid on V’CO2. Since
more than 20 years V’CO2 could be monitored with simple
technique [9]. In ARDS, often high and sometimes extremely
high values of V’CO2 are observed. Reasons may be anxiety,
pain, fever, inflammation and nutritional imbalance leading to
a catabolic metabolism. For reasons difficult to accept monitoring of V’CO2 is rarely available. Therefore, in clinical practise,
the incitement to reduce metabolic requirements on ventilation
is missing. A goal of fundamental importance for goal oriented
ventilation is to reduce metabolism and thereby the demands
on alveolar ventilation. This goal merits an increased attention.
Alveolar ventilation must be adapted to the metabolic rate in
order to reach the target PaCO2 (Eq. (1)). A serious obstacle to
maintain normocapnia is in ARDS a high dead space fraction.
Beydon et al. [11] reported physiological dead space values up
to 65% and Nuckton et al. [10] up to 83%. A simple monitoring technique known for many years is the single breath test
for CO2, SBT-CO2, also denoted volumetric capnography,
Fig. 1 [12]. Again, the problem of high dead space is often
overlooked because of deficient monitoring systems.
The physiological background of the high dead space in
ARDS is complex. Microvascular pathology, notably thrombosis within small pulmonary arteries, is an important cause of
the problem [13]. To address the problem of microthrombosis
by any particular pattern of ventilation has not been suggested.
However, it is possible that microthrombosis is provoked or
aggravated by lung damaging ventilation. If lung protective
ventilation might decrease such pathology needs to be studied.
A further reason for high dead space is intrapulmonary
shunt that may reach above 50% of the cardiac output. Shunted
blood augments PaCO2 above alveolar PCO2, thereby contributing to dead space. Fig. 2 shows that shunt contributes to
alveolar dead space, particularly in the presence of other factors leading to low saturation of venous blood. Such factors are
Fig. 1. The complete single breath test for CO2 depicts partial pressure of CO2
against the tidal volume in expired and inspired gas (arrows) and PaCO2. The
volume of CO2 eliminated, VTCO2, corresponds to the crosshatched area.
Airway dead space, VDaw , is identified. Alveolar dead space, VDA, is reflected
by the difference between PaCO2 and the alveolar plateau (hatched area). Large
VDaw reflects that a humidifying filter was used.
16
B. Jonson / Réanimation 15 (2006) 14–20
Fig. 2. Alveolar dead space fraction, VDA, that results from intrapulmonary
shunt was calculated at different levels of intrapulmonary shunt fraction, Qs/Qt,
at normal haemoglobin (Hb) concentration and normal cardiac output, CO, at
low Hb and at combined low Hb and CO.
anaemia, low cardiac output and increased metabolism. To reduce alveolar dead space, shunt should be reduced, anaemia,
low cardiac output and increased metabolism should be
avoided. In a study of Beydon et al. [11] the benefit in terms
of lower alveolar dead space at increased PEEP was balanced
by enlarged airway dead space caused by airway distension. In
the small material only few patients showed important recruitment at increased PEEP. Further studies are merited.
In ARDS, the single breath test for CO2 usually shows a
highly sloping alveolar plateau, Fig. 1. This indicates the existence of lung regions with very different alveolar PCO2
which regions empty in a non-synchronous way. If such regions with highly varying ventilation/perfusion ratio can be
ventilated more efficiently remains to be studied.
To minimise dead space is anyway an important and realistic goal. The first way that is not always practised is to replace
humidifying filters with active humidifiers. A further mean to
reduce dead space is expiratory flushing of airways, later denoted tracheal gas injection (TGI) [14]. TGI has several drawbacks. For example, it interferes with regular ventilator function. When used in conjunction with increased respiratory
frequencies associated with a significant flow at the end of expiration, TGI can only dilute rather than eliminate CO2 in the
tracheal tube and y-piece. An alternative is then to aspirate
dead space from an extra channel close to the tip of the tracheal
tube and replace that gas by fresh gas through the ordinary
inspiratory ventilator line. This method, aspiration of dead
space (ASPIDS), has proven efficient in animals, healthy man
and in patients with ARDS [15,16]. ASPIDS is not commercially available. A simple way to reduce dead space is to deliver the tidal volume in a way that prolongs the mean time
available for inspired gas for distribution and diffusion in the
respiratory zone (MDT) [17]. Preliminary results indicate that
this is also practicable in ARDS (Fig. 3). A logarithmic relationship between tidal elimination of CO2 and MDT implies
that MDT may become critically low at high respiratory rates.
Then, a longer inspiration time and particularly a long postinspiratory pause is advantageous. It is time to reconsider routine
settings with expiratory time about 66% of the respiratory cycle.
Fig. 3. In an ARDS patient mean distribution time for inspired gas, MDT, was
changed by variation of postinspiratory pause time. The change in volume of
CO2 eliminated during a breath was measured in percent of the volume
eliminated at a normal pause time, ΔVTCO2. A logarithmic relationship
between ΔVTCO2 and MDT shows that at low values of distribution time CO2
elimination falls dramatically. (Aboab J., Brochard L., Jonson B. Unpublished).
2. The goal of oxygenation
Adequate oxygenation requires that intrapulmonary shunt is
reduced by keeping a sufficient part of the lung open for at
least a greater part of the respiratory cycle. PEEP is the traditional resort to reduce end-expiratory lung collapse. It is often
argued that PEEP is an inefficient means to recruit the lung in
ARDS and that specific recruitment manoeuvres should be
used. However, ventilation is a dynamic process in which one
must observe what happens during the full respiratory cycle
and over a prolonged period of time. In this perspective it has
been shown that a PEEP some cmH2O above the lower inflection point of the elastic pressure volume curve combined even
with low tidal volumes is an efficient way to achieve lung recruitment [18,19]. In an immediate perspective recruitment
manoeuvres may certainly be more effective in some patients,
but the effect above that of an adequate PEEP is usually short
lasting. Still, there appears to be a room for recruitment manoeuvres, particularly when much of the lung is collapsed in a
patient with a short history of ARDS. Overall, adequate oxygenation can usually be adequately achieved in ARDS at modest values of PEEP (i.e. <20 cmH2O) and by using a fraction of
inspired oxygen, FIO2, well below 100%.
3. The goal of lung protection
The classical form of VILI, barotrauma, was caused by the
very high airway pressures applied to compensate for low lung
compliance caused by collapse and morphological lung damage. In the past, barotrauma frequently led to air leakage to
the pleura, mediastinum and to subcutaneous emphysema. By
limiting airway pressure we have learnt to avoid most of these
problems. Currently it is recommended that postinspiratory plateau pressure, Pplat, should be limited to about 30 cm H2O. If
the abdominal pressure, and thereby pleural pressure, is high,
higher pressures may be needed and tolerated. Barotraumas is
now a rare problem, not further discussed.
Surfactant deficiency is the primary pathogenetic factor in
the infantile respiratory distress syndrome (IRDS) and a sec-
B. Jonson / Réanimation 15 (2006) 14–20
ondary factor in ARDS. In both these syndromes lung collapse,
intrapulmonary shunt, hypoxia and poorly compliant lungs are
at least in part caused by surfactant deficiency.
In 1970, Mead et al. stated: ‘At a transpulmonary pressure
of 30 cm H2O the pressure tending to expand an atelektatic
region surrounded by a fully expanded lung would be approximately 140 cm H2O’ [20]. This represents even today a fundament behind the concepts ventilator induced lung injury, VILI,
and its antonym lung protective ventilation (LPV). In 1982 I
drew the conclusion from available studies: ‘A respiratory pattern should open up closed units and maintain aeration and
stability throughout the respiratory cycle.’ [21]. Fig. 4 illustrates how shear forces may rip the epithelial cells from the
bronchiolar basal membrane. Leakage of plasma proteins from
the denuded surface leads to surfactant inactivation. A vicious
circle is accelerated in which collapse and re-expansion of lung
compartments lead to damage, accentuated surfactant inactivation and so on. In ARDS repetitive collapse and re-expansion
has been verified with computer tomography (CT) [22]. Notably, healthy lungs tolerate thousands of cycles of breath by
breath collapse and re-expansion [23], while the opposite is
true after even a slight surfactant perturbation [24]. A prerequisite for the vicious circle mentioned above is therefore an already damaged lung.
In a pioneering study Reynolds reasoned that ventilation
with pressure-controlled ventilation at inverse inspiratory/expiratory (I/E) ratio would increase PaO2 by keeping alveoli
open for a longer proportion of each breath [25]. His ideas
did not penetrate and it took more than a decade until my
group showed that they were valid and allowed protection of
the surfactant deficient lung against VILI [26]. In a very large
number of studies it has been shown that lung protection is
offered by different modes depressing tidal collapse and re-expansion. Examples are high frequency jet ventilation or high
frequency oscillation. Neither inverse I/E ratio nor high frequency modes of ventilation have been widely applied. Inverse
I/E ratio is difficult to control. When status improves and com-
Fig. 4. Drawing illustrating events in a zone undergoing re-expansion from a
collapsed state. Densely distributed alveolar septa, which are obliquely attached
to bronchiolar walls, cause large shear forces.
17
pliance increases the longer time constant for the lung to empty
may lead to sudden and deleteriously high auto-PEEP. High
frequency ventilation is hampered by the fact that one must
adopt concepts for controlling gas exchange, which differ fundamentally from traditional physiological concepts [27,28].
Nevertheless, high frequency ventilation remains an alternative
that merits further investigation, although additional risks motivate that the technique should be preferred only in the most
experienced centres [29,30]. For the foreseeable future mechanical ventilation will in most centres rely upon traditional
modes characterised by tidal ventilation at frequencies and
other characteristics allowing application or classical concepts
like minute ventilation, tidal volume, dead space etc. Such ventilation must then be delivered so that repeated lung collapse
and re-expansion is avoided as far as possible.
In a classical study by Mead et al. based upon recording of
pressure-volume (Pel/V) loops of collapsed lungs it was observed that re-expansion was irregular while different lung
units “popped open” [31]. The large hysteresis of the Pel/V
loop reflected that collapse reoccurred at much lower airway
pressures than re-expansion. The physics behind these observations makes it theoretically possible to ventilate the lung at an
initial pressure, i.e. PEEP, which is sufficient to keep an adequate part of the lung open, and stop the insufflation at a pressure that is low enough not to cause barotrauma. Lung partitions particularly difficult to recruit might then be left alone in
a collapsed state. If the tidal volume is low enough, its delivery
could then be achieved by expansion of open units with minimal if any recruitment of closed units. Setting of PEEP level,
tidal volume and other parameters which are optimal in the
individual patient remains a challenge.
Already in 1972, Falke et al. [32] realised that the point of
increasing compliance of the inspiratory Pel/V curve indicated
recruitment of closed lung units in ARDS. This point, later
denoted the lower inflexion point (LIP) has been suggested as
a guideline in the setting of PEEP in ARDS [33,34]. However,
recruitment is a continuous phenomenon affecting the whole
Pel/V curve. In a study based upon a multi-compartment lung
model with variable distribution of opening pressures it was
shown that the LIP reflects the onset of recruitment rather than
its fulfilment. Recruitment continues up to about the upper inflexion point of the Pel/V curve [35]. In a recent review the
limited information obtained in a single inspiratory Pel/V curve
recorded from zero airway pressure was underlined [36]. A
family of inspiratory Pel/V curves provide a much more comprehensive information of the distribution of opening and closing pressures of lung units [16,37,38]. This information also
including expiratory Pel/V curves can be obtained bedside and
automatically using a computer controlled ventilator [39]. In
theory, setting of PEEP and other parameters may be optimised
to minimise tidal collapse and re-expansion of lung units on the
basis of multiple pressure volume loops (Fig. 5). However,
there may be alternative ways to reach this goal and combine
it with the equally important goal, to achieve adequate gas exchange.
18
B. Jonson / Réanimation 15 (2006) 14–20
This high PEEP should offer optimal oxygenation at a properly
chosen FIO2. How should the ventilator be set to reach or to
come as close as possible to this combination of goals? Considering complex physiology with regards to mechanics and to
gas exchange together with the high degree of freedom in the
setting of a ventilator, nobody would be able to choose the
optimal minute ventilation or VT, respiratory rate, I/E ratio,
pause time, external PEEP and shape of inspiratory pressure
or flow wave form. However, the experienced physician with
a deep insight in physiological mechanisms and with an adequate system for monitoring in his hand can sometimes come
much closer to the combined goal of normoxia, normocapnia,
low tidal volume and low plateau pressure than what is accomplished in routine care. For routine care we need much better
tools than those available.
Fig. 5. Multiple elastic pressure volume loops recorded in an ARDS patient
illustrate that for each level of lower starting pressure of the loop (numbers)
volume is lost because of lung collapse, derecruitment. Gradual convergence of
the inspiratory curves illustrate successive re-expansion, recruitment, which is
not complete until pressure reaches about 40 cmH2O. Expiratory curves, all
recorded from 50 cmH2O, run in parallel. They show the maximum volume that
theoretically can be maintained at each level of airway pressure. (Aboab J.,
Brochard L., Jonson B. Unpublished).
4. How to reach all goals in the individual patient
The responsible physician must always apply a holistic perspective in order to tailor diagnostic measures and treatment to
the individual patient. The immediate goals of mechanical ventilation in the critically ill ARDS patient should be defined
with respect to the actual situation. There are no magic numbers like universally recommendable tidal volume, PEEP, plateau pressure or PaCO2. Patients with high abdominal pressure
might need and tolerate higher PEEP and plateau pressure than
other patients. PaCO2 should as far as we understand be lower
in a patient with in the risk for cerebral oedema while a patient
with well preserved vital organ function in general might well
tolerate a higher PaCO2. The definition of the immediate therapeutic goals in the individual patient is a highly demanding
task that appears often to be taken too lightly.
A goal that can hardly bee questioned is that tidal volume
should be low in severe ARDS, even if how low remains an
open matter. Take together the positive effects of high frequency ventilation with extremely low VT, an abundance of
experimental work showing improved function and preserved
lung morphology at very low VT ventilation and recent knowledge about the very wide pressure ranges over which lung collapse and re-expansion occurs. From this aspect, it is difficult
to comprehend that VT should not be as low as possible, while
simultaneously CO2 elimination and oxygenation should accord with the goals.
Let alone that several ways to reason may be as rational as
the following example. One scenario and an example may be
that in an individual patient a plateau pressure of 30 cmH2O is
considered safe, PaCO2 of 6 kPa or 45 mmHg is desired, as is a
tidal volume that is the lowest possible that fulfils these goals.
A fixed plateau pressure and a minimal tidal volume imply that
total PEEP will be the highest possible, given the other data.
5. Computer simulation, a tool for goal oriented action
Mechanical ventilation in patients with life threatening lung
disease can from some aspects be compared to radiation therapy in malignant disease. In both cases efficient treatment is a
prerequisite for life while it at the same time is a dangerous
procedure. In both cases treatment should be adapted to the
exact nature of the disease. Diagnostic procedures need to be
taken which provide as much details as possible so that treatment could be tailored to the exact circumstances at the time of
the curative procedure. It appears that in the case of mechanical
ventilation we have a long way to go before we approach a
stage at which radiotherapy is operating.
As concerns diagnostics, one can come very far on the basis
of signals available from modern ventilator systems, which are
instant values of flow, pressure and CO2, (Figs. 1,5). On the
basis of the single breath test for CO2, (Fig. 1), one can calculate the volume of CO2 eliminated as a function of tidal volume. One should also take into account the effect of MDT at
an alternative ventilator setting. From a family of Pel/V curves
(Fig. 5), one may evaluate the relationship between pressure
and re-expansion and collapse at increasing and decreasing airway pressure, respectively. Such information is still not generally available and cannot be taken into account in tailoring
therapy to the status of the patient.
Computer simulation is a universally used tool in engineering, physics and in many other fields when it comes to foresee
what a given action would have on a complex system, the
properties of which can be described in mathematical terms.
A second step is to simulate a large number of possible actions
in order to find out which action it would take to reach a certain effect on the complex system. Already Sir Isaac Newton
(1642–1727) defined mathematical strategies as to how to find
out which action it would take to reach a defined result by
using iterative analysis of action and reaction within complex
systems. It seems timely to explore such strategies in medicine
and particularly in intensive care and mechanical ventilation.
Computer simulation to predict the result of ventilator resetting with respect to mechanics and CO2 exchange was recently
tried in pigs by Uttman and Jonson [40]. In healthy pigs, the
B. Jonson / Réanimation 15 (2006) 14–20
hypothesis was tested that the effect of ventilator resetting
could be predicted by computer simulation based on a physiological profile. The physiological profile comprised compliance, constant inspiratory and volume dependent expiratory resistance. CO2 elimination per breath was expressed as a
function of tidal volume. During simulation pressures and flow
within the respiratory system was calculated moment by moment from data describing ventilator action. In the study respiratory rate was changed in five steps between 10 and
30 min–1. At each step minute ventilation was adjusted in an
effort to keep CO2 elimination constant. Computer simulation
allowed precise prediction of airway pressures after resetting.
At the rate of 30 min–1, errors up to 6% with respect to CO2
elimination were explained by the fact that the model did not
incorporate the feature that a shorter MDT at high rates lessens
CO2 elimination, (Fig. 3) [17]. Future models used in computer
simulation should incorporate this mechanism. In patients with
acute respiratory failure, the group of Beydon (Uttman et al.
[41]) showed that computer simulation may precisely predict
the effect on airway pressures following PEEP resetting. After
large increments of PEEP, CO2 elimination was lower than
predicted by simulation, probably because of hemodynamic effects. Obviously, much work remains to be done before computer simulation is used in clinical practise to guide the physician to achieve the specific goals strived for in the individual
patient. However, it is difficult to see alternatives, if one day
we will be able to finely tune mechanical ventilation to the
actual status and the immediate needs of the critically sick patient.
6. Conclusions
Ventilation is for CO2 exchange! Oxygenation depends
upon an open lung! To ventilate and keep the lung open while
ventilator induced lung injury is avoided is a major challenge
in ARDS treatment. It is unquestionable that tidal volume
should be low to avoid lung injury. The tidal volume remains
high in most intensive care units in patients ventilated for
ARDS [42]. This indicates the difficulties to make an impact
in clinical intensive care routines. Further progress can be foreseen when treatment is finely tuned to the status of the individual patient at all times. To approach this utopia improved
monitoring is required. Such monitoring is feasible on the basis
of simple techniques going out from the traditional signals representing flow, pressure and CO2. Optimal ventilator setting
should comprise the full spectrum of settings, like respiratory
rate, tidal volume or minute ventilation, PEEP, inspiratory and
pause time as well as shape of inspiratory flow or pressure
wave. An optimal setting tuning the ventilator to the therapeutic goals requires tools based upon computer simulation of alternative ventilator function.
Acknowledgements
Supported by the Swedish Research Council and the Swedish Heart Lung Foundation.
19
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