Physiological rationale of noninvasive mechanical ventilation use in acute respiratory failure

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CHAPTER 1
Physiological rationale of noninvasive
mechanical ventilation use in acute
respiratory failure
G. Prinianakis, M. Klimathianaki, D. Georgopoulos
Intensive Care Medicine Dept, University Hospital of Heraklion, University of Crete, Heraklion, Greece.
Correspondence: D. Georgopoulos, Dept of Intensive Care, University Hospital of Heraklion, University of
Crete, Heraklion, Crete 71110, Greece. Fax: 30 2810392636; E-mail: georgop@med.uch.gr
Introduction
The present article will begin with a general presentation of the effects of noninvasive
mechanical ventilation (NIMV) on the respiratory and cardiovascular systems. It is
important to note that these are the physiological effects of NIMV and that they are
applicable during both normal conditions and various disease states. Depending on the
pathophysiology of respiratory failure of any given disease state, the various
physiological effects of NIMV may have relatively greater or lesser importance or
may even be undesirable. Consequently, knowing the underlying pathophysiology is
fundamental for adapting NIMV mode and parameters to the specific disease state in
order to maximise benefits and minimise any adverse effects. A short review of major
pathophysiological patterns in relation to NIMV physiology is included.
Effect of NIMV on respiratory mechanics
Equation of motion
The simplified equation of motion:
Ptot(t) 5Pres(t) +Pel(t) (1)
describes the relationship between any driving pressure (Ptot(t)) applied to the
respiratory system (RS) at any time (t), and the opposing resistive (Pres(t)) and elastic
(Pel(t)) pressures of the RS (inertia is considered to be negligible).
Pres(t) is the pressure dissipated to overcome resistance to flow:
Pres(t) 5V9(t)?Rrs (2)
where V9(t) is instantaneous gas flow and Rrs is the resistance of the RS.
Pel(t) is the elastic recoil pressure exerted by the RS when volume increases above
passive functional residual capacity (FRC),
Pel(t) 5V(t)?Ers (3)
where V(t) is instantaneous volume relative to passive FRC, and Ers is the elastance of
the RS. Note that tidal volume (VT) is not always equal to volume above passive FRC.
When dynamic hyperinflation (DH) exists, at end-expiration the RS has not reached
passive FRC and the trapped volume exerts additional outward elastic recoil pressure,
which is called ‘‘intrinsic positive end-expiratory pressure’’ (PEEPi). When the next
Eur Respir Mon, 2008, 41, 3–23. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2008; European Respiratory Monograph;
ISSN 1025-448x.
3

inspiration starts, Ptot must first overcome the elastic threshold of PEEPibefore any
flow is produced and VTenters the RS. Thus, equation 3 may be rewritten as:
Pel(t) 5VT(t)?Ers +PEEPi(4)
where VT(t) is the instantaneous VT.
The equation of motion is always applicable to the RS at any phase of the respiratory
cycle (i.e. during inspiration or expiration) and regardless of the ventilation mode (i.e.
spontaneous breathing, invasive or noninvasive mechanical ventilation (MV), assisted or
controlled MV, pressure or volume targeted etc.).
During spontaneous breathing, the only Ptot applied to the RS is that generated by
the respiratory muscles Pmus(t), while during MV (invasive or non-invasive), the
inspiratory pressure provided by the ventilator Paw(t) is also incorporated into the
equation (fig. 1), which can then be expressed as follows:
Ptot(t) 5Pmus(t) +Paw(t) 5V9(t)?Rrs +VT(t)?Ers +PEEPi(5)
Effect of continuous positive airway pressure/PEEP
During continuous positive airway pressure (CPAP)/PEEP, a constant positive
pressure is applied to the RS throughout the respiratory cycle (i.e. during both
inspiration and expiration), while the patient breathes spontaneously. Since this pressure
is constant, it does not generate flow and it does not increase VT[1, 2] and it can not be
considered to be a form of noninvasive ventilation in a strict sense; yet, it exerts
important effects to respiratory system mechanics.
FRC increase. When CPAP/PEEP is applied, passive FRC is increased by a volume DV
that depends on the Ers and can be calculated from:
CPAP 5DV?Ers (6)
or
DV5CPAP / Ers (7)
In other words, CPAP supplies the Ptot to overcome the additional Pel imposed by the
additional volume (DV) above passive FRC. The effect of this increase might be
beneficial or detrimental, depending on the underlying pathophysiology.
Passive FRC
Pel=DV·Ers
DV
Pres = V´·Rrs
Paw (Pvent)
PmusI
Fig. 1. – Schematic representation of pressures acting on the respiratory system during assisted mechanical
ventilation. Pressure generated by inspiratory muscles (PmusI) and ventilator (Paw) drive inspiratory flow (V9) into the
lungs (open arrows), which is opposed by resistive (Pres) and elastic (Pel) pressures (closed arrows). Rrs: resistance of
respiratory system; FRC: functional residual capacity; DV: change in volume;Ers: elastance of the respiratory system.
G. PRINIANAKIS ET AL.
4

This increase in FRC might prevent or reverse atelectasis, and thus improve shunt and
ventilation/perfusion (V9/Q9) relationships and gas exchange. Alternatively, when
excessive, it might cause hyperinflation and increase of functional dead space volume
(VD), therefore worsening V9/Q9relationships. Excessive FRC increase will also pose a
mechanical disadvantage to the inspiratory muscles, because it shortens their length and
according to their length–strength relationship, their capacity to produce pressure will
be reduced. This is very important for the diaphragm, which becomes increasingly
flattened when FRC increases. The disadvantaged inspiratory muscles will also have to
work on a less steep portion of the RS pressure–volume curve (i.e. Ers increases). All
these physiological effects of CPAP should be appreciated when choosing the
appropriate CPAP/PEEP level for a given patient.
Decrease of elastic workload due to DH. When DH is present, the disadvantaged
inspiratory muscles have to overcome the additional elastic threshold of PEEPibefore
generating inspiratory flow [3]. This additional elastic workload may be significant.
When CPAP/PEEP is applied externally, it supplies all or part of the driving pressure
required to overcome PEEPi, and equation 5 can be expressed as:
Ptot(t) 5Pmus(t) 5V9(t)?Rrs +VT(t)?Ers +(PEEPi- CPAP) (8)
for spontaneous breathing with CPAP. It is obvious that pressure generated by
inspiratory muscles is not wasted to overcome PEEPi and thus is available for
generating inspiratory flow and pull air into the lungs. Thus, CPAP may indirectly
increase VTby unloading the inspiratory muscles.
For NIMV with assisted inspiration, equation (5) becomes:
Ptot(t) 5Pmus(t) +Paw(t) 5V9(t)?Rrs +VT(t)?Ers +(PEEPi- PEEP) (9)
Again PEEP applied externally unloads the inspiratory muscles in exactly the same
manner presented for CPAP [1]. Additionally, it permits faster and easier triggering of
the assisted inspiration, thus improving patient–ventilator synchrony.
This effect of CPAP/PEEP is of major importance in clinical situations where DH is
significant (i.e. disease states with obstructive pathophysiology pattern like chronic
obstructive pulmonary disease (COPD) or asthma).
Effect of positive inspiratory pressure
During NIMV with assisted inspiration, PEEP is combined with positive inspiratory
pressure. The delivery of positive inspiratory pressure is triggered by the patient’s
inspiratory effort, and usually titrated to produce either constant volume (assist volume
control; AVC) or constant pressure (pressure-support ventilation; PSV). In both modes,
equation 9 is applicable. It is evident, from equation 9, that Paw(t) delivered by the
ventilator is meant to act as an ‘‘additional inspiratory muscle’’; this is true for PSV but
not for AVC.
AVC. In this mode, inspiratory pressure delivered by the ventilator is titrated in order
to achieve a preset constant volume target. This ensures that the preset volume will be
delivered, despite any changes in the mechanical properties of the RS and in the
magnitude of the patient’s inspiratory effort. The minimum inspiratory effort required
by the patient is to trigger the ventilator. Alternatively, when the patient increases their
inspiratory effort, due to increased ventilatory needs, the inspiratory pressure delivered
by the ventilator will decrease in order to keep the constant volume target [4]. The
greater the patient’s inspiratory effort, the lesser the ventilator’s assistance. The
ventilator might even deliver negative inspiratory pressure (i.e. pull air back), when the
patient makes an adequately strong inspiratory effort, in order not to exceed the preset
RATIONALE OF NIV IN ARF
5

volume target (fig. 2e and f). Thus, in AVC the ventilator antagonizes, rather than
assists, the patient. Additionally, it has been shown that some home ventilators are
inaccurate in delivering the preset VT, especially when faced with deteriorating
mechanical properties of the RS [5]. For this reason, AVC has been disfavored for
use as NIMV in the acute setting [6] and, currently, is used merely for home NIMV for
patients with chronic respiratory failure due to neuromuscular disease [7, 8]. Therefore,
this mode of ventilation will not be focused on any further.
Pressure support. In this mode, inspiratory pressure delivered by the ventilator is
constant to the preset pressure level, regardless of the magnitude of the patient’s
inspiratory effort (fig. 2c and d). In this mode, the ventilator truly acts as an ‘‘additional
inspiratory muscle’’, increasing Ptot(t) and thus increasing VTand minute ventilation
(V9E) [2]. It also unloads the fatigued inspiratory muscles [2] by decreasing their
inspiratory work of breathing and oxygen consumption. For these reasons, it has gained
widespread acceptance as a mode of delivering NIMV in both the acute and chronic
setting [6–8]. However, caution is needed because, despite the perceived simplicity in its
settings, inspiratory and expiratory synchronisation with patient’s respiratory effort is
not always optimal (see section on patient–ventilator interaction). Patient–ventilator
dys-synchrony is very common with PSV, and its effects may diminish or even totally
cancel out the beneficial role of PSV [9].
With PSV, breath-by-breath delivered VTwill depend on not only the pressure-support
level, but also on the patient’s inspiratory effort and the mechanical properties of the RS
(i.e. Rrs,Ers, presence of DH). When the patient increases their inspiratory effort, they are
able to partially increase the delivered VT(within the limits of patient–ventilator
interaction) while the ventilator’s assistance remains constant [4]. Thus, in PSV, the
ventilator assists the patient with constant pressure support and certainly does not
antagonise; however, it does not follow up and does not adapt according to the patient’s
ventilatory needs (fig 2c and d). The only assist mode capable of adapting to the patient’s
breathing pattern and ventilatory needs is proportional assist ventilation (PAV).
Ventilators with mixed volume and pressure-targeted modes. In an effort to combine
the advantages of pressure- and volume-targeted modes into one ventilation mode, new
hybrid modes such as average volume-assured pressure support [10] and adaptive
servoventilation [11] have recently been introduced in the NIMV setting.
PAV
With PAV, inspiratory pressure delivered by the ventilator is instantaneously adapted
to keep up with the patient’s instantaneous inspiratory effort. When the patient
increases their inspiratory effort due to increased ventilatory needs, the ventilator
proportionally increases the delivered Paw [4]. When the patient terminates their
inspiratory effort, it is immediately sensed by the ventilator, which promptly terminates
the delivered Paw and thus patient–ventilator synchrony is optimised.
In contrast to the previously mentioned assist modes, a preset target level of volume,
pressure or flow does not exist. What is preset is only the proportionality between the
patient’s inspiratory effort and the ventilator’s assistance.
The principle underlying PAV is that any changes in instantaneous flow represent
changes in patient’s inspiratory effort. Again, equation 9 is applicable.
Flow and volume leaving the ventilator are continuously measured. When the patient
increases Pmus(t), alveolar pressure will decrease and this will cause additional
instantaneous flow (and volume) to leave the ventilator. This is sensed by the ventilator
G. PRINIANAKIS ET AL.
6

70
-20
60
50
40
30
20
10
0
-10
PET,CO2 mmHg
b)
30
20
10
0
-10
-15
-5
5
15
25
Paw cmH2O
f)
e)
d)
c)
a)
i)h)
Flow L·s-1
3
2
1
0
-1
-2
-3
3
2
1
0
-1
-2
-3
Volume L
l)
k)
j)
20
10
0
-10
-20
Poes cmH2O
o)
n)
m)
g)
40010 3020 40010 3020
40010 3020 40010 3020 40010 3020 40010 3020
-+ -+ -
+
Time s Time s Time s
Fig. 2. – Effect of increased inspiratory drive on respiratory motor and ventilatory output, and airway pressure
during different modes of noninvasive assisted mechanical ventilation. End-tidal carbon dioxide tension (PET,CO
2
),
airway pressure (Paw), flow (inspiration up), volume (inspiration up), and oesophageal (Poes) pressure in a
representative subject during a, d, g, j, m) proportional assist ventilation, b, e, h, k, n) pressure support and c, f, i, l, o)
assist-volume control without (-) and with (+)CO
2
challenge. Of note is the different response in Paw after CO
2
challenge between the different modes of support. 1 mmHg 50.133 kPa. Reproduced from [4].
RATIONALE OF NIV IN ARF
7

which responds by instantaneously increasing Paw(t) proportionally to the sensed increase
in instantaneous flow (and volume). Further details on PAV design and application [12]
are beyond the scope of this article. What is important for NIMV physiology is the
improved patient–ventilator synchrony and the breath-by-breath adaptability of the
delivered assist according to the patient’s ventilatory needs (fig 2a and b).
Cardiovascular effects of NIMV
The cardiovascular effects of (both invasive and noninvasive) MV are complex and
mediated through different mechanisms, often interdependent or counteracting (fig. 3) [14].
The most important cardiovascular effects of NIMV are: decreased venous return
(VR); decreased left ventricle (LV) afterload; decreased work of breathing (WOB) and
oxygen consumption; and effect on pulmonary vascular resistance (RVafterload).
Any change in pleural pressure during the respiratory cycle will be transmitted to the
heart; therefore, the pressure gradients for both systemic VR (preload to RVand LV)
and systemic arterial outflow (LV afterload) will also change [15].
Spontaneous inspiratory efforts decrease pleural pressure, which can become
extremely negative during acute or chronic respiratory failure, when respiratory system
mechanics and when lung gas exchange properties are altered [16–18]. When positive
inspiratory pressure is applied and the respiratory muscles are unloaded, these negative
pleural pressure swings during inspiration will be decreased or even abolished.
Furthermore, PEEP/CPAP increases pleural pressure during expiration [18, 19].
Positive pressure during acute cardiogenic pulmonary oedema
Improved
arterial
oxygenation
Work of
respiratory
muscles
Positive
intrathoracic
pressure
Gradient of
systemic venous
return
Gradient between the
left ventricle and the
extrathoracic arteries
Abolition of negative
swings in intrathoracic
pressure
Left-ventricular
afterload
Right ventricular
preload
Intrathoracic blood volume
Cardiac improvement
Fig. 3. – Schematic physiological effects of positive-pressure ventilation in a case of acute cardiogenic pulmonary
oedema. Reproduced from [13] with permission from the publisher.
G. PRINIANAKIS ET AL.
8

Decreased VR (RVand LV preload)
Any NIMV-induced increase in pleural pressure will increase right atrial pressure and
consequently decrease the pressure gradient for systemic VR, which will decrease. This
will lead to a decrease of both RVand LV preload. The consequences will depend on the
underlying cardiovascular status [20]. If the patient is relatively hypovolaemic, or has
pre-existing RVfailure, then NIMV may severely impede VR, leading to a decreased
Cardiac output (CO), decreased mixed venous oxygen saturatution (SV,O
2
) and
paradoxical worsening of arterial oxygen saturation (Sa,O
2
), or even cardiovascular
collapse [21]. Conversely, in hypervolaemic congestive heart failure, this NIMV-induced
decrease in VR is much less, yet beneficial [22, 23].
Decreased LV afterload
The exaggerated negative pleural pressure swings during laboured spontaneous
breathing increase LV afterload, while NIMV-induced increase in pleural pressure will
decrease it. For the normal heart, cardiac function is mostly preload rather than
afterload dependent [19], so the effects of pleural pressure on LV afterload have limited
clinical significance. Conversely, when LV is dilated, with impaired contractility, cardiac
function heavily depends on afterload. For such patients the beneficial effects of NIMV
on LV afterload reduction are of major clinical importance [19, 20, 22, 23] .
Decreased WOB and oxygen consumption by respiratory muscles
During lung disease states the respiratory WOB and consequently oxygen
consumption by respiratory muscles is severely increased. This causes a shift of blood
flow to the respiratory muscles, so that for the same CO blood flow and oxygen delivery
to other organs will be decreased, leading to peripheral tissue hypoperfusion, lactic
acidosis and decreased SV,O
2
(due to a greater oxygen extraction ratio by the hypoxic
tissues). As a consequence, Sa,O
2
will also decrease, even without any other change in
lung gas exchange properties. These effects are greater in patients with a limited
cardiovascular reserve, who are unable to increase CO in response to the increased
demand. Even NIMV may unload the respiratory muscles and decrease their oxygen
consumption [18], thus increasing oxygen delivery to other organs, increasing SV,O
2
and
Sa,O
2
and decreasing lactic acidosis [14].
Effect on pulmonary vascular resistance (RVafterload)
Pulmonary capillaries are situated within the alveolar septa, therefore they are subject
to compression by adjacent alveolar pressure. They are also subject to hypoxic
pulmonary vasoconstriction (HPV) when adjacent alveolar oxygen partial pressure
PA,O
2
falls below 7.98 kPa (60 mmHg). NIMV (mainly CPAP/PEEP application) may
reverse HPV by inducing recruitment of atelectatic regions, thus reducing PVR.
Adversely, when NIMV induces hyperinflation (excess PEEP) rather than recruitment,
pulmonary capillaries are compressed and PVR is increased. This increase in RV
afterload, if severe, may precipitate acute RVfailure, again also depending on the
previous cardiovascular status of the patient.
For interpreting and anticipating the cardiovascular effects of NIMV, apart from
knowledge of the aforementioned mechanisms, the physician should also be aware of
three important points as follows. First, the importance of underlying cardiovascular
RATIONALE OF NIV IN ARF
9

status (including intravascular volume, ventricular pump function and myocardial
reserve), as it was presented above. Furthermore, the cardiovascular response to NIMV-
induced increase in pleural pressure may be used as a clue to the underlying
haemodynamic status of the patient. Secondly, Paw is variably transmitted to the
pleural space; positive airway pressures (inspiratory pressure and CPAP/PEEP)
delivered by the ventilator are variably transmitted to the pleural space (Ppleural)
depending on the RS mechanical properties, particularly on the compliance of the lungs
(CL) versus the compliance of the chest wall (CCW). When CL is low, pressure is mostly
dissipated to inflate the stiff lungs (high transpulmonary pressure required). Conversely,
when CL is high, little pressure is dissipated to inflate the compliant lungs (low
transpulmonary pressure required) and, thus, pressure is mostly transmitted to the
pleural place. This effect is exaggerated when CCW is low, which means that a high
Ppleural is dissipated to inflate the stiff chest wall (high distending pressure required
across the chest wall). Therefore, pressure transmitted to the pleural space and thus
affecting cardiovascular structures depends on not only the magnitude of Paw/PEEP
delivered by the ventilator but also the RS mechanical properties. Finally, Withdrawal
of MV is accompanied by the opposite cardiovascular effects. Withdrawal of NIMV in
patients with limited cardiovascular status may precipitate myocardial ischaemia and
heart failure, which might manifest as overt acute cardiogenic pulmonary oedema
(ACPO) or as otherwise unexplained weaning failure.
Patient–ventilator interaction during NIMV
During assisted modes of mechanical ventilation, including noninvasive ventilation,
the synchrony between patient and ventilator is fundamental for successful patient
outcome. Synchrony is defined as the condition when the ventilator fully meets the
patient’s ventilation demands. In other words, the patient’s neural timing and flow
demand coincide with ventilator timing and flow supply, a condition which rarely occurs
in daily clinical practice. During NIMV, dys-synchrony is even worse because of the
presence of air leaks and the alert status of the patients. These factors make the problem
of patient–ventilator synchrony during NIMV more complex than that described for
invasive mechanical ventilation.
The dys-synchrony between patient and ventilator depends on factors related both to
the ventilator and the patient [24, 25]. The ventilator-related factors include the
triggering variable, the variable that controls gas delivery, and the cycling off criterion.
Patient-related factors include the respiratory system mechanics and the Pmus
characteristics.
The trigger variable
Commonly used trigger variables during NIMV are flow or pressure trigger. With
these variables, the patient effort must generate a preset decrease in airway pressure or in
ventilator bias flow in order to trigger the assisted breath. NAVA et al. [26] found that in
both normal and COPD patients, flow triggering is better than pressure triggering in
terms of patient inspiratory effort and triggering delay.
Under certain conditions, however, the inspiratory muscle contraction does not
trigger the ventilator, a dys-synchrony phenomenon called ‘‘missing’’ or ‘‘ineffective’’
effort occurs [27, 28]. Ineffective efforts are common in patients who exhibit DH, due to
excessive level of mechanical support and altered mechanical properties. Indeed,
excessive support results in high VT, which, in combination with a long time constant,
G. PRINIANAKIS ET AL.
10

may force the mechanical inspiration to invade into the patient’s neural expiration.
Consequently, the following inspiratory effort is likely to begin at end expiratory lung
volume above passive FRC, which may lead to ineffective effort.
Recently, a new microprocessor-controlled positive pressure ventilatory assist system
has been introduced (BiPAP Vision; Respironics, Pittsburg, PA, USA), which has new
algorithms to trigger the ventilator. These are designed to improve patient–ventilator
interaction, with the flow waveform mainly used to trigger the ventilator. This method
of triggering is referred to as the ‘‘shape signal method’’. It is based on the generation of
a new flow signal (flow-shape signal) by offsetting the signal from the actual flow by
0.25 L?s
-1
and delaying it for 300 ms. This intentional delay causes the flow shape signal
to be slightly behind the patient’s actual flow rate. As a result, a sudden decrease in
expiratory flow, due to an inspiratory effort will cross the shape signal and this creates a
signal for ventilator triggering (fig. 4). This triggering method was found to be more
sensitive to patient effort than the flow triggering, with less ineffective patient efforts
[29]. Similarly, the flow-shape signal can be used to terminate the mechanical breath.
A new ventilation mode called neurally adjusted ventilatory assist (NAVA) has recently
been developed, in which the ventilator supports the patient effort according to the
diaphragm electrical activity [30]. With this mode, synchrony between neural and
mechanical timing should be guaranteed at any phase of respiration despite PEEPior
altered respiratory mechanics. Indeed, animal studies have shown that NAVA can be
effective in delivering noninvasive ventilation, even when the interface is excessively leaky,
and can unload the respiratory muscles while maintaining synchrony with the subject’s
demand [30]. Improved patient–ventilator interactions have been shown in humans,
during helmet NIMV using NAVA versus conventional triggering methods [31].
Interfaces choice is also important to improve patient–ventilator synchrony.
NAVALESI et al. [32] have demonstrated, in COPD patients, that the helmet significantly
worsens patient–ventilator synchrony when compared with the facemask; indicated by
longer delays between inspiratory muscle effort and support delivery, both at the onset
and at the end of inspiration, and by the occurrence of wasted efforts.
NIMV use may improve the respiratory system mechanics and decrease DH. DIAZ
et al. [33] showed that when NIMV is applied to severe stable hypercapnic COPD
patients, it significantly decreases pulmonary hyperinflation and inspiratory loads, due
to the adoption of a slow deep-breathing pattern by the patients.
In everyday clinical practice, a more-sensitive trigger threshold is set, in order to
reduce the number of ineffective efforts; however, this strategy in not always
advantageous. By setting a more sensitive threshold in the presence of air leaks, water
in the ventilator circuit or large heart stroke volume may lead to a mechanical breath
that is not patient triggered. This dys-synchrony phenomenon is called autotriggering
[25]. Therefore, when ventilator trigger level is set, the lowest possible threshold, that
does not result in autotriggering, should be chosen.
The variable that controls gas delivery
During NIMV, either AVC or PSV can be used as ventilation mode. Generally, it is
accepted that patients with poor respiratory drive are the appropriate candidates to
receive AVC. GIRAULT et al. [34] studied the physiological effects of the two modes, in
patients suffering from acute respiratory failure. Briefly, they found that both modes of
gas delivery are efficient in improving breathing pattern and gas exchange. These
physiological effects though are achieved with a lower inspiratory workload but at the
expense of a higher respiratory discomfort with AVC compared with PSV mode [34].
RATIONALE OF NIV IN ARF
11

Usually, assist level is set according to clinical and/or physiological variables.
VITACCA et al. [35] demonstrated that when using clinical variables to set pressure
support, almost half of their home ventilated patients showed ineffective efforts. Even
by using more invasive techniques, such as gastric and oesophageal balloons, they did
not totally avoid patient–ventilator dys-synchrony [35].
PAV is a ventilatory mode in which the ventilator follows the patient’s neural output
(see preceding section on PAV), so, in theory, it achieves perfect patient–ventilator
interaction. Generally, using PAV noninvasively may improve gas exchange and
dyspnoea [36, 37], but no difference was found in terms of patient–ventilator synchrony
when compared with PSV in stable COPD patients [38]. Furthermore, these studies have
demonstrated no differences in clinical endpoints, such as mortality, number of
endotracheal intubations and length of hospital stay [36, 37].
PAV is underused in everyday clinical practice because setting the ventilator
parameters is complex. In fact, the ventilator settings must be adjusted every time the
patient’s mechanical proprieties change. ‘‘PAV+’’, a new sophisticated option of PAV,
¶
#
#
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
Flow L·s-1
3.02.52.01.51.00.50.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
Flow L·s-1
#
¶
#
a)
b)
Time s
Fig. 4. – Flow–time waveform in two patients ventilated with a Vision ventilator on pressure support mode.
Inspiration is down and expiration is up. The flow shape signal, generated by offsetting (0.25 L?s
–1
; ) and delaying
(300 ms) the actual flow during inspiration and expiration (
#
) and the electronic signal rising in proportion to actual
inspiratory flow in each breath (
"
) are shown. a) Mechanical breath was triggered and terminated by the shape
method. During expiration the actual flow decreased abruptly (due to the onset of inspiratory effort), crossed the flow
shape signal and triggered the ventilator. Reproduced from [29] with permission from the publisher.
G. PRINIANAKIS ET AL.
12

which semicontinuously estimates patient’s mechanical properties noninvasively, may
simplify PAV application in clinical practice [39].
Recently, the effects of varying pressurisation rate, the incremental increase in Paw per
time unit, have been assessed in 15 COPD patients on NIMV. No significant differences
were found in breathing pattern and gas exchange between four different pressurisation
rates. The fastest rate seemed to reduce the pressure–time product, an estimate of
oxygen consumption of diaphragm; however, this resulted in increased air leaking and
worse patient tolerance, as measured with a visual scale. Patient–ventilator synchrony
was assessed by calculating the ratio between the neural and mechanical inspiratory
time. With the fastest pressurisation rate, this ratio was shorter, indicating that the
mechanical inspiration invaded into the patient neural expiration. Two factors seemed
to determine NIMV tolerance: the presence of high air leaks and the dys-synchrony
between neural and mechanical inspiratory time [40].
During noninvasive ventilation, setting pressure-support level is difficult because of
the presence of mask air leaks. SCHETTINO et al. [41] have shown that the leaks increase
in proportion to the pressure delivered into the mask. Although modern ventilators
compensate for mask leaking, still any pressure support increase may lead to decreased
VTbecause of leaks [41].
The cycling-off criterion
Ventilators permit transition from inspiration to expiration according to a
predetermined cycling-off criterion. The most commonly used criterion is the decrease
of inspiratory flow to a predetermined percentage of peak inspiratory flow.
During noninvasive ventilation, the presence of leaks may lead to a prolonged
mechanical inspiration because inspiratory flow does not reach the cycling-off criterion.
Consequently, the machine’s inspiration invades into the patient’s expiratory phase, a
phenomenon known as delayed cycling-off. CALDERINI et al. [42] have compared time
cycling with flow cycling and they found that using time-cycling criterion essentially
reduced the inspiratory effort and WOB, and improved expiratory synchronisation (fig. 5).
Every effort should be made to minimise mask air leaks. However, excessive tightness
of the mask may lead to patient discomfort and NIMV intolerance. It should be noted
that high pressurisation rate increases air leakage despite sufficient mask fitting, which
may provoke delayed cycling off (fig. 6) [40].
COPD: physiological role of NIMV
The cardinal feature of COPD pathophysiology is DH. DH is the result of expiratory
flow limitation (EFL), due to the increased Rrs and compliance of the respiratory system
(Crs) which prolong the time constant (t5Rrs 6Crs) for lung emptying and increase
the end-expiratory lung volume above passive FRC. DH poses important mechanical
disadvantages for the inspiratory muscles, which have to overcome additional elastic
load (PEEPi) to initiate inspiratory flow (or trigger the ventilator during MV [43] and
must also operate on the flat part of the Crs curve (fig. 7). Conversely, the pressure
generating capacity of the shortened inspiratory muscles is additionally limited by DH
(fig. 8). These pathophysiological mechanisms apply to stable COPD, but are further
exaggerated during exacerbations [44].
NIMV is capable of partly reversing this pathophysiology and thus unloading the
respiratory muscles (fig. 8). PEEP/CPAP decreases the elastic workload due to DH,
because it supplies all or part of the Ptot required to overcome PEEPiand initiate
RATIONALE OF NIV IN ARF
13

inspiratory flow (or trigger the ventilator). The addition of positive inspiratory pressure
further unloads the inspiratory muscles and increases VT,V9Eand improves gas
exchange [1, 46]. NIMV has been used with favorable physiological and clinical
outcomes for both stable COPD (PSV and AVC) [1] and for exacerbations (mostly PSV
[46] and recently PAV), as well as to facilitate weaning from invasive MV.
In a principal study of NIMV during COPD exacerbation, APPENDINI et al. [46]
showed that PEEP/CPAP set between 80% and 90% of dynamic PEEPi decreased the
diaphragmatic pressure-time product (PTPdi), and additional PSV further decreased
PTPdi, increased VTand V9Eand improved gas exchange.
During stable COPD, long term NIMV has been shown to decrease inspiratory
muscle workload due to dynamic PEEPi[35]. The beneficial effects of long-term NIMV
seem to persist also during the period of daytime spontaneous breathing. WINDISCH et
al. [47] showed that controlled nocturnal NIMV therapy is capable of increasing VTand
V9Eduring the three subsequent hours of daytime spontaneous breathing and of
sustaining increased diurnal VTand V9E. It has also been shown that PSV induces a
decrease of daytime lung hyperinflation, as quantified by the decreased total lung
0
-0.5
0.5
1.0
1.5
2.0
Flow L·s-1
a)
20
15
20
25
10
5
0
-5
Flow cyclingTime cycling
Time s
b)
c)
Poes cmH2OPaw cmH2O
Fig. 5. – A representative experimental record of a) flow, b) oesophageal pressure (Poes) and c) airway pressure (Paw)ina
patient treated with noninvasive mechanical ventilationusing time and conventional flow percentage as cycling-off criteria.
The perfectsynchronisation between patient and machine during time cycling offcriterion. With flow cycling off criterion,
the prolonged mechanical assist into the neural expiratory time results into wasted next inspiratory effort, as evident by the
following negative deflections on the Poes curve. Reproduced from [42] with permission from the publisher.
G. PRINIANAKIS ET AL.
14

200
30
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
VT,exp:VT,insp
80 120
Pressurisation rate cmH2O·s-1
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
Fig. 6. – Amount of air leaks through the mask, as assessed by the ratio between expiratory (VT,exp) and inspiratory
tidal volume (VT,insp) in the different values of pressurisation rate for each patient. The amount of leak was bigger at
highest (200 cmH
2
O?s
-1
) pressurisation rate. Reproduced from [40] with permission from the publisher.
EELV
Volume
EELV
TLC
IRV
VT
IC
DP
RV
Pressure
a) b)
ITL
EELV
PEEPi
Pressure
TLC
Volume
IC
IRV
VT
DP
EELV
RV
Fig. 7. – Schematic representation of mechanical effects of chronic obstructive pulmonary disease (COPD)
exacerbation. Representative pressure–volume plots during a) stable COPD and b) COPD exacerbation. During
exacerbation, worsening expiratory flow limitation results in dynamic hyperinflation with increased end-expiratory
lung volume (EELV) and residual volume (RV). Corresponding reductions occur in inspiratory capacity (IC) and
inspiratory reserve volume (IRV). Total lung capacity (TLC) is unchanged. As a result, tidal breathing becomes
shifted rightward on the pressure–volume curve, closer to TLC. Mechanically, increased pressures must be generated
to maintain tidal volume (VT). At EELV during exacerbation, intrapulmonary pressures do not return to zero,
representing the development of intrinsic positive end-expiratory pressure (PEEPi), which imposes increased
inspiratory threshold loading (ITL) on the inspiratory muscles; during the subsequent respiratory cycle, PEEPimust
first be overcome in order to generate inspiratory flow. From [44] with permission.
RATIONALE OF NIV IN ARF
15

capacity (y10%), FRC (y25%) and residual volume (y35%), and the increased VT
(y180 mL) [33]. Mouth occlusion pressure (P0.1), a measure of inspiratory drive, also
decreases, while 6 min walking distance increases [48]. NIMV (PSV plus PEEP) has also
been reported to exert positive cardiovascular effects in stable COPD patients, including
improved heart rate variability, decreased circulating natriuretic peptide levels and
enhanced functional performance [49]. There is no consensus regarding the titration to
optimal level of PSV [35, 50, 51] . Noninvasive PAV has also been studied for stable
COPD, and was comparable to PSV in increasing VTand V9E, and in unloading
inspiratory muscles [38].
Recently, a method to noninvasively detect expiratory flow limitation by the
difference between mean inspiratory and expiratory reactance, measured with a forced-
oscillation technique has been proposed for titration of CPAP/PEEP level in stable
COPD patients, so that increase of operating lung volumes, by PEEP/CPAP, above the
levels imposed by EFL and concomitant disadvantageous effects may be avoided [52].
Congestive heart failure: physiological role of NIMV
NIMV in the setting of congestive heart function (CHF) has three major goals: to
improve cardiac function; to unload the respiratory muscles; and to improve gas
exchange. It is mainly used for management of ACPO, but it has also been studied in
chronic stable CHF.
ACPO
ACPO represents a vicious cycle of progressive LV (systolic and/or diastolic) failure,
which results in a progressive decrease in systemic CO as well as increase in extravascular
Air trapping
IPPV
Diaphragm
flattening
Muscle
weakness
CPAP/
PEEP
Respiratory
muscle
failure
Raw
Elastic
recoil
PEEPi
Work of
breathing
VT
Dyspnoea
Pa,CO2
Bronchospasm
Airway mucus
Airway inflammation
Fig. 8. – Schematic physiological effects of noninvasive mechanical ventilation in chronic obstructive pulmonary
disease. Continuos positive airway pressure (CPAP)/ positive end-expiratory pressure (PEEP) decreases the elastic
work of breathing because it supplies all or part of the driving pressure required to overcome intrinsic PEEP (PEEPi)
and initiate inspiratory flow. The addition of inspiratory positive pressure ventilation (IPPV) further unloads the
inspiratory muscles and increases tidal volume (VT) and decreases arterial carbon dioxide tension (Pa,CO
2
).
Raw: airway resistance. Published from [45] with permission from the publisher.
G. PRINIANAKIS ET AL.
16

lung water in lung interstitium and alveoli. The interstitial oedema, apart from worsening
gas exchange, may also cause lung resistance and elastance to increase; therefore,
inspiratory muscles must generate greater pressure swings to sustain the increased
ventilatory demands (fig. 9) [18, 19]. Oxygen consumption by respiratory muscles is
increased but cannot be satisfied by the already limited CO, thus metabolic acidosis, as
well as progressive muscle fatigue, may occur. Of even greater clinical importance are the
effects of the increased negative intra-thoracic pressure swings on the failing heart; VR
and thus RV (and LV) preload increases, while LV afterload also increases [19].
Additionally, the overloaded RV may become dilated and, through ventricular
interdependence (i.e. interventricular septum shift), may further impose LV diastolic
dysfunction. These pathophysiological mechanisms not only increase myocardial oxygen
demand but also compromise oxygen delivery and, thus, may further precipitate
myocardial ischaemia and worsen heart failure.
NIMV has mostly been studied in LV systolic failure (i.e. with a decreased ejection
fraction (EF)), and has consistently been shown to break this vicious cycle (fig. 3).
CPAP/PEEP application increases expiratory pleural pressure [18, 19], and consequently
decreases VR, RV and LV preload, RV dilatation, and improves LV diastolic function
[53]. It additionally decreases LV afterload by decreasing LV transmural pressure during
systole [18, 19] and, thus, also improves LV systolic function, decreases LV stroke work
and decreases myocardial oxygen consumption [54]. It has also been shown to unload
the inspiratory muscles [18, 19]. End-expiratory lung volume increases [55], thus
improving lung gas-exchange properties and respiratory mechanics [18, 56–58].
The addition of positive inspiratory pressure (mainly studied is PSV), and recently
PAV may further unload the inspiratory muscles [59, 60], decrease or even totally
-20
+20
0
-20
+20
0
Poes cmH2O
ECG
0 5 10 15 20 0 5 10 15 20
Poes cmH2O
ECG
Time s Time s
a) b)
c) d)
Fig. 9. – Oesophageal pressure (Poes) and electrocardiogram recordings from a healthy subject (a and b) and a patient
with congestive heart failure (CHF; c and d) at baseline (a and c) and on 10 cmH
2
O of continuous positive airway
pressure (CPAP; b and d). Note that in the healthy subject, CPAP caused both end-expiratory Poes and peak inspiratory
Poes to become more positive but caused no change in the amplitude of the inspiratory Poes swing. Respiratory rate also
decreased. In the patient with CHF, the Poes amplitude at baseline was greater than in the healthy subject. On CPAP,
end-expiratory Poes becomes more positive and Poes amplitude is reduced, such that peak inspiratory Poes becomes more
positive. Respiratory rate did not change. Reproduced from [19], with permission from the publisher.
RATIONALE OF NIV IN ARF
17

abolish the detrimental negative inthrathoracic pressure swings, and may also decrease
inspiratory muscle work of breathing and oxygen consumption.
It is important to note that these direct effects of NIMV take advantage of the heart–
lung interactions and occur above and beyond any change in gas exchange. Gas
exchange is also greatly improved, both by the improved gas exchange properties of the
lung and by the indirect effect of increased cardiac output and decreased oxygen
consumption by the inspiratory muscles [18].
NIMV has also been studied in LV diastolic failure (i.e. with a preserved EF .45%),
and is also associated with clinical improvement [61], although debate exists about its
exact pathophysiological effects in this setting [62]. The NIMV-induced decrease in
cardiac preload and LV end-diastolic volume (LVEDV) may be detrimental and actually
decrease stroke volume in patients with impaired diastolic filling, which displays a steep
curve for LV diastolic pressure in relation to volume. Indeed, BENDJELID et al. [61] showed
that, in a small group of patients presenting with ACPO with preserved systolic function,
CPAP decreased LVEDV, albeit to a lesser degree compared with patients with systolic
dysfunction, and does not increase LV EF. Yet, CPAP was associated with consistent
clinical improvement even in the diastolic dysfunction group [61]. A possible explanation
of these findings might be that patients with diastolic dysfunction who present with
ACPO, in contrast to stable diastolic HF, might already be excessively volume
overloaded, so that any decrease in preload and LVEDV has beneficial rather than
detrimental effects, setting LV in a more favorable position on its compliance curve. In
addition, noncardiac-function beneficial effects of NIMV (i.e. decreased work and oxygen
cost of breathing, improved gas exchange and lung mechanical properties) may contribute
to the clinical benefit. Nevertheless, treating physicians should be aware of a possible
detrimental effect of NIMV-induced preload decrease in patients with LV diastolic failure,
depending on their underlying RV and LV function and hydration status.
Chronic CHF
NIMV in chronic CHF exerts similar effects to those presented above for ACPO,
since pathophysiology is similar, and many of the studies presented previously were
performed on stable rather than acutely decompensated CHF patients [19, 53, 54].
Additionally, it has been shown that CPAP may increase the low heart rate variability
these patients exhibit and is recognised as a poor prognostic factor [55].
Nocturnal long-term NIMV (mainly CPAP but also adaptive servoventilation) has
been used for the management of central sleep apnoea and Cheyne–Stokes respiration
(CSA-CSR), which is a cardinal feature of chronic CHF [11, 63–66]. CPAP improves
cardiac function, as evidenced by the increased LV ejection, decreased mitral
regurgitation and decreased plasma atrial natriuretic and norepinephrine levels [58,
63, 64]. Similar effects have been shown when pressure support is added (BiPAP) [65].
Exercise capacity also improved [57, 63]. Although, the clinical significance of long-term
NIMV in CHF with CSA-CSR is doubtful, especially in the face of potent
pharmacological treatments like b-blockers that have been introduced in the manage-
ment of stable CHF [63, 66].
It should be noted that CPAP has been successfully used in the management of
obstructive sleep apnoea (OSA) which is a major comorbidity in many patients with
CHF [66, 67]. Although beyond of the scope of this discussion about the physiological
basis of NIMV in CHF, again the beneficial effect of CPAP on cardiac function is
mainly mediated by keeping the obstructed upper airway open and thus abolishing the
detrimental large negative inspiratory intrathoracic pressure swings [68].
G. PRINIANAKIS ET AL.
18

NIMV during weaning
Reverse pathophysiological mechanisms are expected to occur during abrupt
withdrawal of NIMV and shift from positive to negative intrathoracic pressures,
culminating in: a) increased VR and cardiac preload; b) increased LV afterload; c)
decreased LV diastolic compliance due to myocardial ischaemia and/or biventricular
interdependence; and d) increased WOB and increased myocardial oxygen consumption
[67]. These mechanisms may precipitate ACPO and myocardial ischaemia. Although
these effects have mainly been studied during withdrawal from invasive MV [69], they
are also applicable in the NIMV setting and treating physicians should be aware of and
expect possible worsening of cardiac function during weaning from NIMV.
NIMV has been proposed as a tool for weaning from invasive MV, in patients who
failed a spontaneous breathing trial. VITACCA et al. [70] showed that in patients affected
by chronic respiratory disorders who failed to sustain spontaneous breathing,
postextubation PSV delivered non-invasively was equally effective in reducing work
of breathing and dyspnoea level, and in improving arterial blood gases compared with
pre-extubation, invasively delivered PSV.
Conclusion
Thorough understanding of the physiological effects of noninvasive mechanical
ventilation on respiratory system mechanics and heart–lung interactions, as well as the
principles of patient–ventilator interaction are fundamental for rational noninvasive
mechanical ventilation application in the clinical setting. Noninvasive mechanical
ventilation effects should be interpreted in the context of the pathophysiology of the
underlying disease and the cardiovascular status of the patient. Pathophysiological
rationale for the two most common acute noninvasive mechanical ventilation
applications, in chronic obstructive pulmonary disease exacerbations and acute
cardiogenic pulmonary oedema, were presented as an example.
Summary
Noninvasive mechanical ventilation (NIMV) exerts multiple effects on respiratory
(functional residual capacity increase, elastic workload decrease due to dynamic
hyperinflation and decrease of inspiratory muscle workload) and cardiovascular
systems (left ventricle afterload decrease, venous return and right ventricle preload
decrease and O
2
consumption decrease). The relative importance of these effects
depends on the underlying pathophysiology. Chronic obstructive pulmonary disease
and acute cardiogenic pulmonary oedema are two of the most common NIMV
indications and are used in the present chapter as an example of rational physiological
application of NIMV.
For optimal performance of NIMV, attention must be paid to patient–ventilator
interaction during NIMV, by tailoring mode (assist volume control, pressure-support
ventilation or proportional assist ventilation) and trigger and cycling-off parameters
to the specific patient needs.
In conclusion, when NIMV is rationally applied to carefully chosen patients with the
appropriate indication, it has physiological effects similar to those of invasive
mechanical ventilation, with fewer complications.
Keywords: Acute cardiogenic pulmonary oedema, cardiovascular effects, COPD,
noninvasive mechanical ventilation, patient–ventilator interaction, respiratory effects.
RATIONALE OF NIV IN ARF
19

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