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Ventilatory Failure, Ventilator Support,
and Ventilator Weaning
Martin J. Tobin,*1 Franco Laghi,1 and Amal Jubran1
ABSTRACT
The development of acute ventilatory failure represents an inability of the respiratory control
system to maintain a level of respiratory motor output to cope with the metabolic demands of
the body. The level of respiratory motor output is also the main determinant of the degree of
respiratory distress experienced by such patients. As ventilatory failure progresses and patient
distress increases, mechanical ventilation is instituted to help the respiratory muscles cope with
the heightened workload. While a patient is connected to a ventilator, a physician’s ability to align
the rhythm of the machine with the rhythm of the patient’s respiratory centers becomes the primary
determinant of the level of rest accorded to the respiratory muscles. Problems of alignment are
manifested as failure to trigger, double triggering, an inflationary gas-flow that fails to match
inspiratory demands, and an inflation phase that persists after a patient’s respiratory centers
have switched to expiration. With recovery from disorders that precipitated the initial bout of
acute ventilatory failure, attempts are made to discontinue the ventilator (weaning). About 20% of
weaning attempts fail, ultimately, because the respiratory controller is unable to sustain ventilation
and this failure is signaled by development of rapid shallow breathing. Substantial advances in
the medical management of acute ventilatory failure that requires ventilator assistance are most
likely to result from research yielding novel insights into the operation of the respiratory control
C 2012 American Physiological Society. Compr Physiol 2:2871-2921, 2012.
system. Introduction
This review encompasses aspects of control of breathing that
pertain to three states sequentially experienced by a patient
with respiratory disease of sufficient severity to require admission to an intensive care unit. Firstly, the patient may have
such severe derangements of respiratory function that he or
she develops ventilatory failure. Secondly, the ventilatory failure may be of sufficient severity to require the institution of
mechanical ventilation. Thirdly, after the precipitating respiratory disorder has resolved to a reasonable degree, the patient
is weaned from the ventilator; these weaning attempts, however, may be followed by recurrences of respiratory distress
of such severity as to require the temporary reinstitution of
mechanical ventilation.
Ventilatory Failure
Relationship between ventilation and PaCO2
Ventilatory failure is conventionally defined as an increase
in arterial carbon dioxide tension (PaCO2 ) that exceeds the
normal range. When PaCO2 is higher than 45 mmHg, the
respiratory system is deemed to have failed in maintaining an
adequate level of ventilation. As such, the physiological determinants of PaCO2 constitute the framework for consideration
of ventilatory failure (306).
In healthy subjects, PaCO2 remains remarkably stable
despite wide variations in minute ventilation (54). Such
Volume 2, October 2012
stability depends on exquisite control of breathing achieved
primarily through negative feedback. According to this
model, the controlled variable is PaCO2 , the controlled system is the pulmonary gas-exchange organ, and the controller
is the entire system of respiratory centers, neurons, and
muscles that achieve alveolar ventilation (269). The system
is designed to maintain a stable PaCO2 despite fluctuations
in CO2 production by the body (V̇ CO2 ), and a reference
PCO2 , or “set point,” is maintained in the brainstem. Under
steady-state conditions, the relationship between alveolar
CO2 tension (PACO2 ), alveolar ventilation (V̇ A ) and V̇ CO2
is given by the alveolar-gas equation:
PACO2 = K
V̇ CO2
V̇A
where K is a constant that converts measurement of V̇ CO2
from standard conditions to body temperature conditions.
Because PaCO2 is in equilibrium with PACO2 and because
V̇ A equals minute ventilation (V̇ E ) minus dead-space
* Correspondence
to mtobin2@lumc.edu
of Pulmonary and Critical Care Medicine, Edward Hines Jr.
Veterans Affairs Hospital and Loyola University of Chicago Stritch
School of Medicine, Hines, Illinois
Published online, October 2012 (comprehensivephysiology.com)
1 Division
DOI: 10.1002/cphy.c110030
C American Physiological Society
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Comprehensive Physiology
Ventilation (L/min)
40
30
20
10
0
40
20
0
60
PaCO2 (torr)
Figure 1 The relationship between minute ventilation (V̇ E ) and arterial carbon dioxide tension (PaCO2 ) in a healthy subject with a constant level of CO2 production (200 mL/min) and a dead space to tidal
volume ratio of 0.40; this relationship is termed the metabolic hyperbola. Also shown is a normal normoxic ventilatory response to CO2 of
5 L/min/mmHg, the controller curve (dotted straight line). The set point
of the system is determined by the intersection of the two relationships
(269).
(V D /V T ) ventilation,
PaCO2 =
K V̇ CO2
V̇E (1 − VD /VT )
For any given values of V D /V T and V̇ CO2 , this equation
describes a curve, the metabolic hyperbola, on a plot of V̇ E
against PaCO2 . Figure 1 shows the relationship between
PaCO2 and V̇ E for a constant V̇ CO2 of 200 mL/min and a
constant V D /V T of 0.40 in the absence of normal feedback
control between V̇ E and PaCO2 . This relationship implies that
at a constant V̇ CO2 , an increase in V̇ A must be accompanied
by a reciprocal fall of PaCO2 . In other words, the metabolic
hyperbola represents the simple response of the controlled
system (the organ of pulmonary gas exchange) to changes in
ventilation per se. Increases in V D /V T or V̇ CO2 will produce
different hyperbolae, shifted upward and to the right.
The sensitivity of the controller system (the entire system of respiratory centers, respiratory neurons and respiratory muscles) is evaluated by forcing an increase in PaCO2
and measuring the consequent increase in V̇ E (213, 269). Increases in PaCO2 to test the sensitivity of the controller system
can be achieved with the steady-state method, in which the
subject breathes air enriched with different concentrations
of CO2 , or with the rebreathing method. The resulting V̇ E PaCO2 relationship, termed the controller curve, is usually
described as a straight line (Fig. 1). The greater the sensitivity
of the controller system to an increase in V̇ CO2 , the steeper
will be the controller curve. Sensitivity to CO2 is reported
as the slope of the controller curve (V̇ E per mmHg), and
the normal range in healthy adults is 0.5 to 8.0 L/min/mmHg
(1.5-5.0 in 80% of subjects) (269).
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In a steady state, the values of PaCO2 and V̇ E must simultaneously satisfy the equations of both the controller curve and
the metabolic hyperbola. That is, the subject must lie at the
intersection between the metabolic hyperbola (controlled system) and the controller curve (controller system); this unique
point is the operating point or set point of the system, which
specifies the normal resting levels of V̇ E and PaCO2 (269).
According to the alveolar-gas equation, an increase in
metabolic rate or an increase in V D /V T can theoretically produce an increase in PaCO2 . In reality, a sole increase in V̇ CO2
or a sole increase in V D /V T is never sufficient to constitute
a primary mechanism of hypercapnia (306). Substantial increases in either V̇ CO2 or V D /V T are readily compensated for
by a normal ventilatory apparatus. Accordingly, an increase
in PaCO2 always signifies an abnormality in the mechanical
or control components of the respiratory system. An increase
in CO2 or V D /V T can, however, aggravate hypercapnia when
the respiratory system is already compromised. Patients with
chronic obstructive pulmonary disease (COPD) are especially
vulnerable to the development of hypercapnia when treated
with supplemental oxygen (13, 65, 70, 225). Several mechanisms may contribute to the development of hypercapnia: a
decrease in hypoxic ventilatory response consequent to the administration of oxygen; an increase in dead space consequent
to worsening of ventilation-perfusion relationships secondary
to release of hypoxic vasoconstriction; and the Haldane effect
(for any given amount of CO2 bound to hemoglobin, PaCO2
is considerably higher in the presence of a high vs. a low oxygen saturation). Figure 2 provides an example of why some
patients develop marked hypercapnia after administration of
oxygen and others do not.
Clinical disorders producing ventilatory failure
Table 1 lists a large number of clinical disorders that can lead
to ventilatory failure. The classification is based on anatomical
site, extending from conditions that affect the central nervous
system to those affecting the neuromuscular apparatus, the
airways, or lung tissue. Problems with control of breathing
for four of these disorders are discussed later: central alveolar
hypoventilation (briefly), neuromuscular disorders, COPD (in
greater detail), and the acute respiratory distress syndrome
(ARDS).
Central alveolar hypoventilation
Several structural and functional disorders of the central
nervous system can produce hypoventilation and ventilatory
failure. Among these is central alveolar hypoventilation,
which is caused by a failure of the respiratory centers to
provide sufficient activation to the lower motor neurons.
Ambulatory patients with central alveolar hypoventilation exhibit hypercapnia despite normal spirometric measurements
of lung function. In mechanically ventilated patients, the
disorder is suspected when patients develop marked increases
in PCO2 despite relatively normal measurements of resistance
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Table 1 Examples of Clinical Disorders that Produce
20
Ventilation (L/min)
Ventilatory Failure
A
10
B
0
10
30
50
70
PaCO2 (torr)
Figure 2 Schematic representation of mechanisms that contribute to
variable degrees of hypercapnia in patients with COPD who receive
supplemental oxygen. Patient A has a baseline PaCO2 of 30 mmHg
(green symbol) and a V D /V T of 0.40 (the lower black metabolic hyperbola). Administration of supplemental oxygen results in a 2-L decrease
in minute ventilation (blue symbol; represented as a vertical drop for the
sake of simplicity). This patient has a normal CO2 controller response
(slope of the red line, 1.0 L/min/mmHg), which brings his minute ventilation back up to the black hyperbola (red arrowhead). Consequently,
administration of supplemental oxygen produces an increase in PCO2
of only 1.5 torr. Patient B also has a baseline V D /V T of 0.40, but his
PCO2 is 50 mmHg (green symbol). Administration of supplemental
oxygen again results in a 2-L decrease in minute ventilation (blue symbol). This patient has a depressed CO2 controller response (slope of
the red line, 0.2 L/min/mmHg), and administration of oxygen produces
an increase in dead space from 0.40 to 0.60 secondary to worsening
of ventilation-perfusion relationships (consequent to release of hypoxic
vasoconstriction and the development of CO2 -induced bronchodilation); the patient accordingly moves from the lower black metabolic
hyperbola to the upper blue hyperbola. Consequently, administration
of supplemental oxygen produces an increase in PCO2 of 15 torr (10fold greater than in Patient A).
and elastance and no apparent evidence of lower motor neuron
disease (127). Specific features of various hypoventilation
syndromes are discussed in detail in other articles of the series.
Neuromuscular disorders
Respiratory muscle weakness frequently goes undetected in
patients with neuromuscular disease until ventilatory failure is
precipitated by aspiration pneumonia or cor pulmonale. Diagnosis is delayed because limb muscle weakness prevents patients from exceeding their limited ventilatory capacity (39).
A few patients develop severe respiratory muscle weakness
despite little or no peripheral muscle weakness (112).
Severe weakness of the inspiratory muscles produces a
restrictive pattern: decreases in vital capacity, total lung capacity (TLC), and functional residual capacity (FRC), with a
relatively normal ratio of forced expiratory volume in one second to forced vital capacity (FEV1 /FVC). Whether expiratory
muscles are weak or not, residual volume remains relatively
normal. Diffusing capacity, corrected for alveolar volume, is
not only normal in patients with respiratory muscle weak-
Volume 2, October 2012
A. Central disorders
Central nervous system: structural
Primarily (upper or lower) neuronal disorders
Central (primary) alveolar hypoventilation
Cerebrovascular accidents
Congenital diseases (Arnold-Chiari II malformation)
Degenerative diseases (Parkinson’s disease)
Infections (polio virus infection)
Spinal cord injury
Amyotrophic lateral sclerosis
Paraneoplastic disorder (anti-Hu antibodies)
Primarily myelin disorders
Multiple sclerosis
Central nervous system: functional
Drugs (narcotics, sedatives, anesthetics)
Metabolic alkalosis
Resetting of CO2 set point
Sleep-related hypoventilation
B. Neuromuscular disorders
Peripheral nerve
Metabolic disorders (diabetes mellitus, porphyria)
Vasculitis
Guillain-Barre syndrome
Neuralgic amyotrophy
Trauma
Neuromuscular junction
Myasthenia gravis
Lambert-Eaton syndrome
Botulism
Tick paralysis
Drugs (neuromuscular blocking agents)
Muscle disorders
Critical illness myopathy
Inflammatory/Autoimmune disorders
Endocrinopathies
Congenital myopathies
Drugs (colchicine), electrolyte disturbances
C. Mechanical derangements
Obstructive diseases
COPD
Asthma
Cystic fibrosis
Restrictive diseases
Pulmonary parenchyma
Idiopathic pulmonary fibrosis and congeners
Acute respiratory distress syndrome (ARDS)
Pulmonary resection
Chest wall deformity
Trauma and flail chest
Scoliosis
Ankylosing spondylitis
Thoracoplasty
Fibrothorax
Abdominal distension
Obesity
Ascites
ness, but it can also be normal in patients with pulmonary
fibrosis (135) and is of limited value in differentiating the
two conditions. Vital capacity is normal, or only minimally
reduced, if respiratory muscle strength is more than 50% of
predicted (61). This finding results from the sigmoid shape
of the pressure-volume relationship of the respiratory system.
When strength is less than 50% of predicted, however, the loss
in vital capacity is greater than expected (61,78). The decrease
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is secondary to the associated decrease in compliance of the
chest wall and lungs (78, 172). The latter probably results
from fibrosis consequent to recurrent aspirations, arrested
lung growth in early-onset abnormalities of the chest wall,
and diffuse microatelectasis (306). The decreased chest-wall
compliance probably results from stiffening of tendons and
ligaments of the rib cage, activity of antagonistic muscles (expiratory muscle activity during inspiration in myotonic dystrophy), thoracic deformities accompanying muscle weakness
(kyphoscoliosis in poliomyelitis), fibrotic changes or spasticity of involved muscles, and ankylosis of the costosternal and
thoracovertebral joints (306).
Patients with respiratory muscle weakness take rapid shallow breaths (172), possibly as a result of afferent signals
in weakened respiratory muscles, intrapulmonary receptors,
or both (30, 172). PaCO2 may be reduced early in the disease (217), but hypercapnia is likely when respiratory muscle
strength falls to 25% of predicted (31). Reduction in strength,
however, does not consistently predict alveolar hypoventilation because factors such as elastic load and breathing pattern also contribute (172). Abnormalities in respiratory muscle performance may initially be evident only during sleep
(10,293), during immersion in water (176,231) or, in patients
who are able to exercise, during physical activity (241). When
inspiratory strength and vital capacity are 50% of predicted,
hypoventilation can occur with minor upper respiratory tract
infections.
Patients with neuromuscular diseases, irrespective of
the primary pathology (10, 113), commonly develop abnormalities during sleep: frequent arousals, increased Stage
1 sleep, decreased rapid-eye movement sleep, hypoventilation, and hypoxemia (27). Patients with diaphragmatic weakness or diaphragmatic paralysis are at particular risk of developing hypoventilation during rapid-eye movement sleep
(27, 242, 254, 293). To decrease this likelihood, the central
nervous system can adopt two strategies: phasic recruitment
of inspiratory muscles other than the diaphragm during rapideye movement sleep (10) or suppression of rapid-eye movement sleep (10, 27, 293). The failure of all patients to develop
these adaptive strategies may explain discrepancies among
reports on oxygenation during sleep in patients with isolated
diaphragmatic paralysis (147, 254, 293).
Chronic obstructive pulmonary disease
COPD is estimated to affect more than 200 million people
worldwide, and now constitutes the fourth most common
cause of death. Suspicion for the presence of COPD is aroused
by taking a patient’s history and performing physical examination. The diagnosis, however, hinges largely on spirometric
measurements, specifically the demonstration of a forced expiratory volume in 1 s (FEV1 ) below the normal range combined with a decrease in the FEV1 /FVC ratio of less than
70% or so (230). Being defined in this manner, the development of ventilatory failure in COPD is commonly perceived to
have resulted from a mechanical impediment, primarily from
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Flow
Normal
Vmax
COPD
Vmax
Pleural pressure
Inspiration
Expiration
Figure 3 Schematic representation of the isovolume pressure-flow
relationship. Patients with COPD exhibit an initial diagonal segment,
where increases in pressure produce increases in airflow (the effortdependent region on the left), followed by a flat portion, where increases in pressure do not produce increases in flow (the effortindependent region on the right). Compared with a healthy subject,
the slope of the initial diagonal segment is decreased, indicating an
increase in airway resistance, and maximum flow is much reduced in
the remaining portion as a result of expiratory flow limitation. [Modified, with permission, from Pride and Macklem (206).]
an increase in the resistance to air flow during expiration.
In reality, the pathophysiology of ventilatory embarrassment
and ventilatory failure in COPD involves many factors other
than airway resistance. Even when COPD is severe, the increase in resistance in the effort-dependent range is only 5
to 10 cmH2 O/L/s above normal (37) (Fig. 3). Subjects facing inspiratory and expiratory resistances of this magnitude
can achieve a normal level of ventilation with very minor
adjustments in respiratory motor output (306). Studies using
modeling techniques reveal that uncomplicated obstructive
disease imposes virtually no stress on the respiratory control
system despite reductions in FEV1 to 50% of predicted (306).
Even when FEV1 is reduced to 20% of predicted, the increase
in respiratory motor output needed to maintain normocapnia
is fairly small.
The main problem in COPD is not the increase in airway
resistance per se, but expiratory airflow limitation that
results from decreased tethering of the airways secondary
to rupture of elastic fibers (206). At rest, expiratory airflow
limitation is present in about 60% of patients with COPD
(72). Figure 3 provides a schematic representation of the
pressure-flow relationship in COPD (304). In the initial
diagonal segment (on the left), the slope of the relationship is
less than in healthy subjects, indicating that airway resistance
is increased. In this region, airflow in patients with COPD is
sensitive to applied pressure during inspiration and also over
a finite range of expiration (just as in healthy subjects). Over
the remaining portion of the relationship, expiratory flow is
much lower than in healthy subjects and it is also independent
of applied pressure. This region represents flow limitation,
which, by definition, cannot be compensated for by greater
expiratory muscle action. Expiratory airflow limitation
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delays lung emptying, with the result that inspiration begins
before the respiratory system has returned to its relaxation
volume—a state known as dynamic hyperinflation (206).
In COPD, dynamic hyperinflation can also develop or
worsen when ventilatory demands are increased. When
healthy subjects experience increased ventilatory demands,
they increase minute ventilation through increases in both
tidal volume and respiratory frequency. At the end of a tidal
inspiration, a finite time is required for lung volume to return
to passive FRC. The minimum time is determined by maximum expiratory flow (3). When patients with severe COPD
and expiratory flow limitation develop tachypnea, they necessarily shorten the time available for expiration. The decrease
in expiratory time means that the next inspiration will commence before lung volume has returned to passive FRC, thus
producing dynamic hyperinflation (143). Although flow limitation is the main instigator of the dynamic hyperinflation,
the increased airway resistance is a contributing factor. The
time constant (resistance × compliance) of the normal passive respiratory system is about 0.3 s (3 cmH2 O/L/s × 0.1
L/cmH2 O = 0.3 s). Substantial increases in resistance will
impinge on the time needed for expiration. In a patient with a
respiratory frequency of 40 breaths per minute and a threefold
increase increase in resistance, this factor will contribute to
the development of dynamic hyperinflation (309).
In patients with severe obstruction, this built-in response
can be counterproductive and may exaggerate hypercapnia
rather than relieve it (304). Specifically, the development of
dynamic hyperinflation decreases the effectiveness of the respiratory system through at least four mechanisms. First, dynamic hyperinflation forces the respiratory muscles to operate
on the upper less compliant portion of the pressure-volume
curve (206). In this region, greater inspiratory effort is required to achieve increases in tidal volume, reflecting the
distinctly nonlinear relationship between the intensity of inspiratory activation and resulting tidal volume (304). Consequently, increases in ventilatory demands that are accompanied by increases in respiratory frequency may lead to a
decrease, rather than an increase, in tidal volume. In this way,
the ventilatory challenge resembles that typically associated
with restrictive lung disease. The decrease in tidal volume
may be sufficiently severe as to completely offset the increase in minute ventilation anticipated with the increase in
frequency. As tidal volume decreases, V D /V T necessarily increases and thus hypercapnia can accompany the tachypneic
response (277). Thus, increased inspiratory muscle activation
is highly inefficient from an energetic perspective in meeting increased ventilatory demands that occur in patients with
severe COPD (304).
Second, dynamic hyperinflation, which develops or worsens in response to tachypnea, leads to an increase in the oxygen cost of breathing because the next inspiration typically
commences before the respiratory system has returned to its
relaxation volume. Consequently, a threshold load is imposed
on the inspiratory muscles, termed auto or intrinsic positive
end-expiratory pressure (PEEP) (Fig. 4) (143).
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Third, end-expiratory lung volume is usually determined
by the static equilibrium between inwardly directed elastic
recoil of the lungs and outwardly directly recoil of the thoracic cage (relaxation volume). The outwardly directed forces
help the inspiratory muscles to inflate the lungs. When endexpiratory lung volume lies above 70% of predicted total lung
capacity (218), however, thoracic elastic recoil is directed
inward and the inspiratory muscles have to work not only
against the elastic recoil of the lungs but also against that of
the thoracic cage.
The fourth mechanism whereby dynamic hyperinflation
decreases the effectiveness of the respiratory system in
the expulsion of CO2 is through a decrease in the resting
length of the diaphragm primarily as a result of a decrease
in the length of the zone of apposition (143). The zone of
apposition normally constitutes 60% of the diaphragm’s total
area, but only 40% in patients with COPD (44). The smaller
zone of apposition means that a small portion of the rib
cage is exposed to the positive abdominal pressure produced
by diaphragmatic contraction, and this further limits the
capacity of the diaphragm to produce rib-cage expansion
(140, 143). Other mechanisms through which hyperinflation
decreases the capacity of the respiratory muscles to generate
negative intrathoracic pressure include worsening of the
length-tension relationship, decrease in the curvature of the
diaphragm, and change in the mechanical arrangement of
costal and crural components of the diaphragm (143). In
addition to functional weakness secondary to hyperinflation,
respiratory muscle weakness in COPD may also result from
reductions in specific force (defined as the maximum tetanic
force per cross-sectional area)—reported by some (153, 190)
but not all investigators (256)—and muscle injury especially
in patients with acute-on-chronic COPD (232).
The reduced pressure output of the inspiratory muscles in some patients with COPD can be completely explained by muscle shortening consequent to hyperinflation
(44, 180, 237, 279). Similowski and co-workers (237) found
that some patients with COPD had greater transdiaphragmatic
pressure (in response to phrenic nerve stimulation) than did
healthy subjects at equivalent lung volumes. The finding suggests that the inspiratory muscles had adapted to hyperinflation. The adaptation is probably secondary to shortening of
diaphragmatic sarcomeres (reported in patients with mild-tomoderate COPD (187) and in a hamster model of emphysema
(80)), which cause a leftward shift of the length-tension relationship. Whether these adaptations to hyperinflation actually
occur in patients with COPD remains highly controversial
(46).
Hyperinflation is not only detrimental but also protective.
First, it optimizes expiratory flow by limiting dynamic airway
closure during exhalation. Second, hyperinflation may protect
the diaphragm against fatigue insofar as susceptibility to fatigue is greater when a muscle is made to contract at optimum
muscle length rather than when it is shortened (88). Third, the
increased mechanical load associated with increased hyperinflation and airway obstruction may produce diaphragmatic
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Onset inspir effort
Flow (L/s)
Onset inspir flow
2
0
–2
Paw cmH2O
25
15
5
–5
Pes cmH2O
10
0
–10
0
2
4
6
8
10
0
1
2
3
4
Time (s)
Figure 4 Differing degrees of intrinsic positive end-expiratory pressure (PEEP) in patients with COPD. Tracings are flow, airway pressure
(Paw ), and esophageal pressure (Pes ) in two patients with COPD receiving assisted ventilation with pressure support set at 20 cmH2 O (no
external PEEP is applied). The patient on the left had a myocardial infarction complicated by congestive heart failure, and the patient on the
right had sepsis. Intrinsic PEEP, estimated as the difference in esophageal pressure between the onset of inspiratory effort (vertical blue line)
and the onset of inspiratory flow (vertical red line), was 0.5 cmH2 O in the patient on the left and 10.6 cmH2 O in the patient on the right.
This method of estimating intrinsic PEEP is based on the assumption that the change in esophageal pressure reflects the inspiratory muscle
pressure required to counterbalance the end-expiratory elastic recoil of the respiratory system.
remodeling consisting of fast-to-slow fiber shift (153), where
slow fibers are more fatigue resistant than are the fast fibers
(143).
Patients with COPD have an increased risk of coronary
artery disease, and 20% to 30% exhibit chronic heart failure
(150). Increased stress on the myocardium during an exacerbation of COPD or an episode of weaning failure could overwhelm an already compromised cardiac reserve and cause
acute left-ventricular failure (125,151). An increased respiratory load resulting from interstitial edema secondary to acute
left-ventricular failure together with decreased blood flow
to the respiratory muscles may markedly impair respiratory
muscle performance and reduce the time to task failure (14).
Healthy subjects recruit their expiratory muscles when
coping with increased ventilatory demands. Activity of the expiratory muscles helps inspiration by moving end-expiratory
lung volume down to below passive FRC, and thus leads to
the storage of elastic energy in the respiratory system. At the
completion of exhalation, the transversus abdominis relaxes
and the release of stored energy causes intrathoracic pressure to fall and inspiratory flow to start before the diaphragm
has begun to contract (143). In this way, expiratory muscle
activity during expiration can assist the inspiratory muscles
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in expanding the respiratory system during inspiration. The
effectiveness of the expiratory muscles in sparing inspiratory
muscle work can be substantial. Phasic activation of the expiratory muscles of the order of 10% of maximum can produce
an increase in tidal volume equivalent to that achieved by a
doubling of inspiratory muscle activity (305). Recruitment
of the expiratory muscles is probably part of the constrained
response of the respiratory centers to increased ventilatory
demands (143). In patients with COPD who have expiratory flow limitation, the associated dynamic airway collapse
makes it impossible for the expiratory muscles to increase expiratory flow, and thus these patients are unable to lower endexpiratory lung volume below passive FRC. Consequently,
the entire burden of breathing must be borne by the inspiratory muscles.
The level of PaCO2 in patients with respiratory disorders
is usually maintained within the normal range until the disease
has reached a very advanced stage (143). The preservation of
ventilation despite an increase in mechanical load is achieved
through greater respiratory muscle recruitment than in healthy
subjects (62). That is, load compensation must be taking place
(309). Immediate (first breath) load compensation to maintain normocapnia occurs only in wakefulness; during sleep,
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application of resistive, or elastic loads does not produce immediate load compensation, with the result that tidal volume
falls and PaCO2 increases (114, 296). Evidence for the occurrence of load compensation has led to considerable interest
in studying the response to externally applied loads. When
resistive loads are applied in healthy subjects, the steady-state
response typically consists of slow deep breathing. In contrast, patients with COPD exhibit an increase in respiratory
frequency, and when they develop progressive ventilatory
failure, tidal volume becomes less than normal (268, 277).
The discrepancy between the response of healthy subjects
to externally applied loads and patients with COPD results
from the fact that external resistive loads do not accurately
simulate the mechanical load of COPD. As already discussed,
an increase in airway resistance is only one component of the
mechanical challenge in COPD (309). Patients also face an
elastic load as a result of breathing on the upper flat portion of
the pressure-volume curve, muscle weakness consequent to
hyperinflation, and an inspiratory threshold load consequent
to the auto-PEEP imposed by dynamic hyperinflation (143).
In addition, patients with COPD are exposed to numerous
other stimuli including airway inflammation, parenchymal
inflammation, hormonal and electrolyte disturbances, high
ventilatory requirements (increase in dead space, metabolic
rate, or both), and pulmonary vascular disease. No external
device that simulates this complex combination of mechanical
loads and other perturbations has been developed and tested.
That patients breathe rapidly rather than slowly suggests that
the influence of increased resistance per se on the breathing
pattern is fairly small, and less than the effect of other stimuli
that promote tachypnea (268).
In patients with COPD, as in many patients with ventilatory failure (306), the combination of an increased load on the
respiratory muscles and their decreased capacity to generate
flow and pressure (143) raises the question of whether contractile fatigue might contribute to the development of ventilatory
failure and hypercapnia. Contractile fatigue can be short lasting or long lasting (143). Short-lasting fatigue results from
accumulation of inorganic phosphate, failure of the membrane electrical potential to propagate beyond T-tubules, and
to a much lesser extent intramuscular acidosis (143). Shortlasting fatigue appears to have a protective function because
it can prevent injury to the sarcolemma caused by forceful
muscle contractions (318). Long-lasting fatigue (139) is consistent with the development of, and recovery from, muscle
injury (122, 318). The topic of respiratory muscle fatigue is
complex and the interested reader is referred to a detailed
review of the topic (143).
Modest intermittent resistive loading (2 h a day over
4 days) can disrupt sarcomeres and the sarcolemma of
diaphragmatic fibers in dogs (319). This mechanism may
also occur in patients. In a study of 21 patients with FEV1
ranging from 16% to 122% of predicted, the proportion of
abnormal fibers in the diaphragm was correlated with airflow
obstruction (160). Abnormalities consisted of myofibers with
internally located nuclei, lipofuscin pigmentation (sign of
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oxidative stress), small angulated fibers, inflammation, and
necrosis; these abnormalities occupied 4% to 34% of the diaphragm (160). Sarcomere disruption has also been reported
in 18 patients with COPD (188). The density and area of
disruptions in the patients was twice that seen in 11 control
subjects, and it was correlated with FEV1 and hyperinflation
(188). Diaphragmatic damage has been reported in patients
dying of COPD (232) and also in those dying of status
asthmaticus (67) and in infants dying of the sudden infant
death syndrome (236). Circumstantial evidence suggestive
of contractile fatigue in patients experiencing respiratory
distress has also been reported (32, 48, 71, 101, 127).
One of the major puzzles in COPD is why do some patients develop hypercapnia and others do not (269). A variety
of factors have been put forward, including respiratory muscle
function (17), configuration of the diaphragm (200), respiratory mechanics (17), abnormalities in ventilation-perfusion
relationships and increased dead-space ventilation (13, 287).
The wide scatter together with the fact that the normal response to added loads in conscious humans is normocapnic
suggests that some abnormality in the control of breathing
contributes to the hypercapnia. It has been suggested that
the development of hypercapnia results from innate or premorbid differences in the chemical control of breathing. The
hypothesis is that patients who exhibit hypercapnia have depressed chemical responsiveness even before they develop
COPD (130, 175). This proposition, however, is impossible
to test once hypercapnia has become established because the
presence of a mechanical abnormality inevitably alters the
ventilatory response to CO2 and hypoxia; moreover, chronic
hypercapnia and hypoxia can also depress chemical responsiveness even in the absence of mechanical abnormalities.
It had been thought that patients presenting with a
blue-bloater profile have hypercapnia as a result of decreased
respiratory motor output and that patients presenting with
a pink-puffer profile maintain eucapnia through increases
in respiratory motor output. Repeated attempts to generate
data to support this simplistic picture have been to no avail.
Indeed, even when patients develop acute increases in PaCO2
as a result of severe progressive respiratory failure they
develop increases in respiratory drive (173, 227, 277).
In addition to its detrimental effects, hypercapnia can be
advantageous in patients with abnormal respiratory mechanics because it can make breathing more efficient. When alveolar PCO2 is increased, more CO2 is expelled for a given
exhaled volume. Thus, the oxygen cost to the respiratory
muscles in excreting CO2 is more efficient in hypercapnic
patients.
In patients experiencing an acute exacerbation of COPD,
a further mechanism that may contribute to the development
of hypercapnia is impaired voluntary activation of the
diaphragm. Topeli and co-workers (280) investigated this
possibility using the twitch-interpolation technique in 15
patients with stable COPD. When the phrenic nerves are
stimulated during a voluntary contraction, the increase in
transdiaphragmatic pressure reflects the proportion of muscle
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result of hyperinflation), a threshold load (as a result of autoPEEP), and functional weakness of the inspiratory muscles
(as a result of hyperinflation) with only a small increase in
inspiratory airway obstruction.
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Figure 5 Tracings of transdiaphragmatic pressure (Pdi ) during bilat-
eral phrenic nerve stimulation in a patient with COPD. During a forceful
Mueller maneuver, stimulation produced a superimposed twitch pressure (arrow). On the right is a twitch pressure achieved by stimulation
during resting breathing just after the Mueller maneuver. The ratio of
the amplitude of superimposed twitch pressure to resting twitch pressure (expressed as a percentage) measures the extent that muscle is not
recruited by the central nervous system during the Mueller maneuver.
The extent of muscle recruitment is usually expressed as the voluntary
activation index, which is calculated as: 100 minus the superimposed
twitch pressure to resting twitch pressure ratio. In the displayed example, the amplitude of the superimposed twitch pressure is 19% of the
amplitude of resting twitch pressure, yielding a voluntary activation index of 81%; if the superimposed stimulus had evoked no increase in
pressure, the activation index would have been 100% (143). Of note, a
twitch pressure recorded shortly after forceful contractions (potentiated
twitch) is greater than a twitch pressure recorded after 15 to 20 min of
rest (nonpotentiated twitch) (140). Nonpotentiated twitches are usually
used to quantify diaphragmatic force output at rest, and changes in
force following fatiguing protocols (140, 143).
ARDS is a form of noncardiogenic pulmonary edema that
results from severe acute alveolar injury. The main physiological features are marked increase in respiratory elastance
and resistance, a decrease in the number of functional lung
units, decrease in FRC, severe hypoxemia secondary to intrapulmonary shunt, and pulmonary hypertension. Despite the
overall reduction in FRC (79), patients with ARDS commonly
exhibit dynamic hyperinflation and intrinsic PEEP (137) as a
result of loss of lung recoil, increased peripheral airway resistance, or both. Breathing at a low lung volume also promotes
airway closure and gas trapping, which is further aggravated
by the increase in closing volume that results with alveolar
edema and the deficiency of surfactant in ARDS (137). While
the abnormalities in respiratory mechanics, gas exchange and
pulmonary vascular resistance impose stresses on the respiratory controller, systematic studies of the effect of ARDS on
respiratory controller function have not been conducted.
Ventilator Support
Goal of mechanical ventilation
not recruited by voluntary activation (Fig. 5). Voluntary
activation was higher in six patients who had hypercapnia
than in nine patients with normocapnia, 95% versus 89%;
the value in normocapnic patients was equivalent to that
reported in healthy subjects (88%; (5)). The extent of
voluntary activation of the diaphragm and PaCO2 were both
positively correlated with inspiratory muscle load (280). The
results suggest that, contrary to expectations, development of
hypercapnia is not the result of impaired voluntary activation
of the diaphragm and that patients with a high load may have
learned to fully activate their diaphragm on an intermittent
basis (280). The latter explanation is supported by data that
suggest that suprapontine compensatory mechanisms are
active in defending ventilation in awake human subjects
challenged with an inspiratory load (212). The ability to
mount an increase in voluntary drive to the diaphragm may
be especially important during an acute exacerbation of
COPD. Moreover, patients with COPD who are capable of
lowering PaCO2 upon acute voluntary increases in ventilation
exhibit significant correction of chronic hypercapnia with
the chronic administration of respiratory stimulants such as
medroxyprogesterone or acetazolamide (244-246).
In summary, the pathophysiology of COPD presents a
curious paradox in that the name of the disease focuses on
airway obstruction and the diagnosis is based on decreased
airflow during expiration, yet the mechanical consequences
occur during inspiration and consist of an elastic load (as a
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Many patients who require mechanical ventilation have relatively normal arterial blood gases but have clinical signs of
increased work of breathing: nasal flaring, vigorous activity of the sternomastoid muscles, tracheal tug, recession of
the suprasternal, supraclavicular and intercostal spaces, paradoxical motion of the abdomen, and pulsus paradoxus (144).
The oxygen cost of breathing of patients in acute respiratory
distress is increased to as much as 50% of total oxygen consumption (85). By decreasing respiratory work, mechanical
ventilation allows precious oxygen stores to be rerouted from
the respiratory muscles to other vulnerable tissue beds. The
institution of mechanical ventilation is most commonly based
on a physician’s clinical gestalt, formed through assessing
a patient’s signs and symptoms, rather than because a patient satisfies a certain set of criteria on a checklist. Indeed,
the most common—and honest—reason that mechanical ventilation is instituted is a tautology: a physician thinks that
“the patient looks like he (or she) needs to be placed on the
ventilator” (144).
Modes of mechanical ventilation
The most commonly used ventilator modes are assist-control
ventilation, pressure support, and intermittent mandatory ventilation (IMV). Figure 6 shows the typical appearance of tidal
volume and airway pressure in patients receiving ventilator
assistance with each mode.
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20
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Figure 6 Recordings of tidal volume (V T ) and airway pressure (Paw ) in patients receiving ventilator assistance with assist-control ventilation
(ACV), synchronized intermittent mandatory ventilation (SIMV), and pressure support ventilation (PSV). The ordinates and abscissae differ from
one panel to the next because the tracings were recorded in three different patients. See text for details.
Assist-control ventilation
With assist-control ventilation, the ventilator delivers a breath
either when triggered by the patient’s inspiratory effort (pressure or flow triggered) or, independently, if such an effort does
not occur within a preselected time period (162). When the
patient’s inspiratory effort successfully triggers the machine,
the total respiratory rate can exceed the preset rate. All breaths
are delivered under positive pressure by the machine. The
breath delivered by the ventilator can have a predetermined
volume (volume-cycled form of assist-control ventilation)
or a predetermined inflation pressure that is applied for a
predetermined inflation time (pressure-control form of assistcontrol ventilation). When delivering the breath, the ventilator
adjusts pressure output such that total applied pressure (Paw +
Pmus ) remains in excess of elastic recoil until the target volume
(volume-cycled ventilation) or target inflation time (pressurecontrol ventilation) is reached (308). With this mode, there is
no inherent coupling between the end of a patient’s inspiratory effort and the onset of expiratory flow. If the patient stops
making an inspiratory effort before a set tidal volume or the set
target inflation time is delivered, the ventilator simply continues to deliver gas until the target volume or the target inflation
time is reached. Conversely, when the set tidal volume (or
the set inflation time) is reached before the end of a patient’s
inspiratory effort, the ventilator will cycle off while patient
effort is ongoing and this may cause expiratory flow to begin
prematurely (308).
By design, the volume of gas delivered during the volumecycled form of assist-control ventilation is independent of
patient effort, except where the set tidal volume is less than
that which a patient would generate based on his or her own
level of effort. The greater the inspiratory effort made by
the patient, the lower will be the airway pressure during the
volume-cycled form of assist-control ventilation, such that
the overall airway pressure on the ventilator monitor bears an
inverse relationship to patient-generated pressure. During the
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pressure-control form of assist-control ventilation, the more
the patient contributes to inspiration, the less volume of gas is
provided directly by the machine, and ventilator-generated
volume bears an inverse relationship to patient-generated
effort.
The amount of active work performed by a patient ventilated in volume-cycled assist-control is critically dependent
on the trigger sensitivity and inspiratory flow settings. Even
when these settings are selected appropriately, patients actively perform about a third of the work performed by the
ventilator during passive conditions (165).
When employing the volume-cycled form of assist-control
ventilation, the clinician selects some tidal volume and an
inspiratory flow; indirectly, the clinician is also selecting a
mechanical inspiratory time despite having no idea of the duration of the patient’s own neural inspiratory time. Likewise,
when employing the pressure-cycled form of assist-control
ventilation, the clinician selects a mechanical inspiratory time
despite having no idea of the duration of the patient’s own neural inspiratory time. Given that neural inspiratory time varies
widely in duration both within patients and among patients,
it is very unlikely that machine inspiratory time will coincide
with that of a patient.
Pressure-support ventilation
Pressure-support ventilation is a patient-triggered, pressuretargeted, and flow-cycled mode of mechanical ventilation
(33). The physician sets a level of pressure that assists every
spontaneous effort, and the patient can alter respiratory
frequency, inspiratory time, and tidal volume. Tidal volume
is determined by the pressure setting, the patient’s effort and
pulmonary mechanics, in contrast to volume-targeted ventilation such as volume-cycled assist-control ventilation, where
a guaranteed volume is delivered. With volume-targeted
ventilation, the inspiratory flow setting is a crucial determinant of patient work. There is no flow setting with pressure
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(L/s)
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PS 0
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–10
10
0
–10
–20
0
2
4
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8
10
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6
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Figure 7 Increase in elastic recoil and expiratory muscle recruitment during pressure support. Flow (inspiration directed
upward), airway pressure (Paw ), and esophageal pressure (Pes ) in a patient receiving pressure-support of 0 (upper left
panel), 5 cmH2 O (upper right panel), 10 cmH2 O (lower left panel), and 20 cmH2 O (lower right panel). As pressure
support was increased from 0 to 20 cmH2 O, respiratory frequency decreased from 20 to 13 breaths/min and tidal swings
in esophageal pressure decreased from 20 to 10 cmH2 O. End-inspiratory esophageal pressure returned to preinspiratory
values at pressure support of 0, whereas the end-inspiratory value was higher than preinspiratory esophageal pressure at
pressure support of 20, suggesting recruitment of expiratory muscles and increased elastic recoil. The increase in airway
pressure above the preset level (best seen at pressure support of 5 and 10) probably resulted from relaxation of the
inspiratory muscles while mechanical inflation was still active; the extent of expiratory muscle contribution to the increase
in airway pressure cannot be determined in the absence of measurements of chest-wall recoil pressure. The flow signal
at the start of inhalation demonstrates an initial spike that increases as the level of support increases; this phenomenon
reflects the need for higher flows to achieve the higher target airway pressures.
support, although the initial peak flow determines the speed
of pressurization and the initial pressure ramp profile.
Pressure support can be very effective in decreasing the
work of inspiration. The degree of inspiratory muscle unloading, however, is variable, with a coefficient of variation of up to
96% among patients (129). The level of pressure delivered by
the ventilator is usually adjusted in accordance with changes
in the patient’s respiratory frequency. The frequency, how-
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ever, which signals a satisfactory level of respiratory muscle
rest has never been well defined, and recommendations range
from 16 to 30 breaths per minute (129).
Cycling to exhalation is triggered by a decrease in inspiratory flow to a preset level, such as 5 L/min or 25% of peak
inspiratory flow, depending on the manufacturer’s algorithm.
The algorithm for “cycling-off” of mechanical inflation can
cause problems in patients with obstructive airway diseases,
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Flow
(L/s)
Paw
(cmH2O)
–2
40
Transversus abdominis
EMG (arbitrary units)
–10
10
10
3
20
Time (s)
Figure 8 Recordings of flow, airway pressure (Paw ), and transversus
abdominis electromyography (EMG) in a critically ill patient with COPD
receiving pressure support of 20 cmH2 O. The onset of expiratory muscle activity (vertical dotted line) occurred when mechanical inflation was
only partly completed. [From Parthasarathy S, Jubran A, Tobin MJ. Cycling of inspiratory- and expiratory-muscle groups with the ventilator in
airflow limitation. Am J Respir Crit Care Med 1998; 158: 1471-1478
(192).]
because increases in resistance and compliance produce a
slow time constant (of the respiratory system) (Fig. 7). The
longer time needed for flow to fall to the threshold value can
cause mechanical inflation to persist into neural expiration.
In 12 patients with COPD receiving pressure support of 20
cmH2 O, Jubran et al. (129) found that five recruited their expiratory muscles while the machine was still inflating the thorax
(Fig. 8). The patients who recruited their expiratory muscles
during mechanical inflation had an average time constant of
0.54 s, as compared with an average of 0.38 s in the patients
who did not exhibit expiratory muscle activity. The persistence of mechanical inflation into neural expiration is very
uncomfortable, as well recognized with use of inverse-ratio
ventilation (where, contrary to the normal pattern, inflation
lasts longer than exhalation) (7).
Intermittent mandatory ventilation
With IMV, the patient receives periodic positive-pressure
breaths from the ventilator at a preset flow, volume, and frequency, but the patient can also breathe spontaneously between these mandatory breaths (221). A problem not raised at
the time IMV was introduced is the ability of a patient to adapt
to the intermittent nature of ventilator assistance. It had been
assumed that the degree of respiratory muscle rest achieved
by IMV would be proportional to the number of mandatory
breaths delivered. Studies, however, have demonstrated that
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that is not the case; instead, inspiratory effort is equivalent
for spontaneous and assisted breaths during IMV (117, 166).
Indeed, the tension-time index (the product of two fractions:
[mean pressure per breath/maximum inspiratory pressure] ×
[fractional inspiratory time, T I /T TOT ]) for both the spontaneous and assisted breaths was above the threshold associated
with task failure of the respiratory muscles at IMV rates of
14 breaths per minute or less (166). Similarly, at a moderate level of machine assistance (where the ventilator accounts
for 20%-50% of total ventilation), Imsand et al. (117) reported that electromyographic activity of the diaphragm and
sternomastoid muscles was equivalent for assisted and the
adjacent unassisted breaths.
That inspiratory muscle activation is equivalent during
assisted and unassisted breaths has led to the notion that activation is “preprogrammed” before the onset of the breath
and that it is not altered by inter-breath changes in the level
of assistance. Younes (312) considers this explanation untenable because several investigators have revealed immediate
changes in inspiratory output with changes in ventilator settings (such as with changes in inspiratory flow). It is more
likely, he argues (312), that the lack of differences in electrical activation between assisted and unassisted breaths in
the study of Imsand et al. (117) were related to factors that
minimized the development of responses. For example, differences in flow between assisted and unassisted breaths in
IMV are not always large (98). All of the patients in the study
of Imsand et al. (117) had severe COPD, and reflexes mediated by mechanoreceptors are attenuated in such patients
(202,282,314). Moreover, patients with COPD have dynamic
hyperinflation and a substantial proportion of neural inspiratory time will have elapsed before the commencement of
inspiratory flow. Under these conditions, there is no reason to
expect any difference between neural output in assisted and
unassisted breaths because in both cases virtually all of neural
inspiratory time will take place without receiving ventilator
assistance (312).
The studies on IMV emphasize how alterations in respiratory load from one breath to the next are not sufficient to
arouse reflex compensation. In the past, it had been believed
that an increase in the mechanical load produced reflex increases in respiratory drive (41). Despite extensive research,
no load-related source of respiratory drive has been identified
and it is thought that none exists (309). An additional finding
pertinent to this issue is that occlusion of the airway during
inspiration in anesthetized animals does not produce an increase in inspiratory muscle activity during the first occluded
breath other than what can be explained by prolongation of
inspiration (secondary to loss of vagal feedback) (309). As
such, relief of respiratory distress by mechanical ventilation
is unlikely to be secondary to simple unloading of respiratory
muscles. It is more likely that relief is related to a decrease in
drive achieved by other means, such as improvement in gas
exchange, improvement in blood pressure (in hemodynamically compromised patients), or decrease in metabolic rate
secondary to relief of anxiety and agitation (313).
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Control of breathing during
mechanical ventilation
The respiratory control system consists of an automatic
(metabolic) control system that integrates peripheral information in the brainstem and a behavioral or voluntary controller in supramedullary and cortical structures (161, 286).
In healthy subjects, the automatic drive to breathe has three
main sources (313). First, chemical drive, which is related
to changes in arterial PO2 and to arterial and brain PCO2
and pH, and is mediated by peripheral and central chemoreceptors. The second is metabolic drive, which is related to
the metabolic rate and mediated by unknown mechanisms.
Third is wakefulness drive, which is manifested through its
disappearance during sleep. Metabolic rate does not appear
to be sufficiently high to produce oscillation of the respiratory centers during sleep; instead, respiratory rhythm is almost completely dependent on chemical factors (PaCO2 , pH,
PaO2 ) (313). Consequently, a minor decrease in PaCO2 in the
presence of normoxia can produce central apnea during sleep
(243) and anesthesia (86).
In addition to the automatic controller, the voluntary controller (forebrain) transmits signals to the respiratory system
along neural pathways, some of which can bypass the automatic metabolic controller in the brainstem (58,185,186,216).
These observations raise two points. First, within some range,
awake human subjects can develop a wide variety of breathing patterns at will. Second, when mechanically ventilated,
the manner in which a patient responds to changes in ventilator settings is heavily influenced by how the respiratory
control system responds in different circumstances, including
state of wakefulness or sleep.
Wakefulness drive and behavioral factors
influencing ventilated patients
The pattern of breathing during hypocapnia highlights the importance of cortical-subcortical interactions in the control of
ventilation. Hypocapnia induces recurrent apneas during sleep
and anesthesia (86, 243), but it fails to induce apneas during
wakefulness (56, 207, 235, 311). These observations provide
circumstantial evidence for the existence of a ventilatory oscillator that is sensitive to PCO2 (83) and for a “wakefulness
drive to breathe.” The suprapontine origin of the wakefulness
stimulus is suggested by its disappearance in patients with
forebrain lesions (201). The magnitude of the wakefulness
stimulus is quite variable among healthy subjects (207).
Various forms of mental activity can alter the overall output of the respiratory controller and can influence breath-tobreath variability of breathing pattern (161, 275). In general,
mental activity causes greater alterations of breath-to-breath
variability in tidal volume and expiratory time than in inspiratory time (161). The behavioral response to a given perturbation is also highly varied: the same mechanical stimulus may
elicit respiratory acceleration in some subjects and respiratory
slowing in others (15).
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Behavioral responses to mechanical perturbations are
important determinants of patient-ventilator interactions.
Changes in the mechanical state of the respiratory system during mechanical ventilation are promptly sensed by
mechanoreceptors and relayed to higher brain centers. Alterations in lung volume, flow, and airway pressure are readily
perceived by awake patients and may evoke behavioral respiratory responses, with an intention of preserving a tidal
volume to which one is accustomed, attempting to minimize unpleasant sensations, purposeless panic, and the startle
response—in short, to enhance comfort (313).
Chemical control of breathing during
mechanical ventilation
Changes in PaO2 , PaCO2 , and pH influence respiratory motor output through altered activity of chemoreceptors (54). In
turn, changes in respiratory motor output produce alterations
in blood gas tensions. In general, the chemical feedback system tends to moderate the changes in blood gas tensions that
would otherwise occur as a result of changes in metabolic
rate or the gas-exchanging properties of the respiratory
system (308).
Changes in PaO2 are sensed by the peripheral chemoreceptors, located close to the bifurcation of the common carotid
arteries (54), and also in the rostral ventrolateral medulla,
which responds by increasing ventilation and sympathetic efferent activity (55, 184, 258). The peripheral chemoreceptors
respond to reductions in PaO2 (but not oxygen saturation)
and arterial pH, and an increase in PaCO2 —the latter probably mediated via intracellular acidification. The peripheral
chemoreceptors increase ventilation much more rapidly than
the central chemoreceptors; a lag equal to the circulation time
from the lungs to the carotid body elapses before a change
in PO2 at the lungs begins to influence breathing, and the
half-time response is about 10 s (93). The time constant of
the central chemoreceptors is 75 s (124). Thus, the carotid
bodies offer faster fine tuning of respiratory control than the
central chemoreceptors. Recent research emphasizes the role
of the retrotrapezoid nucleus, located in close proximity to
the ventral surface of the medulla oblongata, which appears
to function generally along the lines previously suggested
for the hypothetical ventral surface chemoreceptors (104).
This nucleus has a dual function: to drive respiration and
to stabilize PCO2 . Neuroanatomical and physiologic findings
from recent research have elucidated how sensory input from
the peripheral chemoreceptors influence the gain of the central chemoreceptors in response to changes in central CO2
(24, 104). The ventilatory response to PaO2 is hyperbolic, being almost flat in the high PaO2 range and the slope increases
progressively as PaO2 decreases (313). The aortic bodies play
a minor role in modulating spontaneous respiratory activity,
although they have a discernible effect when their gain is
increased by hypercapnia (292).
In conscious healthy humans, resting ventilation falls
about 15% in the absence of carotid body activity. The precise
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role of the carotid bodies, however, during natural breathing
is uncertain because hypoxia is rare in healthy subjects and
people survive with few problems when the carotid bodies
are removed (158, 289). Peripheral chemoreceptors are likely
to be more important in hypoxic patients, as demonstrated by
worsening hypercapnia when patients with respiratory failure
breathe a high concentration of oxygen (13,65,70,225). There
is a multiplicative interaction between PCO2 and PO2 at the
carotid bodies, in that the sensitivity to hypoxia is greater
in the presence of hypercapnia and almost disappears during
hypocapnia (89).
An increase in PaCO2 and/or hydrogen ion (with or without hypercapnia) results in an increase in the respiratory motor
output (313). The response is mediated both by peripheral and
central chemoreceptors (54). Studies using carotid body denervation in unanesthetized animals show that the slope of the
steady-state ventilatory response to inhaled CO2 is determined
by a 60% to 80% contribution from central chemoreception
and 20% to 40% contribution from peripheral chemoreception (63). The ventilatory response to CO2 in healthy subjects exhibits a very wide range, 0.47 to 8.16 L/min/mmHg
(110,118,214), although approximately 80% of subjects have
a response between 1.5 and 5 L/min/mmHg (118). The ventilatory response to CO2 is enhanced in the presence of hypoxia
and/or metabolic acidosis (313).
Alterations in ventilatory demand are met through a combination of alterations in tidal volume and respiratory frequency. Hey et al. (107) compared the responses to hypoxia,
hypercapnia, metabolic acidosis, elevated body temperature,
and exercise in healthy subjects. The responses to pyrexia
differed from those to other stimuli in that they were primarily tachypneic in nature. For all other stimuli, increases
in ventilatory demand were met by initial increases in tidal
volume. Respiratory frequency changed little until a much
higher level of respiratory stimulation. Typically a fivefold
increase in minute ventilation (from 8 to 40 L/min) is accomplished through a threefold increase in tidal volume (for
example, from 0.65 to 2.0 L) and only a 50% to 60% increase in respiratory frequency (307). Greater increases in
ventilatory demand are achieved mainly through increases in
respiratory frequency rather than tidal volume.
This pattern of response should be borne in mind when
employing different ventilator modes. With assist-control, if
an increase in ventilatory demand causes a patient to predominantly increase effort per breath, as opposed to respiratory frequency, the ventilator will be unresponsive: tidal
volume is pre-set with this mode, and an increase in patient effort per breath will not produce an increase in minute
ventilation (313). With pressure support, an increase in patient effort per breath will result in increases in tidal volume (33). In contrast, when an increase in ventilatory demand causes a patient to predominantly increase respiratory
frequency, minute ventilation will increase similarly with
both ventilator modes provided the changes in a patient’s
true neural respiratory rate are reflected faithfully in the
ventilator rate.
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The aforementioned responses to hypercapnia and hypoxemia occur in mechanically ventilated patients irrespective of whether they are awake or asleep (313). Responses
to hypocapnia, however, occur only during sleep (and anesthesia) (86, 243) and are not present during wakefulness
(56, 207, 235, 311) (see below). As already stated, hyperoxia
can decrease minute ventilation during wakefulness in hypoxic patients (13, 65, 70, 225).
Control of breathing during hypocapnia Patients receiving mechanical ventilation are commonly exposed to levels
of PaCO2 that extend well into the hypocapnic range. The
ventilatory response to CO2 below resting PCO2 has been the
subject of considerable interest for several decades, and it is
also particularly important in the management of ventilated
patients (54, 63). The behavior of the respiratory controller in
the presence of hypocapnia differs between wakefulness and
sleep, and thus these states will be discussed separately.
Control of breathing during hypocapnia while awake Based
on limited data, it was widely believed in the past that the
ventilatory response to CO2 was discontinuous, and made up
of two segments. Above eupnea, the response was known to be
steep, producing a linear segment. Below eupnea, the response
was viewed as gradually decreasing and then essentially flat.
At the lowest PCO2 , a finite level of rhythmic ventilation
is still observed in awake subjects, which is related to the
wakefulness drive to breathe (313). The terms “hockey-stick”
and “dogleg” were used to describe the configuration of the
two segments, and the intersection was viewed as the normal
resting set point (90) (Fig. 9).
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10
0
20
30
40
50
PACO2 (mmHg)
Figure 9 Schematic representation of the “dogleg” or “hockey-stick”
configuration of the ventilatory response to CO2 during wakefulness. At
alveolar carbon dioxide tension (PACO2 ) levels above eupnea, minute
ventilation increases linearly in proportion to increases in PACO2 . At
PACO2 levels below eupnea, the ventilatory response gradually decreases and becomes essentially flat. [Based on data presented by
Nielsen M, Smith H. Studies on the regulation of respiration in acute
hypoxia. Acta Physiol Scand 1952; 24: 293-313 (182).]
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Change in
frequency (b/m)
dP/dt
(cmH2O.s)
Among investigators who argued for the presence of a
discontinuous “hockey-stick” configuration, some estimated
the apneic threshold by extrapolating the hypercapnic ventilatory response to the zero V̇E intercept (54). Such extrapolation, however, is highly uncertain because of the unknown
shape of the CO2 response near and below eupnea (63, 132).
Other proponents of the “hockey-stick” configuration employed alveolar hypoxia to induce hypocapnia (107, 182)—a
highly problematic approach.
The presence of a “hockey-stick” configuration has been
challenged by several investigators (196, 207, 313). Awake
subjects exhibit CO2 responsiveness over a wide range,
extending down to PaCO2 levels in the low 20s. At the lowest
PCO2 , there remains a finite rhythmic output, and the magnitude of this “minimum” output varies considerably among
subjects (207,313). In 16 healthy awake subjects, Patrick et al.
(196) used assist-control ventilation to induce hypocapnia;
hyperoxia was added to avoid the problem with the older
methodology. All subjects continued rhythmic breathing
despite high tidal volumes and severe hypocapnia (alveolar
PCO2 of approximately 25 mmHg). As inspired CO2 was
increased in steps to increase end-tidal carbon dioxide tension
(PET CO2 ) from about 25 mmHg to about 40 mmHg, respiratory motor output (quantified as muscle pressure) increased
progressively and the slope of the motor response increased.
In contrast, the response of respiratory frequency to increases
in PCO2 was very weak or absent in the hypocapnic range,
and increased significantly only above 36 mmHg (196) (Fig.
10). These observations have particular relevance in the
management of ventilated patients. Contrary to common
assumptions, respiratory frequency did not fall as a result
of negative chemical feedback: decreases in PCO2 down to
25 mmHg had no effect on respiratory frequency (196).
12
8
4
0
1
0
26
28
30
32
34
36
38
40
42
PET CO2 (mmHg)
Figure 10 Contrasting response of respiratory motor output and respiratory frequency over a 15 mmHg variation in PCO2 . Average responses of change in respiratory motor output, quantified as change
in pressure over time (dP/dt), and change in respiratory frequency in
response to changes in end-tidal carbon dioxide tension (PET CO2 ) from
about 26 to 41 mmHg. Respiratory motor output increased progressively in response to increases in PET CO2 , even at hypocapnic levels,
whereas the response of respiratory frequency to change in PET CO2 was
very weak or absent in the hypocapnic range and increased significantly
only when PET CO2 exceeded 36 mmHg. [Adapted, with permission,
from Patrick et al. (196).]
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In further research from the same group, Puddy et al. (207)
studied 18 healthy awake subjects receiving assist-control
ventilation. Ventilator tidal volume was increased in steps
from the minimum tolerable level up to 80% of the subject’s inspiratory capacity or the ventilator’s maximum tidal
volume. Increases in tidal volume were accompanied by little change in respiratory frequency (Fig. 11). The decrease
in respiratory frequency was statistically significant but very
small relative to the increase in tidal volume, approximately
12% versus 100%; consequently, ventilation increased substantially and PET CO2 dropped precipitously (Fig. 11).
The findings of Puddy et al. (207) and Patrick et al. (196)
have been corroborated by other investigators. Lofaso et al.
(155), Morrell et al. (174), and Scheid et al. (229) observed
no significant decrease in respiratory frequency with the addition of pressure support of 10 cmH2 O in awake subjects. Also
using pressure support of approximately 10 cmH2 O, Georgopoulos et al. (95) found that respiratory frequency remained
relatively stable over an even broader range of PET CO2 , 23
to 45 mmHg; frequency increased significantly only when
PET CO2 approached 50 mmHg.
These observations (95, 155, 174, 196, 207, 229) have particular relevance in the management of ventilated patients.
Most patients are ventilated with some assisted mode, where
the patient’s respiratory center output determines the rate of
ventilator triggering. The delivered volume is largely preset, either by a selected volume [assist control (162), IMV
(221)] or by a set level of pressure [pressure support (33)].
If the volume is excessive in relation to a patient’s CO2
stores, contrary to the assumption of many clinicians, respiratory frequency will not fall as a result of negative chemical
feedback. Hypocapnia will follow and the associated respiratory alkalemia can cause cardiac arrhythmias and seizures
(16,133,219). Because tidal volume is preset by the ventilator,
a decrease in respiratory frequency becomes the only means
of guarding against hypocapnia. Many clinicians assume that
a fall in PaCO2 consequent to an increase in delivered tidal
volume will lead to a fall in respiratory frequency as a result
of negative chemical feedback.
An additional factor of considerable clinical importance
is the ventilatory response to hypoxia during acute stable
hypocapnia, which has been investigated by Corne et al.
(52). Stable levels of PET CO2 below eucapnia of 6 mmHg
(mild hypocapnia) and 12 mmHg (moderate hypocapnia)
were achieved in eight healthy subjects using volume-cycled
ventilation. The respiratory motor output response, assessed
in terms of change in muscle pressure (Pmus ), was depressed
during mild hypocapnia versus eucapnia: 0.26 ± 0.33 versus
0.53 ± 0.59 cmH2 O per percentage oxygen saturation
(SaO2 %). During moderate hypocapnia, the Pmus response
was negligible: 0.003 ± 0.09 cmH2 O per SaO2 %—a value
that is not significantly different from zero. Mild and
moderate hypocapnia caused proportional reductions in the
response of respiratory frequency to hypoxia. In all subjects,
including those who displayed a vigorous response to hypoxia
at eucapnia, the hypoxic response was completely ablated
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Respiratory frequency (breaths/min)
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16
12
8
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24
16
8
4
0
0
0.4 0.8 1.2 1.6 2.0 2.4
Tidal volume (L)
f at VT min
14.1 ± 3.9
f at VT max
12.4 ± 4.0
0
0
.
0.4 0.8 1.2 1.6 2.0 2.4
Tidal volume (L)
VE at VT min
13.0 ± 4.2
.
VE at VT max
23.0 ± 7.5
Figure 11 Limited decreases in respiratory frequency in response to increases in ventilator tidal volume. Individual changes in respiratory frequency (left panel) and minute
ventilation (right panel) in healthy subjects as tidal volume was increased from a minimum
to a maximum setting during assist-control ventilation, resulting in tidal volumes of 944 ±
198 and 1867 ± 277 (SD) mL, respectively. The average respiratory frequency and minute
ventilation at the minimum and maximum tidal volume settings are listed below the horizontal axes. Doubling of delivered tidal volumes produced minimal decreases (∼12%) in
respiratory frequency. [Adapted, with permission, from Puddy et al. (207).]
when PET CO2 was reduced by an average of 11 mmHg
below eucapnia. The progressive depression of the hypoxic
response with decreases in PCO2 is of special concern in the
management of ventilated patients because it may prevent
the respiratory motor output from increasing vigorously in
response to a ventilator malfunction, such as a disconnected
circuit, and thus lead to hypoxic brain injury.
Control of breathing during hypocapnia while asleep In
anaesthetized cats, stepwise reductions in PCO2 in the perfusate of the pontomedullary region produced progressive
decreases in tidal volume with no change in breathing stability (19). These data suggest that hypocapnia at the carotid
or central chemoreceptors is not in itself sufficient to cause
apnea (63). Despite these observations, most if not all studies performed in sleeping animals (177) and sleeping humans
(170, 243, 298) support the presence of an apnea-hypopnea
threshold for CO2 .
These data (56, 87, 243) indicate that rhythmic breathing
during sleep is critically dependent on the level of PCO2 in
arterial blood. Reductions in PaCO2 of only a few torr below
the awake, eupneic value consistently produce central apnea
and periodic breathing in sleeping human subjects (157,178).
Moreover, susceptibility to periodic breathing during hypoxia
(146) or in patients with Cheyne-Stokes respiration in congestive heart failure (120, 248, 294) have been shown to coincide
with a relatively high degree of ventilatory responsiveness to
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hypoxia and/or CO2 . Paradoxically, however, driving ventilation higher and reducing steady-state background PaCO2
can also alleviate central apnea and periodic breathing during sleep (22, 59, 121, 259). These two sets of observations
are compatible only if the apneic CO2 threshold changes in
response to sustained hyperventilation.
To investigate this issue, Nakayama et al. (177) used pressure support to increase tidal volume, reduce PaCO2 , and
produce apnea and periodic breathing in sleeping dogs, and
then examined the effects of several respiratory stimuli and inhibitors on the apnea threshold. They used the difference between PET CO2 during eupnea and the PET CO2 that resulted
in apnea (apnea threshold), PET CO2 , as an index of the susceptibility to apnea. During normoxia, apnea occurred when
PET CO2 was decreased from 39 to 34 mmHg (PET CO2 of
−5 mmHg). Changes in background ventilatory drive were
found to alter the apnea threshold and, thus, also the proximity of the spontaneous PCO2 to the apnea threshold. Increased
respiratory motor output induced by metabolic acidosis and
nonhypoxic peripheral chemoreceptor stimulation (almitrine)
produced stable hyperventilation (PET CO2 of 28-29 mmHg).
Apnea occurred when PET CO2 was decreased to 22 mmHg
during metabolic acidosis and to 23 mmHg during almitrine
infusion (PET CO2 −6 mmHg). In other words, increased
respiratory motor output induced by metabolic acidosis or
almitrine produced widening of PET CO2 from −5 mmHg at
baseline to −7 and −6 mmHg, respectively. The exception to
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this pattern was hypoxia that produced stable hyperventilation
(PET CO2 of 31 mmHg). With this background of increased
respiratory motor output, apnea occurred when the PET CO2
was decreased to 27 mmHg, which corresponds to a PET CO2
of −4 mmHg. That is, despite a substantial increase in ventilatory drive and an attendant decrease in spontaneous PaCO2 ,
hypoxia increased the ventilatory sensitivity to CO2 below
eupnea and significantly reduced PET CO2 .
To further define the role of hypoxia in producing central
apnea and periodic breathing, Xie et al. (297) used pressure
support to lower PaCO2 in human subjects during sleep. Pressure support induced hypopneas (failure to trigger the ventilator) and apneas (no breathing effort) in all subjects during
both normoxia and hypoxia (SaO2 80%). Eupneic PET CO2
was 45.0 ± 1.1 mmHg during normoxia and it fell to 42.1 ±
1.4 mmHg during hypoxia. The apnea threshold was equivalent with hypoxia and normoxia (∼41 mmHg), as was the
hypopnea threshold (∼42.5 mmHg). The main determinant of
the development of central apneas and periodic breathing was
PET CO2 , which was 3.4 ± 0.3 mmHg during normoxia and
1.1 ± 0 mmHg during hypoxia (the pattern for the hypopnea
threshold was similar).
Periodic breathing and central apneas are especially common during sleep in patients with congestive heart failure
(120, 121), and studies conducted in these patients have
yielded fundamental insights into the effects of mechanical
ventilation on control of breathing. To investigate the mechanism of breathing instability in patients with heart failure,
Xie et al. (298) recorded PET CO2 during spontaneous breathing and used pressure support to estimate the apnea threshold in 19 stable patients with congestive heart failure, 12
of whom exhibited and 7 of whom did not exhibit central
sleep apnea. The patients without central sleep apnea experienced a significant increase in PET CO2 at the onset of sleep
(of approximately 2.5 mmHg), whereas patients with central
sleep apnea did not. As a result, the difference in PET CO2
between eupnea and the apnea threshold was smaller in the
patients with central sleep apnea than in those without central sleep apnea: −2.8 ± 0.3 versus −5.1 ± 0.7 mmHg. The
ventilatory response to CO2 below eupnea was higher in patients with central sleep apnea than in those without central
sleep apnea: 3.86 ± 0.79 versus 1.47 ± 0.18 L/min/mmHg.
The close proximity of PET CO2 during eupnea to the apnea
threshold makes a transient reduction of PCO2 much more
likely to fall below the apnea threshold, and the increased
ventilatory response to CO2 below eupnea makes the respiratory system more sensitive to any reduction of CO2 —both
factors predisposing to breathing instability. The failure of
PET CO2 to increase during sleep in the patients with central
sleep apnea signifies the presence of some additional ventilatory drive that offsets the removal of “the wakefulness drive
to breathe.” Possibilities include an increase in interstitial
pressure that stimulates pulmonary irritant and juxtacapillary
receptors (96).
In contrast with marked alterations in respiratory motor
output that result from slight reductions in chemoreceptor
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stimulation consequent to very small decreases in PCO2 , large
increases in PO2 have no comparable effects on respiratory
motor output in most patients (63). Induction of a state of
extreme hyperoxia (PaO2 > 500 mmHg) using extracorpeal
perfusion of the isolated carotid body does not produce apnea
(247).
Effect of mechanical ventilation on sleep quality in
critically ill patients
Behavioral factors and the wakefulness drive to breathe can
interfere with patient-ventilator interaction and thus lead to
dysynchrony between the cycling of a ventilator and a patient’s respiratory rhythm. By ablating these stimuli, sleep
might be expected to enhance respiratory muscle rest during
mechanical ventilation (195). Moreover, ventilated patients
experience numerous derangements, including sepsis, abnormal gas exchange, and increased work of breathing, which
may disturb sleep (21, 99). To characterize the extent and nature of sleep disruption in critically ill patients, Cooper et al.
(50) performed polysomnography in 20 mechanically ventilated patients. Eight patients exhibited electrophysiological
features of sleep, and these experienced 42 arousals and awakenings per hour of sleep. This level of sleep fragmentation
is equivalent to that experienced by patients with obstructive sleep apnea who have excessive day-time sleepiness and
impaired cognition (103). Gabor et al. (91) investigated the
factors that might lead to disrupted sleep in ventilated patients
and found that 21% of disrupted sleep resulted from noise and
a further 7% resulted from all medical care. While much of
the unexplained sleep disruption is likely to result from the
underlying illness, operation of the ventilator, and especially
the choice of ventilator mode, may be another contributor.
To address this possibility, Parthasarathy and Tobin (194)
compared the effects of pressure support and assist-control
ventilation on sleep in 11 critically ill patients. Six patients
developed central apneas during pressure support, but not during assist-control by virtue of the backup rate (Fig. 12). The
occurrence of apneas during pressure support was not related
to tidal volume, as the pressure level was titrated to achieve
a tidal volume equivalent to that during assist-control ventilation (8 mL/kg). Sleep fragmentation, measured as the sum
of arousals and awakenings, was greater during pressure support than during assist-control: 79 ± 7 versus 54 ± 7 events
per hour. Disturbed sleep during pressure support was related
to the development of central apneas (r = 0.57), which in
turn was significantly related to PET CO2 (r = −0.83) (Fig.
13). PET CO2 was the most important determinant for the
development of apneas: as PET CO2 grew wider, the number of central apneas decreased. The addition of 100 mL of
dead space to the ventilator circuit in the six patients who
developed apneas produced a 4.3 mmHg increase in end-tidal
CO2 , decreased the frequency of central apneas, from 53 to
4 apneas/h, and the frequency of arousals and awakenings,
from 83 to 44 events/h. This study shows that while critically ill patients have a background level of sleep disturbance,
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Assist control
Pressure support
C -A1
4
O3-A2
ROC
LOC
Chin
Leg
VT
RC
AB
1 min
Figure 12 Polysomnographic tracings during assist-control ventilation and
pressure support in a representative patient. Electroencephalogram (C4 -A1 , O3 A2 ), electrooculogram (ROC, LOC), electromyograms (Chin and Leg), integrated
tidal volume (V T ), rib-cage (RC), and abdominal (AB) excursions on respiratory
inductive plethysmography are shown. Arousals and awakenings, indicated by
horizontal bars, were more numerous during pressure support than during assistcontrol ventilation. [Adapted, with permission, from Parthasarathy S and Tobin
MJ. Effect of ventilator mode on sleep quality in critically ill patients. Am J Respir
Crit Care Med 166: 1423-1429, 2002 (194).]
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No dead space
Dead space
8
PETCO2 minus apnea threshold (mmHg)
secondary to factors such as pain, medications, staff interruptions, noise and light, the mode of mechanical ventilation can
further aggravate sleep disruption.
The observation that ventilator mode can aggravate sleep
disruption was confirmed by Bosma et al. (26). These investigators performed polysomnography in 13 ventilated patients
who received pressure-support ventilation or proportional assist ventilation (PAV) according to a randomized crossover
design. (PAV is a form of synchronized ventilator support
in which the ventilator generates pressure in proportion to instantaneous patient effort while correcting for respiratory system elastance and resistance.) The two modes were adjusted
to achieve a similar degree of inspiratory muscle unloading.
Pressure support of 9.2 ± 2.8 cmH2 O achieved a 54 ± 3% decrease in pressure-time product per minute. The resistive and
elastic proportionality factors were adjusted during PAV to obtain a 53 ± 5% decrease in pressure-time product per minute.
At these settings, tidal volume was higher with pressure support than with PAV: 0.63 ± 0.13 versus 0.59±0.13 L (SD).
End-tidal CO2 for the entire night was lower with pressure
support than with PAV: 37.3 ± 5.3 versus 39.4 ± 6.8 mmHg
(P < 0.05). Overall sleep quality was significantly inferior
with pressure support. More arousals occurred with pressure
support than with PAV: median (range) of 16 (2–74) versus
9 (1–41) per hour of sleep. Awakenings were greater with
pressure support than with PAV: 5.5 (1–24) versus 3.5 (0–24)
per hour. Patient-ventilator asynchronies per hour were also
greater with pressure support than with PAV: 53 ± 59 versus
24 ± 15. Moreover, the number of patient-ventilator asynchronies per hour correlated significantly with the number of
6
r = –0.83
P < 0.001
4
2
0
–2
–4
–6
0
40
80
Central apneas per hour
Figure 13 The difference between the average end-tidal CO2 and
the apnea threshold plotted against the number of central apneas per
hour of pressure support alone (closed symbols) and pressure support
with added dead space (open symbols) in six patients. The average
end-tidal CO2 was measured during both sleep and wakefulness. The
mean number of central apneas per hour was strongly correlated with
the end-tidal CO2 during a mixture of both sleep and wakefulness
(including the transitions between sleep and wakefulness) (r = −0.83,
P < 0.001). [Adapted, with permission, from Parthasarathy S and Tobin
MJ. Effect of ventilator mode on sleep quality in critically ill patients.
Am J Respir Crit Care Med 166: 1423-1429, 2002 (194).]
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arousals per hour (r2 = 0.71). In brief, for an equivalent degree
of inspiratory muscle unloading, sleep was more fragmented
with pressure support than with PAV, and the poorer quality of
sleep was related to increased patient-ventilator dysynchrony
with pressure support.
Cabello et al. (40) undertook polysomnography in 15
mechanically ventilated patients and compared sleep quality while patients were randomized between assist-control
ventilation, pressure support set by the patient’s attending
physician, and pressure support continuously adjusted by
a closed-loop knowledge-based system. Sleep architecture,
sleep quantity, and sleep fragmentation were equivalent with
the three ventilator modes. The findings differ from those
reported by Parthasarathy and Tobin (194) in part because
of the method of selecting tidal volume in the study of Cabello et al. (40). A tidal volume of 8 mL/kg was employed
during assist-control ventilation, whereas a tidal volume between 6 and 8 mL/kg was targeted during pressure support
(40). The median (25-75th percentile) tidal volumes were
500 mL (380-500) during assist-control ventilation, 450 mL
(357-521) during clinician-adjusted pressure support, and 390
mL (330-492) during automated pressure support. The findings of these three studies of mechanical ventilation during
sleep in critically ill patients suggest that pressure support,
when carefully adjusted to avoid hyperventilation, does not
increase the amount of sleep fragmentation over that experienced with assist-control ventilation. If, however, pressure
support is set in the manner of everyday clinical practice, it is
likely to lead to sleep fragmentation (26, 194).
The findings of Parthasarathy and Tobin (194) carry important implications for how physicians set the ventilator.
Compared to wakefulness, sleep lowered respiratory rate by
32.6 ± 6.1% during pressure support and by 14.9 ± 3.2%
during assist-control. Likewise, sleep raised end-tidal CO2
by 11.0 ± 2.3% during pressure support and by 4.6 ± 1.8%
during assist-control ventilation. In clinical practice, the level
of pressure support is typically adjusted in accordance with a
patient’s respiratory rate, which provides reasonable guidance
as to a patient’s inspiratory effort (129). Pressure is commonly
titrated during the daytime without the clinician being sure
whether the patient is asleep or awake. If the patient is asleep
at the time of the adjustment, a point at which respiratory rate
will be relatively low, then, on awakening, the increase in a
patient’s rate may cause a considerable increase in effort.
Ventilator-induced neuromechanical inhibition
When assisted ventilation is used to progressively increase
tidal volume, apnea results during sleep when PaCO2 is lowered by as little as 2 mmHg over 2-3 breaths (63). Even
in the absence of hypocapnia, Dempsey and colleagues have
demonstrated that positive-pressure ventilation can induce inhibition of the respiratory centers and even apnea in animals
and human subjects during nonrapid eye movement (NREM)
sleep (106, 148, 163, 228, 295). These investigators argue that
mechanical ventilation can markedly inhibit or even elimi-
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nate respiratory motor output solely as a result of alterations
in mechanoreceptors in the lungs or chest wall—so-called
neuromechanical inhibition (64). Neuromechanical inhibition is manifested as changes in the amplitude of respiratory
motor output, 20% to 60% decreases in the diaphragmatic
electromyogram (Edi ), transdiaphragmatic pressure (Pdi ),
and respiratory timing, and prolonged expiratory time and
apnea (64).
In sleeping (228) or lightly anesthetized animals (136),
a single ventilator breath can produce a prolonged expiratory time when the breath is delivered during the “inflationsensitive” phase of expiration. When a single breath is applied in the first 25% to 65% of expiration, the resumption of
diaphragmatic electromyographic (EMG) activity is delayed
and expiratory time is prolonged; the effect on expiratory
prolongation is increased when the tidal volume of the single
breath is 75% to 150% of eupneic tidal volume—the greater
the tidal volume, the greater the expiratory time prolongation (228). A ventilator breath that is about half eupneic tidal
volume does not significantly prolong expiratory time (228).
When a single ventilator breath of any volume is applied in the
last 25% of expiration, expiratory time does not change (228).
Application of a ventilator breath in the 65% to 75% range of
expiratory time has a variable effect—expiratory time may be
prolonged, shortened or unchanged (228). A single ventilator
breath alters only the expiratory time of the perturbed breath
and does not affect the next respiratory cycle (228).
In sleeping humans during normocapnic conditions, Rice
et al. (215) studied the effect of increased tidal volume, with
and without increases in respiratory rate, through the respective use of controlled and assist-control ventilation. During
and after assist-control ventilation, an increase in tidal volume
to 135% to 220% of the eupneic value never completely eliminated inspiratory motor output and expiratory time was only
slightly (although significantly) prolonged. During controlled
mechanical ventilation, in contrast, an increase in respiratory
rate by 1-3 breaths/min above the mean eupneic value and an
increase in tidal volume to 165% to 200% of the baseline eupneic value eliminated inspiratory motor output at the cessation
of mechanical ventilation, and expiratory time was prolonged
by two to four times the control value (215). (The prolongation of expiratory time with assist-control ventilation was less
than 20%-25% of the prolongation observed after controlled
ventilation at comparable increases in tidal volume.) These
results suggest that the combination of increases in respiratory rate in combination with (moderate) elevations in tidal
volume during mechanical ventilation can reset respiratory
rhythm and inhibit respiratory motor output more than that
achieved by increases in tidal volume alone.
The duration of apnea following the cessation of normocapnic controlled ventilation is influenced by several factors.
One, apnea duration is proportional to the increase in ventilator tidal volume (once inspiratory motor output has been
silenced by an increase in ventilator frequency) (228, 295).
Two, apnea duration increases in proportion to the duration of
the passive controlled ventilation, at least up to about 1 min of
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controlled ventilation (228). The latter response is similar to
the prolongation of expiratory time that occurs after repeated
electrical stimulation of vagal or superior laryngeal nerves,
where expiratory duration is proportional to the duration of
the phasic sensory input (315). Three, controlled ventilation at
an increased frequency can eliminate respiratory motor output
even when PaCO2 is as much as 5 mmHg above normocapnia (228); postventilator apneas occur in the presence of such
hypercapnia, however, only when the ventilator tidal volume
is much higher than eupneic tidal volume (64).
Why does a constant ventilator frequency (above the
average eupneic frequency) cause silencing of the diaphragmatic EMG? A single ventilator breath affects the
respiratory controller only if it is delivered during the
“inflation-sensitive” phase of the respiratory cycle (136).
For each repeated ventilator breath to be delivered precisely
during the inflation-sensitive phase is unlikely unless the
inflation-sensitive phase becomes prolonged. Dempsey and
Skatrud postulated that such prolongation might result from
a cumulative carryover of an inhibitory influence, which in
effect would widen the inflation-sensitive phase as controlled
ventilation is continued beyond the first delivered breath
(64). In support of such a cumulative effect are the observations that the duration of postventilator apneas during normocapnic mechanical ventilation is dependent on the total
number of ventilator cycles and the amplitude of their tidal
volume (148, 228).
The mechanisms responsible for the inhibitory aftereffects of normocapnic mechanical ventilation are not precisely known. It has been reasoned that the means of informing
the respiratory controller of the adequacy of ventilation must
involve neurally mediated sensory information (concerning
pressure, volume, and/or muscle tension) from one or more
sites of mechanoreception (136, 148, 156, 239). The sustained
inhibition of respiratory motor output in animals and humans does not appear to involve vagal or intercostal afferents
(148, 238). When a sensory stimulus is delivered, several investigators have documented that changes in synaptic efficacy
persist beyond the duration of the stimulus (321). Recordings
from the nucleus of the solitary tract show that potentiation
of synaptic input to these neurons enhances inhibitory outflow and reduces the neuronal response to subsequent afferent
chemoreceptor input (171). Accordingly, the apneas that follow mechanical ventilation may reflect an imbalance between
a dominant continued short-term suppression of inspiratory
motor output and a rise in chemoreceptor input as asphyxia
intensifies during the postventilator apnea (64). Dempsey has
argued that the resumption of normal rhythm following the
apneas must represent the eventual dominance of the excitatory chemoreceptor input over the continued “inertia” of
central respiratory motor neurons; even at these high levels
of PaCO2 (and reduced PO2 ), however, a central inhibitory
effect is still present as indicated by the reduced amplitude
and gradual recovery of successive spontaneous breaths (64).
The occurrence of apnea following the cessation of (normocapnic) controlled ventilation supports the concept of
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strong central “inhibitory memory” effects imposed by repetitive mechanoreceptor feedback (228). Satoh et al. (228) commented that the apnea induced by controlled ventilation resembles the prolonged apneas in patients with central sleep
apnea, which often last well beyond the normal threshold for
chemoreceptor excitation. Once the medullary rhythm generator is silenced by mechanical or chemical mechanisms, the
respiratory rhythm is not easily restored (228).
It is possible that mechanical feedback linked to ventilator frequency plays an important role in the resetting of the
natural breathing cycle. If resetting of respiratory rhythm is
sufficiently strong, Puddy and co-workers (207) postulated
that increased ventilator frequency may cause apnea by “superseding” the inherent rhythm—a case of where the tidal
volume and rate set on the ventilator exceed the tidal volume and frequency demands of the patient—as opposed to
reflecting the action of a built-in inhibitory neural mechanical
feedback that suppresses ventilatory drive. It should be noted,
however, that use of an augmented tidal volume can in itself
inhibit respiratory motor output.
Studies demonstrating neuromechanical inhibition have
been largely, although not exclusively (149), conducted during sleep to eliminate the confounding influence of behavioral
responses. When healthy subjects received controlled mechanical ventilation during wakefulness, Puddy et al. (207)
found little evidence of neuromechanical inhibition. The investigators maintain that the apneas were confined to circumstances where the subject remained passive and both the
delivered tidal volume and mandatory ventilator frequency
exceeded the subject’s tidal volume and frequency demands
at that moment. It should be noted, however, that Puddy
et al. (207) did not control for end-tidal PCO2 in their experiments. Despite the presence of hypocapnia, awake subjects did not experience postventilator apnea, which suggests that behavioral influences played an important role.
Neuromechanical inhibition has been mainly documented
in instances where hyperventilation has been passively induced; apneas, however, have also been observed during
sleep when a transient ventilatory overshoot and hypocapnia were elicited through the release of a brief airway occlusion (mimicking obstructed apnea) (115) and with the
use of pressure support to increase tidal volume and reduce
PaCO2 (297).
In six healthy subjects, Sharshar et al. (234) investigated
excitability of the diaphragmatic motor cortex by measuring
diaphragmatic motor-evoked potentials elicited by transcranial magnetic stimulation during isocapnic volume-cycled
ventilation. Isocapnic volume-cycled ventilation produced
a decrease in the motor-evoked potentials elicited by
transcranial magnetic stimulation, but not in those elicited
by phrenic-nerve stimulation. These results suggest that
isocapnic volume-cycled ventilation causes depression of the
diaphragmatic motor cortex. Whether or not the observed
depression is another manifestation of the neuromechanical
inhibition reported by Dempsey and colleagues remains to be
determined.
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Flow delivery
Paw
cmH2O
I-E switchover
5
0
Triggering
250 ms
Figure 14 Three points at which patient-ventilator dysynchrony may
arise: point of triggering (cycling-on function), inspiratory flow delivery
(posttrigger inflation), and the point of switchover between inspiration
and expiration (cycling-off function). Each is discussed in the text.
Patient-ventilator dysynchrony
For effective unloading of the inspiratory muscles, the ventilator should cycle in synchrony with the patient’s central respiratory rhythm (266). Dysynchrony may originate at several
points in the cycling of the two pumps (192) (Fig. 14). If the
onset of machine assistance lags significantly behind the commencement of patient inspiratory muscle activity (trigger delay), the ventilator’s ability to produce respiratory muscle rest
is markedly impaired (152, 220). Inadequate respiratory muscle rest may also result from failure of the gas-delivery system
to meet a patient’s inspiratory flow demands (165, 220, 288).
Most studies of patient-ventilator dysynchrony have focused
on these two inspiratory phenomena, and scant attention has
been paid to expiratory events during ventilation. Depending on the algorithm used for “cycling off” of the ventilator,
recruitment of the expiratory muscles can occur during mechanical inflation (129). A final source of dysynchrony is a
delay in the termination of a patient’s expiratory muscle activity before the onset of the next mechanical inflation. All of
the foregoing considerations are further complicated by the
recognition that the inspiratory and expiratory muscle groups
can contract simultaneously (66).
Framework for evaluating patient-ventilator
interaction
The interplay between a patient and a ventilator depends on
a number of factors, and, most importantly, the physiologic
characteristics of a given patient. During mechanical ventilation, the total pressure applied to the respiratory system
(Ptotal ) is the sum of the pressure provided by the ventilator
(Paw ) and the pressure generated by the patient’s respiratory
muscles (Pmus ) (264). Thus, at any time, (t), from the onset of
inspiratory flow,
Ptotal(t) = Paw(t) + Pmus(t)
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The fundamental relationship between the patient and the
ventilator is contained in the equation of motion. At a given
moment, the total pressure applied to the respiratory system
is balanced by (or dissipated against) the opposing forces
produced by the resistive and elastic properties of the respiratory system—assuming that inertia is negligible. The pressure
dissipated against resistance (Pres ) is a function of the instantaneous rate of flow [Pres = f (V̇ )] (308). The pressure dissipated against the elastic properties (Pel ) at a given moment is a
function of how far respiratory volume is from the relaxation
volume of the respiratory system (FRC) as opposed to the
volume inhaled. For ease of convenience, the function of volume that defines the instantaneous elastic recoil [Pel = f (V)]
is commonly considered as a constant (elastance), describing
recoil pressure per unit of volume above FRC. This approach
may be reasonable in a healthy subject during resting ventilation, because the usual tidal volume of 400 mL constitutes
a small fraction of vital capacity, and it is positioned on the
linear portion of the sigmoid pressure-volume relationship of
the respiratory system. The approach can be very misleading
in ventilated patients, where set tidal volume (600-800 mL)
may take up half or more of vital capacity and the delivered
volume may be located close to TLC, consequent to dynamic
hyperinflation, or be located close to residual volume, consequent to abdominal distention or obesity. At both extremes,
the pressure-volume relationship is grossly nonlinear. As a
result of these influences, the total pressure applied to the
respiratory system (Ptotal (t) ) can be calculated as:
Ptotal(t) = V̇(t) · Rrs + V(t) · E rs
where Rrs is the resistance and Ers the elastance of the respiratory system, and V̇ (t) and V (t) are, respectively, instantaneous
inspiratory flow and volume above passive FRC at time t from
the onset of inspiration. The values of Rrs and Ers are readily measured during passive mechanical ventilation using the
end-inspiratory occlusion technique (38).
The response of a patient to the institution of mechanical
ventilation depends on the patient’s breathing pattern, which
in turn depends on the degree of chemoreceptor stimulation
secondary to hypoxia or hypercapnia, the degree of agitation
secondary to mechanical derangements of respiratory function, the degree of respiratory muscle weakness, systemic
disorders, medications that have been administered (such as
sedatives), and many other factors.
Point of triggering (cycling-on function)
Most ventilators contain a demand valve and deliver positivepressure assistance whenever a patient’s inspiratory effort
decreases pressure in the ventilator circuit by 1-2 cmH2 O
(Fig. 15). The latter value, selected by a clinician, is termed
the set sensitivity (223). Patients reach the set sensitivity by
activating their inspiratory muscles. For a given trigger sensitivity, the delay between onset of patient inspiratory effort
and onset of ventilator assistance is a function of a patient’s
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20
Onset inspiratory effort
r = 0.78
Valve opening
Patient effort during
ventilator assistance (cmH2O.s)
I:E flow switch
Flow
(L/s)
1
0
Pes
cmH2O
Paw
cmH2O
–1
20
10
0
–5
15
10
5
0
10
0
–5
0
0
1
2
3
4
Time (s)
Figure 15 Patient effort related to ventilator triggering. Tracings of
flow, airway pressure (Paw ), and esophageal pressure (Pes ) in a patient
receiving the volume-cycled form of assist-control ventilation. The vertical blue line represents the onset of patient inspiratory effort, the vertical
red line represents the onset of flow delivery (opening of the ventilator
valve), and the vertical green line represents the transition from inspiratory flow to expiratory flow; the dashed tracing above the Pes recording
on the bottom panel is an estimate of the patient’s chest-wall recoil
pressure, measured during passive ventilation. The effort of triggering
is divided into two phases. First, the effort of the trigger phase (single hatched area). Second, the effort of the posttrigger phase (double
hatched area) is the area enclosed between esophageal pressure and
estimated chest-wall recoil pressure between the onset of flow delivery
and the switch from inspiratory flow to expiratory flow.
respiratory motor output. When a patient’s respiratory drive is
low, assistance may not begin until well into the patient’s inspiratory time, thereby causing the ventilator to cycle almost
completely out of phase with the patient’s respiratory cycle. If
respiratory motor output is extremely low, no triggering may
take place and the ventilator will operate at the backup rate
(controlled ventilation) much or all the time.
When the threshold to open the demand valve is reached
and the ventilator starts to provide positive-pressure assistance, the inspiratory neurons do not simply switch off,
and a patient may expend considerable inspiratory effort
throughout the machine-cycled inflation (165). The level
of patient effort during this posttrigger phase is closely
related to a patient’s respiratory motor output at the point of
triggering (152) (Fig. 16).
If respiratory motor output at the point of triggering is
important, one might intuitively expect that effort during the
time of triggering would determine patient effort during the
remainder of inspiration. Such an association was suggested
by Giuliani and co-workers (98). To investigate this issue,
Leung and co-workers (152) applied graded levels of pressure
support in 11 critically ill patients. They achieved a fourfold
reduction in overall patient effort as compared with unas-
Volume 2, October 2012
20
40
60
Respiratory motor output (cmH2O.s)
Figure 16 Patient effort during the time that the ventilator is delivering a breath (measured as inspiratory pressure-time product per breath
in cmH2 O.s) is closely related to a patient’s respiratory motor output
(measured as dP/dt in cmH2 O.s) at the moment that a patient triggers the ventilator (r = 0.78). The inspiratory muscles of a patient who
has a low respiratory drive at the time of triggering the ventilator will
perform very little work during the remainder of inspiration when the
ventilator is providing assistance. Conversely, the inspiratory muscles
of a patient who has a high respiratory drive will expend considerable
effort throughout the period of inspiration even though the mechanical
ventilator is providing assistance. [Based on data published in Leung
P, Jubran A and Tobin MJ. Comparison of assisted ventilator modes
on triggering, patient effort, and dyspnea. Am J Respir Crit Care Med
155: 1940-1948, 1997 (152).]
sisted breathing. Yet patient effort during the time of triggering did not change. The constancy of effort during the trigger
phase was probably secondary to different factors becoming operational as the level of ventilator assistance was varied
(Fig. 17). When patients were receiving a low level of pressure
support, their respiratory motor output was high and the time
to trigger the machine was short; as a result, they generated
large swings in intrathoracic pressure over a short time. When
patients received a high level of pressure support, their respiratory motor output was lower but more time was needed to
trigger the machine; as a result, they generated much smaller
swings in intrathoracic pressure, but over a longer time. Thus,
increases in the level of ventilator assistance do not substantially decrease patient effort during the time of triggering.
Opening a demand valve during pressure triggering can
impose substantial effort (223). In an attempt to overcome this
problem, flow triggering was introduced. With this approach,
the ventilator is triggered when a patient’s effort creates a
difference between the inspiratory and expiratory base flow
in the circuit. Aslanian and co-workers (12) found that the
time required for triggering was 43% less with flow triggering than with pressure triggering, and effort during the time
of triggering was decreased by 62%. Patient effort during the
posttriggering phase, however, was equivalent for pressure
and flow triggering. As a result, the overall effect on total
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15
cmH2O.s
40
Total PTP
dP/ dt
20
0
cmH2O.s
10
Seconds
0.6
5
Trigger PTP
0
0.3
Trigger time
0
0
20
40
60
80
100
0
20
40
60
80
100
Pressure support (%)
Figure 17 Graded increases in pressure support produced a decrease in total pressure-time product (PTP) per breath
(closed symbols), whereas PTP during the trigger phase (open symbols) did not change (left panel). The constancy of
PTP during triggering probably resulted from different factors becoming operational at different levels of assistance (right
panel). At low levels of pressure support, respiratory motor output (dP/dt) and intrinsic positive end-expiratory pressure
(PEEPi ) were high but triggering time was short, resulting in a large change in pleural pressure over a brief interval. At high
levels of pressure support, dP/dt and PEEPi were low but triggering time was long, resulting in a smaller change in pleural
pressure over a longer time. [Adapted, with permission, from Leung P, Jubran A and Tobin MJ. Comparison of assisted
ventilator modes on triggering, patient effort, and dyspnea. Am J Respir Crit Care Med 155: 1940-1948, 1997 (152).]
patient effort was small, and the clinical benefit of flow triggering appears to be much less than commonly stated.
Most studies of patient-ventilator interaction have been
based on indirect measurements, where the onset and offset of
respiratory muscle activity have been estimated from recordings of airflow combined with airway, esophageal pressure,
and transdiaphragmatic pressures (32, 129, 165, 223, 262).
Parthasarathy et al. systematically evaluated the concordance
between such indirect estimates and a more direct measurement of neural activity, namely, the crural Edi (193). Estimates of the duration of inspiration based on flow, esophageal
pressure, and transdiaphragmatic pressures revealed substantial differences from the time durations measured with the
Edi . The average differences (bias error) ranged from −52 to
714 ms. The standard deviation of these differences ranged
from 74 to 221 ms. When inspiratory time measured on the
recording of the Edi was taken as the reference standard, the
inspiratory time estimated from the transdiaphragmatic pressure (from the initial deflection of the signal until the signal
returns to baseline) had a mean difference of 57% from the
reference value and a scatter of 87% (Fig. 18).
Such discrepancies can adversely affect the operation of
the ventilator. Because a ventilator algorithm is based on
recordings of flow and airway pressure, errors in estimating
the onset of inspiratory time may give rise to delay in triggering, and errors in estimating the duration of inspiratory time
that may cause mechanical inflation to persist into expiration.
A delay in opening of the inspiratory valve may arise from
a decreased respiratory motor output (152, 262) or increased
2892
intrinsic PEEP (PEEPi ) (9, 193). In five critically ill patients,
significant delays were noted between the onset of patient
inspiratory effort (measured by crural Edi ) and the onset of
inspiratory flow (193) (Fig. 19). The delay between the onset
of inspiratory effort and the time the ventilator was triggered
was correlated with the level of PEEPi of the breaths (r =
0.59). This observation suggests that when elastic recoil pressure at the end of expiration is high, the subsequent inspiratory
effort also needs to be proportionally increased if the ventilator is to be successfully triggered. A ventilator that is designed
to sense the patient’s effort at a neural level (Edi ) instead of
sensing the final result of patient effort (changes in airway
pressure or flow) should achieve better patient-ventilator synchrony (240). A new mode, neurally adjusted ventilator assist
(NAVA) (240), shows promise in that regard. The machine
has yet to undergo rigorous evaluation in the ICU.
Failure to trigger
When receiving high levels of pressure support or assistcontrol ventilation, a quarter to a third of a patient’s
inspiratory efforts may fail to trigger the machine (152)
(Fig. 20). The number of ineffective triggering attempts
increases in direct proportion to the level of ventilator assistance (152). In a study of factors contributing to ineffective
triggering, a decrease in the magnitude of inspiratory effort
at a given level of assistance was not the cause; indeed, effort
was 38% higher during nontriggering attempts than during
the triggering phase of attempts that successfully opened the
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0.5
360
Raw Edi
(arb. units)
Phase angle (degrees)
240
–0.5
0.5
Processed Edi
(arb. units)
–0.5
0.5
–120
–360
Pes
(arb. units)
Flow
Pdi
Figure 19 The phase angle between the indirect estimate of the on-
–0.5
–90
0
180
360
degrees
25
0
–25
2
Flow
(L/s)
0
–240
MA Edi
Pes
(cmH2O)
120
set of neural inspiratory time and its reference measurement in five
patients during mechanical ventilation; estimates from the esophageal
pressure (Pes ) tracings are shown as closed squares, estimates from
flow tracings are shown as closed circles, and estimates from transdiaphragmatic pressure (Pdi ) tracings are shown as closed triangles.
The closed symbols represent the mean difference (bias) in phase angle; the open symbols to the right of each closed symbol represent
the mean difference between the two measurements noted during the
reproducibility testing of the reference measurement. The error bars
represent ±2 SD (twice the precision). A positive phase angle indicates
a delay in the onset of neural inspiratory time for the flow-based measurements. [Modified, with permission, from Parthasarathy S, Jubran
A and Tobin MJ. Assessment of neural inspiratory time in ventilatorsupported patients. Am J Respir Crit Care Med 162: 546-552, 2000
(193).]
0
–2
Figure 18 Estimations of the duration of neural inspiratory time.
Representative tracings of the raw crural diaphragmatic electromyogram (Edi ), the processed Edi achieved by removing electrocardiography (EKG) artifacts by computer, the moving average (MA) of the
processed Edi , esophageal pressure (Pes ), and flow in a patient breathing spontaneously. The relationship between an indirect estimate of
the onset of neural inspiratory time and its onset on the diaphragmatic
EMG signal was assessed by calculation of the phase angle, expressed
in degrees. In this example, the onset of inspiratory time is estimated
as occurring earlier (negative phase angle of 15◦ ) by esophageal
pressure-based measurements and later (positive phase angle of 110◦ )
by flow-based measurements. The duration of inspiratory time as estimated by esophageal pressure (hatched horizontal bar) is longer than
the true inspiratory time measured by diaphragmatic electromyogram
(note that the hatched bar is wider than 0-360◦ on the solid black
bar of the reference measurement). The duration of inspiratory time
as estimated by flow-based measurements is shorter (clear horizontal
bar) than the true inspiratory time measured by diaphragmatic electromyogram (note that the open white bar is narrower than 0-360◦
on the solid black bar of the reference measurement). [Adapted, with
permission, from Parthasarathy S, Jubran A and Tobin MJ. Assessment
of neural inspiratory time in ventilator-supported patients. Am J Respir
Crit Care Med 162: 546-552, 2000 (193).]
Volume 2, October 2012
ventilator valve (152). Significant differences, however, were
noted in the characteristics of the breaths before the triggering
and nontriggering attempts. Breaths before nontriggering
attempts had a higher tidal volume than did the breaths before
triggering attempts, 486 ± 19 and 444 ± 16 mL, respectively,
and a shorter expiratory time, 1.02 ± 0.04 and 1.24 ± 0.03 s,
respectively. An abbreviated expiratory time does not allow
the lung to return to its relaxation volume, leading to an
increase in elastic recoil pressure. Indeed, PEEPi was higher
at the onset of nontriggering attempts than at triggering
attempts: 4.22 ± 0.26 and 3.25 ± 0.23 cmH2 O, respectively.
Thus, nontriggering results from premature inspiratory
efforts that are not sufficient to overcome the increased
elastic recoil associated with dynamic hyperinflation (152).
When triggering fails as a result of dynamic hyperinflation, the nontriggering on that breath allows the lungs to more
completely empty in preparation for the next breath. Occasionally, two or three failed triggering attempts take place
before triggering becomes successful. Because there is no
lung inflation during a failed triggering attempt, mechanical exhalation continues for a longer time and end-expiratory
volume continues to fall until triggering becomes successful.
This pattern may occur repeatedly such that it resembles the
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Flow
(L/s)
1.5
I
0
Flow
Paw
cmH2O
–1.5
50
E
0
Radians
–50
20
Pes
cmH2O
0
–90 0
90 180 270 360
Mechanical
0
Subject 1, 60°
–20
0
5
10
15
20
25
Time (s)
Transversus
abdominis
EMG
Subject 2, –45°
Figure 20 Failure to trigger the ventilator. Flow, airway pressure
(Paw ) and esophageal pressure (Pes ) in a patient with COPD who is
receiving assist-control ventilation at the following settings: tidal volume 600 mL, inspiratory flow 60 L/min, trigger sensitivity −2 cmH2 O
and positive end-expiratory pressure 0 cmH2 O. The patient’s intrinsic
respiratory rate is 28 breaths/min, whereas the number of breaths delivered by the ventilator is 16 breaths/min. That is, 43% of the patient’s
inspiratory efforts fail to trigger ventilator assistance. Contractions of
the inspiratory muscles during the failed triggering attempts cause a
temporary deceleration of expiratory flow and much less obvious decreases in airway pressure. The temporary decelerations in expiratory
flow are followed by temporary accelerations of expiratory flow that
coincide with the termination of the unsuccessful inspiratory effort.
Wenckebach pattern of atrioventricular block on an electrocardiograph (EKG) (313).
In addition to increase in elastic recoil pressure (152), an
elevated PEEPi can also result from an increase in expiratory muscle activity. Parthasarathy et al. (192) investigated
the relative contributions of these two factors to ineffective
triggering in healthy subjects receiving pressure support, in
whom they induced airflow limitation with a Starling resistor.
The phase relationship of the “on-switch” and “off-switch” of
pertinent muscles with cycling of the ventilator was defined
using wire electrodes to obtain electromyographic recordings of the diaphragmatic crura and transversus abdominis
muscles. The degree of nonsynchronization between the machine and the patient was expressed in terms of phase angle
(θ ) (198). When the start of the transversus abdominis EMG
signal coincides with the end of mechanical inflation, phase
angle is zero; when the transversus abdominis EMG activity
starts after the end of mechanical inflation, phase angle has
a positive value; and when the transversus abdominis EMG
activity starts before the end of mechanical inflation, phase
angle has negative units (Fig. 21).
All nine subjects exhibited nontriggering efforts, and these
were more frequent at a pressure support of 10 and 20 cmH2 O
than at 0 cmH2 O (Fig. 22). The phase angle of the nontriggering attempts was more negative than that of the attempts
that successfully triggered the ventilator: −32.6 ± 3.1 versus −12.6 ± 1.8◦ (P = 0.0002) at a pressure support of
10 cmH2 O, and −50 ± 9.4◦ versus −19.1 ± 3.4◦ (P = 0.01)
2894
Figure 21 The concordance between neural expiratory time and
mechanical expiratory time can be quantified in terms of the phase
angle, expressed in degrees. If neural activity begins simultaneously
with the machine, the phase angle (θ ) is zero. Neural activity beginning after the offset of mechanical inflation results in a positive phase
angle (60◦ for Subject 1). Neural activity beginning before the onset
of mechanical inflation results in a negative phase angle (−45◦ for
Subject 2). [Adapted, with permission, from Parthasarathy S, Jubran
A and Tobin MJ. Cycling of inspiratory and expiratory muscle groups
with the ventilator in airflow limitation. Am J Respir Crit Care Med 158:
1471-1478, 1998 (192).]
at a pressure support of 20 cmH2 O. That is, the length of
time that the expiratory muscles had been active before the
cycling-off of mechanical inflation was longer for nontriggering attempts than for triggering attempts. In other words,
mechanical inflation continued into neural expiration for a
longer time before the failed triggering attempts than before the successful triggering attempts. Such continuation of
mechanical inflation into neural expiration not only directly
counters expiratory flow but also decreases the time available
for unopposed expiratory flow. This leads to an increase in
elastic recoil at the start of the ensuing inspiration, which
in turn necessitates a greater inspiratory effort to achieve effective triggering of the ventilator (105). In this way, the
time that a patient commences an expiratory effort (in relation to cycling-off of mechanical inflation) partly determines
the success of the ensuing inspiratory effort in triggering the
ventilator.
Double triggering
Some patients exhibit two mechanical inflations within a
single neural inspiration, a phenomenon known as double
triggering (Fig. 23). With assist-control ventilation, double
triggering is likely when the set mechanical inspiratory time
is substantially less than a patient’s neural inspiratory time.
In this situation, mechanical inflation terminates while the
patient is still making an inspiratory effort. After a brief
period, the ventilator may trigger again, resulting in a second
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Non triggering attempts
Phase angle (degrees)
0
–30
–60
–90
PS 0
PS 10
PS 20
Figure 22 Phase angle between neural and mechanical expiratory
times before triggering (closed circles) and nontriggering (open circles)
attempts. At pressure support (PS) of 10 and 20 cmH2 O, the phase
angle before nontriggering attempts exceeded that before triggering
attempts, indicating that neural expiratory time during late mechanical
inflation was longer before nontriggering attempts than before triggering attempts (for pressure support 10, P = 0.0002; for pressure
support 20, P = 0.01). [Adapted, with permission, from Parthasarathy
S, Jubran A and Tobin MJ. Cycling of inspiratory and expiratory muscle
groups with the ventilator in airflow limitation. Am J Respir Crit Care
Med 158: 1471-1478, 1998 (192).]
inflation within the same neural inspiration and, thus, greater
alveolar distension than with the delivery of a single tidal
volume (313).
With pressure-support ventilation, double triggering is
likely when the time constant is short (low resistance, high
elastance) and patient neural inspiratory time is relatively
long (a slow, spontaneous respiratory rate) (308). Following
the loss of ventilator pressure after a first triggering attempt,
volume decreases because Pmus alone is not sufficient to sustain elastic recoil. During this phase, the persistence of neural
inhalation will cause a progressive increase in Pmus , while
elastic recoil continues to decrease. If the patient’s neural inspiratory time is sufficiently long, a point is reached where
Pmus will exceed elastic recoil and flow will become inspiratory and double triggering will occur (307).
The mechanical and cellular derangements seen in patients with ARDS have been demonstrated experimentally to
pose major risks for the development of ventilator-induced
lung injury (68, 290). Randomized clinical trials have also
shown an increased mortality in patients ventilated with a
high tidal volume (12 mL/Kg) (1, 6). Consequently, it has
become standard practice to lower the delivered tidal volume to minimize alveolar overdistension—for example, to
keep the inspiratory pressure during a pause at the end of
inspiration (plateau pressure) to 32 cmH2 O or lower (265).
A low tidal volume is typically accompanied by a short
mechanical inspiratory time and thus these patients are especially susceptible to double triggering. Accordingly, conscious attempts to lower tidal volume can paradoxically result
in greater alveolar distension than occurs with conventional
tidal volume settings (Fig. 24). An additional (and often unrecognized) factor that may produce alveolar distension is the
tachypnea-associated increase in intrinsic PEEP that accompanies lowering of tidal volume (60).
0
–1
–2
1.0
Liter
50
Paw
cmH2O
Flow
1
L/s
Triggering attempts
20
Volume
0.5
0
Pes
cmH2O
10
Pes
cmH2O
–10
20
0
–10
5
0
2
4
6
8
Time (s)
–10
0
10
20
30
Time (s)
Figure 23 Four incidents of double triggering, each indicated by an
arrowhead symbol (↑). Airway pressure (Paw ) and esophageal pressure (Pes ) in a patient with COPD and pneumonia who was receiving
assist-control ventilation at the following settings: tidal volume 600 mL,
inspiratory flow 60 L/min, trigger sensitivity −2 cmH2 O and positive
end-expiratory pressure 5 cmH2 O. The duration of neural inhalation of
the double-triggered breaths, roughly equivalent to the width of the associated swings in esophageal pressure, was substantially longer than
the neural inhalation of the normally triggered breaths.
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Figure 24 Volume stacking caused by double triggering. Flow (top
panel), volume (middle panel), and esophageal pressure (lower panel)
in a patient with COPD receiving assist-control ventilation. During first
breath, esophageal pressure remains positive indicating that the patient did not trigger the inflation. During the second breath, esophageal
pressure becomes negative indicating active inspiratory effort, which
lasts more than 1 s; the duration of mechanical inflation is 0.6 s. The
longer duration of neural inspiration as compared with mechanical
inflation causes the ventilator to deliver a second breath before there is
time for exhalation. As a result, end-inspiratory lung volume increases
(breath stacking) with a consequent increase in elastic recoil. The increase in elastic recoil is responsible for the higher peak expiratory flow
on the second breath as compared with the first breath.
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Flow 60 L/s
Flow 90 L/s
Flow
(L/s)
2.0
0
–2.0
Paw
cmH2O
60
0
–60
Pes
cmH2O
30
0
–30
0
4
8 0
4
8
Time (s)
Figure 25 Influence of ventilator flow setting on patient effort. Flow (inspiration
directed upward), airway pressure (Paw ), and esophageal pressure (Pes ) in a patient with respiratory failure who is receiving assist-control ventilation; inspiratory
flow is set at 60 L/min in the left panel and at 90 L/min in the right panel. At an
inspiratory flow of 60 L/min (left panel), the pronounced negative deflection in
airway pressure (patient effort to trigger the ventilator) together with subsequent
extensive scalloping signifies that the inspiratory flow delivered by the ventilator
is insufficient to meet the high demand. At an inspiratory flow of 90 L/min (right
panel), the small negative deflection in airway pressure together with the subsequent smooth convex contour signifies that the delivered flow satisfies the patient’s
respiratory drive. Accordingly, the flow of 90 L/min achieved greater unloading
of the respiratory muscles, as signaled by the shorter duration of inspiratory effort
and the smaller swings in esophageal pressure.
Setting of inspiratory flow and tidal volume
When a patient is first connected to a ventilator, inspiratory
flow is set at some default value, such as 60 L/min. Many
critically ill patients, however, have an elevated respiratory
drive and the initial setting of flow may be insufficient to
meet flow demands. As a result, patients will struggle against
their own respiratory impedance and that of the ventilator,
with consequent increase in the work of breathing (Fig. 25).
Clinicians sometimes increase flow with a goal of shortening
inspiratory time and thus increasing expiratory time. But an
increase in flow causes immediate and persistent tachypnea;
as a result, expiratory time may be shortened (209).
In healthy subjects, Puddy and Younes (209) found that an
increase in inspiratory flow from 30 to 90 L/min caused respiratory frequency to increase from 8.8 to 14.1 breaths/min. The
increase in frequency was nearly complete within the first two
breaths and did not change thereafter despite the development
of respiratory alkalosis. This flow-associated tachypnea has
been shown to be independent of breathing route, temperature of inspired gas, and delivered volume; it also persists after
anesthesia of the airway, denervation of receptors in the lungs
and chest wall, and during sleep (94). In addition to the effect
2896
of delivered flow on frequency, investigators have shown that
frequency is influenced by delivered tidal volume—an effect
seen under isocapnic and hypocapnic conditions, and during
wakefulness and sleep (262).
When studying the effects of a change in a ventilator’s flow
or tidal volume, the results may be influenced unwittingly by
simultaneous changes in ventilator inspiratory time. When
inspiratory flow is increased and tidal volume kept constant,
ventilator inspiratory time must decrease. When tidal volume
is increased and inspiratory flow kept constant, ventilator inspiratory time must increase. Laghi et al. (141) undertook
a series of experiments in healthy volunteers to delineate the
separate influences of these three settings—flow, tidal volume,
and ventilator inspiratory time—in mediating flow-associated
tachypnea.
For inspiratory flow of 30, 60, and 90 L/min, the
respective frequencies were 12.9, 15.5, and 18.2 breaths/min.
Because tidal volume was kept constant, an increase in flow
was accompanied by a proportional decrease in ventilator
inspiratory time. The increase in frequency was proportional
to the decrease in ventilator inspiratory time (r = 0.69). When
flow and tidal volume were held constant and ventilator
inspiratory pauses of as much as 2 s were imposed, frequency
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again changed as a function of ventilator inspiratory time
(r = 0.86). When flow was increased from 30 to 60 L/min,
and tidal volume adjusted to maintain a constant ventilator
inspiratory time, frequency decreased from 17.9 to 16.0
breaths/min. This series of observations shows that imposed
inspiratory time can determine frequency independently of
delivered inspiratory flow and tidal volume (141). The findings have clinical implications. Physicians often increase tidal
volume to lower PaCO2 . An increase in tidal volume without
change in inspiratory flow, however, must be accompanied
by a longer inspiratory time, which is likely to decrease
frequency. The consequent change in minute ventilation and
PaCO2 will fall short of that intended. (The opposite scenario
holds when a lower tidal volume is selected.)
The effects of delivered flow, tidal volume, and inspiratory time on frequency can be interpreted according to current
understanding of the Hering-Breuer reflex. First, for a fixed inspiratory time, an increase in inspiratory flow will necessarily
increase end-inspiratory lung volume. An increase in delivered volume causes a progressive increase in the activity of
the slowly adapting receptors (stretch receptors). This activity
is transmitted by the vagus to the brainstem where it inhibits
inspiration (negative feedback). Any decrease in neural inspiratory time is also likely to be accompanied by a decrease
in neural expiratory time, because the two phases are closely
linked (47). Accordingly, decreases in neural inspiratory time
and expiratory time secondary to lung inflation are likely to be
major factors in explaining flow-associated tachypnea. Second, a decrease in neural inspiratory time fosters the extension
of mechanical inflation into neural expiratory time, which, in
turn, causes prolongation of neural expiratory time (316,322).
A mechanical expiratory time that exceeds neural inspiration,
as can occur with imposed inspiratory pauses, higher tidal
volume, or slower flow rates, is thus an important modulator of frequency. In summary, the response of frequency to a
change in ventilator settings is complex, because it depends
on the relative dominance of physiologic mechanisms acting
in different directions. High flows are often used with the intent of lowering PEEPi by achieving a shorter inspiratory time
and, thus, allowing more time for exhalation. The associated
tachypnea could cause expiratory time to shorten, and thus
increase PEEPi , or to lengthen, secondary to continuation of
mechanical inflation into neural expiration; which of these
opposing scenarios prevails has yet to be determined.
One of the main reasons that clinicians increase inspiratory flow is to decrease inspiratory time in the hope of
allowing more time for expiration and thus decrease PEEPi ,
especially in patients with COPD. Because flow usually leads
to an increase in rate, the expected shortening of expiratory
time might actually produce an increase in PEEPi . Laghi et al.
(142) studied this phenomenon in ten patients with COPD
(Fig. 26). As with healthy subjects, an increase in flow from 30
to 90 L/min caused respiratory rate to increase from 16.1 ± 1.0
to 20.8 ± 1.5 breaths/min. Despite the increase in rate, PEEPi
fell from 7.0 ± 1.3 to 6.4 ± 1.1 cmH2 O. The decrease in PEEPi
arose because of an increase in expiratory time, 2.1 ± 0.2 to
2.3 ± 0.2 s, which allowed more time for lung deflation.
Why did expiratory time increase? An increase in inspiratory
90 L/min
60 L/min
30 L/min
Swing 16.8
19.5
21.5
PEEPi 13.3
14.4
15.6
Flow
(L/s)
2
0
Pes
cmH2O
–2
40
0
Chest
volume
(a.u.)
–40
1
0
–1
0
10
20
30
Time (s)
Figure 26 Continuous recordings of flow, esophageal pressure (Pes ), and the sum of
rib-cage and abdominal motion in a patient with COPD receiving assist-control ventilation at a constant tidal volume. As flow increased from 30 to 60 and 90 L/min (from
right to left; i.e., the opposite of the usual presentation), frequency increased (from 18
to 23 and 26 breaths/min, respectively), PEEPi decreased (from 15.6 to 14.4 and 13.3
cmH2 O, respectively), and end-expiratory lung volume also fell. Increases in flow from
30 L/ min to 60 and 90 L/min also led to decreases in the swings in Pes from 21.5 to
19.5 and 16.8 cmH2 O, respectively. [Adapted, with permission, from Laghi F, Segal J,
Choe WK and Tobin MJ. Effect of imposed inflation time on respiratory frequency and
hyperinflation in patients with chronic obstructive pulmonary disease. Am J Respir Crit
Care Med 163: 1365-1370, 2001 (142).]
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PTP/min
PTP/breath
14
300
200
100
9
0
20
40
60
80
100
25
15
4
0
IMV
PS
35
Breaths/min
cmH2O.s/breath
400
cmH2O.s/min
Frequency
0
20
40
60
80 100
0
20
40
60
80 100
Ventilator assistance (%)
Figure 27 Changes in pressure-time product (PTP) per minute (left panel), PTP per breath (middle panel), and frequency
(right panel) as the level of intermittent mandatory ventilation (IMV) and pressure support (PS) were progressively increased
in 11 ventilator-dependent patients. Ventilator assistance of 0% represents unassisted breathing; PS of 100% represents
the level necessary to achieve a tidal volume equivalent to that during assist-control ventilation (10 mL/kg); IMV of 100%
is the same ventilator rate as during assist-control ventilation. The left panel shows that the rate of change in PTP per
minute over the entire span of assistance did not differ between PS and IMV. The middle panel shows that the rate of
change in PTP per breath decreased linearly as the rate of IMV was increased; the decrease with PS was linear only up
a medium level and decreased little thereafter. The right panel shows that respiratory frequency decreased linearly as PS
was increased, whereas it changed little with IMV until a high level of assistance was provided. See text for interpretation.
[Based on data from Leung P, Jubran A and Tobin MJ. Comparison of assisted ventilator modes on triggering, patient
effort, and dyspnea. Am J Respir Crit Care Med 155: 1940-1948, 1997 (152).]
flow is usually achieved by shortening of mechanical inspiratory time. The shortened inspiratory time combined with
time-constant inhomogeneity of COPD will cause overinflation of some lung units to persist into neural expiration. In
anesthetized animal models (316,322) and in sleeping human
subjects (116), continued inflation during neural expiration
causes stimulation of the vagus, which prolongs expiratory
time. Whether vagal stimulation is responsible for prolongation of expiratory time during wakefulness in humans remains
to be determined.
Mode-specific effects of inspiratory unloading
Leung and co-workers (152) undertook a head-to-head comparison of the relative effectiveness of progressive increases in
the number of ventilator-assisted breaths during IMV and in
the level of pressure support in unloading the inspiratory muscles. Over the entire span of assistance, the rate of change in
effort per minute did not differ between the modes (analyzed
in terms of slopes). The efficacy of unloading, however, did
differ according to the stages of assistance. From zero assistance up to a medium level of assistance (60% of maximum),
the decrease in patient effort per minute was greater with pressure support than with IMV; the converse was observed as
ventilator assistance was increased further to a maximal level
(Fig. 27). The changes in effort per breath and frequency help
with understanding the different responses (152). Effort per
breath decreased linearly as the rate of IMV was increased.
Effort per breath also decreased linearly as pressure support
was increased to a medium level, but little thereafter, presumably because pressure support provides assistance only if a
patient makes some effort. Frequency decreased linearly as
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pressure support was increased; with IMV, frequency changed
little until a high level of assistance was provided. As IMV
is increased from a medium to a high level, all of a patient’s
ventilatory requirements will be met and frequency decreases
dramatically. Thus, a greater rate of respiratory unloading occurred between medium and high levels of assistance with
IMV than with pressure support. Because these two modes
are used primarily to provide partial, as opposed to complete,
assistance, the greater decrease in patient effort per minute
with pressure support at 20% to 60% of assistance makes it a
clinically more useful mode than IMV.
Pressure support and IMV are commonly combined in
a given patient. In an international survey of mechanical
ventilation (74), this combination tied with assist-control
ventilation as the most commonly used mode of ventilation in
North America (34% for each). The rationale for combining
the modes is unclear, but presumably clinicians use pressure
support to overcome the work imposed by the endotracheal
tube and demand valve during the nonmandatory breaths. Examining the response of the respiratory centers to this combination of modes provides useful insight into patient-ventilator
interaction. A decrease in the number of mandatory breaths
produces a decrease in the average tidal volume (152), with inevitable increase in dead space to tidal volume ratio. To avoid
a decrease in alveolar ventilation, the patients increased respiratory motor output, inspiratory effort, and frequency. Adding
pressure support of 10 cmH2 O caused a decrease in effort at
any given IMV rate. Interestingly, the decrease in effort during
the mandatory ventilator breaths was related to the decrease
in respiratory motor output during the intervening breaths
(r = 0.67) (152). In other words, the reduction in motor
output during the intervening breaths achieved by adding
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pressure support was carried over to the mandatory breaths,
facilitating greater unloading.
Onset inspir effort
I:E flow switch
Inspiration-expiration switching
(cycling-off function)
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Flow
(L/s)
0
Paw
H2O
–1.5
70
30
–10
70
Pes
H2O
Patients are commonly ventilated with a volume-cycled mode,
such as the volume-cycled form of assist-control ventilation
or IMV. This system should more precisely be termed timecycled ventilation because inspiratory flow is preset and the
ventilator adjusts inspiratory time to achieve a given tidal volume. Although inflation time is constant with a time-cycled
machine, patients invariably display considerable breath-tobreath variability in neural inspiratory time (278). Accordingly, if the machine delivers the set tidal volume before the
end of a patient’s neural inspiratory time, ventilator assistance
will cease while the patient continues to make an inspiratory
effort and double triggering (two ventilator breaths for a single
effort) will be a likely consequence.
During assist-control ventilation, when a patient’s neural
inspiratory time is short, ventilator inflation may continue
into neural expiration and thus decrease the time available for
lung emptying. The sense of being unable to empty the lungs
may cause patients to activate the expiratory muscles with the
result that the patient appears to fight or buck the ventilator
(Fig. 28). The decrease in time for emptying also increases
the likelihood for dynamic hyperinflation and thus inspiratory
efforts that fail to trigger the ventilator.
The algorithm for cycling-off of mechanical inflation during pressure support varies among brands (33). On most ventilators, the termination of inspiratory assistance during pressure support is set at a default threshold, such as 25% of the
peak inspiratory flow or inspiratory flow of 5 L/min. That is,
when inspiratory flow falls to 25% of the peak value or below
5 L/min, inspiratory pressurization switches off. Such algorithms can be problematic in patients with COPD because
increases in resistance and compliance produce a slow timeconstant of the respiratory system (see Fig. 8). The longer
time needed for flow to fall to the threshold value can cause
mechanical inflation to persist into neural expiration. In 12 patients with COPD receiving pressure support of 20 cmH2 O,
five recruited their expiratory muscles while the machine was
still inflating the thorax (129). The patients who recruited
their expiratory muscles during mechanical inflation had an
average time constant of 0.54 s, compared with an average of
0.38 s in the patients who did not exhibit expiratory muscle
activity. The persistence of mechanical inflation into neural
expiration is very uncomfortable, as is well recognized with
use of inverse-ratio ventilation. Algorithms that achieve better coordination between the end of mechanical inflation and
the onset of a patient’s expiration may lessen this form of
patient-ventilator asynchrony (299).
In ten critically ill patients, Tassaux et al. (260) investigated the influence of variation in the cycling-off threshold
on patient-ventilator interaction. Compared with the usual default setting (25% of the peak inspiratory flow), a threshold of
1.5
30
–10
0
2
4
Time (s)
6
Figure 28 Expiratory activity during mechanical inflation. Flow, airway pressure (Paw ) and esophageal pressure (Pes ) in a patient with
COPD who is receiving assist-control ventilation. The patient’s first two
inspiratory efforts (red vertical lines) trigger the ventilator successfully.
The third and fourth inspiratory efforts are very weak (arrows) and do
not trigger a mechanical inflation. The last inspiratory effort triggers
the ventilator, and at the end of this mechanical inflation (blue vertical
line) the patient recruits his expiratory muscles, producing an increase
in esophageal pressure above the expected elastic recoil of the lung
(dashed tracing) before the termination of mechanical inflation. Expiratory muscle recruitment produces a transient cessation of expiratory
flow, which corresponds to a transient increase in esophageal pressure
to approximately 20 cmH2 O.
75% of peak inspiratory flow produced a predictable decrease
in inspiratory time (from 0.72 ± 0.25 to 0.68 ± 0.23 s), a
decrease in PEEPi (from 5.4 ± 2 to 4.8 ± 1.9 cmH2 O), and
fewer nontriggering efforts. When the threshold for the termination of inspiratory pressurization was set at 10% of peak
inspiratory flow, inspiratory time increased marginally as did
the number of nontriggering efforts. While the threshold of
75% of peak inspiratory flow resulted in fewer nontriggering
efforts, it also resulted in a lower tidal volume as compared
with the default threshold (25% of peak inspiratory flow):
0.46 ± 0.19 versus 0.62 ± 0.2 L (SD). The best trade-off
between number of nontriggering efforts and the size of tidal
volume needs to be balanced for each individual patient.
Younes and co-workers (314) studied 50 patients ventilated with proportional-assist ventilation (PAV), most of
whom did not have COPD. Exhalation was delayed intermittently by briefly delaying the opening of the exhalation
valve. In response to a delay in the opening of the expiratory
valve, all but 5 of 50 patients developed an increase in the
duration of neural expiratory time. The increase in duration
of neural expiratory time, however, offset only 36 ± 20%
of the delay in expiration. Consequently, dynamic hyperinflation worsened. When delays in onset of expiration were
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introduced in a computer-simulated model, similar increases
in dynamic hyperinflation were noted (69).
Although the magnitude of expiratory effort does not appear to influence the success of triggering attempts, the time
that expiratory efforts commence in relation to the cycling
of the ventilator is an important factor. Parthasarathy and
co-workers quantified the relationship between the onset of
expiratory muscle activity, measured with a wire electrode
in the subject’s transversus abdominis, and the termination
of mechanical inflation by the ventilator (192). When mechanical inflation extended into the early part of the patient’s
(neural) expiration, resulting in a negative phase angle, the
time available for unopposed exhalation was shortened. The
inadequate time for exhalation leads to hyperinflation with an
associated increase in elastic recoil. As a result, patients need
to generate greater inspiratory effort to successfully trigger
the ventilator. In this way, the time that a patient commences
an expiratory effort (in relation to cycling-off of mechanical
inflation) partly determines the success of the ensuing inspiratory effort in triggering the ventilator.
A further factor that confounds the delineation of mechanisms of patient-ventilator dysynchrony is that inspiratory and
expiratory muscle groups can contract simultaneously (66). In
the study of Parthasarathy et al. (192), the time of overlap was
defined as the period during which late expiratory (transversus
abdominis) muscle activity overlapped with early inspiratory
muscle (diaphragmatic) activity (see Fig. 18). The average
duration of inspiratory and expiratory muscle overlap was on
the order of 60 to 90 ms in the subjects, with a range of 0
to 200 ms. Although this period is comparable to the time
taken to trigger a ventilator of 100 to 200 ms (220), it did not
appear to have any consistent effect on the success of triggering attempts—the period of overlap was not different for
triggering and nontriggering attempts at pressure support of
0, 10, or 20 cmH2 O.
Variability of breathing
The central respiratory pattern generator can be viewed as
a homeostatic system influenced by various feedback loops.
The confluence of these feedback signals is processed by a
controller that produces a homeostatic output exhibiting considerable breath-to-breath variability (35, 278). Studies employing measures of coefficients of variation (standard deviation/mean) of breath components have revealed a wide
range of variability in healthy subjects (161,274,283). Breath
components that reflect volume and respiratory motor output
display greater variability than time components in a variety
of experimental conditions, with the exception of slow-wave
sleep (161). During slow-wave sleep, breathing is controlled
primarily by the metabolic control system located in the brainstem, whereas higher neural centers exert a greater influence
on breathing during wakefulness and REM sleep (199). Thus,
the greater breath-to-breath variability of respiratory volume
compared with respiratory timing does not appear to be an
intrinsic property of the central pattern generator, but instead
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reflects the modulating action of higher neural centers on respiratory output (161).
Coefficients of variation provide a measure of gross variability, but they do not define the structure within a time series
(263). Data sets may have the same coefficient of variation
yet differ in the sequential ordering in a time series. A typical breath series looks quite erratic and unpredictable, yet
signal-analysis techniques reveal significant structured behavior. Gross variability can be divided into a fixed part,
namely the mean of a time series, and a variable part, which
is the deviation of the magnitude of each breath from the
mean. The variable deviation can in turn be divided into a
random uncorrelated, or white noise, fraction and a nonrandom structured fraction (28, 29, 124, 128). The random fraction of breath variability, which can be viewed as the freedom to vary the respiratory cycle, constitutes more than 90%
of breath-component activity in awake healthy subjects. The
converse of unpredictable random behavior is predictable oscillatory behavior, which accounts for less than 1% of normal
breath-component activity. Correlated behavior falls between
the two extremes and is partly predictable in that the volume
and timing of one respiratory cycle is significantly related
to that of the preceding respiratory cycle. Correlated behavior is usually about 3%-10% of normal breath-component
activity, and it together with the tiny amount of oscillatory behavior can be viewed as the constraint on respiratory
freedom (28, 29, 124, 128).
That breath-to-breath variability is mainly random in
nature makes it possible for the respiratory system to engage in tasks other than gas exchange, such as speaking
(28, 29, 36, 124, 128, 205, 278). A lack of “tightness” in the
control of breathing may also be an important buffer against
the development of dyspnea (45,108). When mechanical loads
are imposed on the respiratory system or when the metabolic
needs of the body are increased, it becomes increasingly
difficult for suprapontine ventilatory commands to compete
against the automatic control system (36, 252). Such challenges are generally accompanied by significant decreases in
the random fraction (28, 29, 124). This decrease in random
variability may lessen the freedom of the respiratory system
to undertake behavioral tasks (28, 29, 100).
Abnormalities in the rhythmicity of breathing can have
devastating consequences and be responsible for sudden death
in patients with the sleep apnea syndrome, sudden infant
death syndrome, Cheyne-Stokes syndrome, and other disorders (269). Information on how breath-to-breath variation in
controller output contributes to the clinical manifestations of
lung disease is scant, and limited to one disease state. Patients
with restrictive lung disease exhibit distinctive alterations in
the variability of breathing (Fig. 29). The random fraction
of breath variability was as much as 27 times smaller in patients with restrictive lung disease than in healthy subjects
(30). Conversely, correlated behavior was up to three times
greater in the patients. Random variability in tidal volume and
expiratory time exhibited the most striking changes, which
were also the fraction and breath component most affected
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1500
Tidal volume (mL)
1000
500
0
2000
1500
1000
500
0
20
40
60
Time (min)
Figure 29 Breath-to-breath values of tidal volume during 1 h of resting breathing in a patient with restrictive lung disease (top panel) and
in a healthy control subject (bottom panel). The coefficient of variation
for tidal volume in the patient (0.13) was more than five times smaller
than that in the healthy subject (0.72). [Adapted, with permission, from
Brack T, Jubran A and Tobin MJ. Dyspnea and decreased variability
of breathing in patients with restrictive lung disease. Am J Respir Crit
Care Med 165: 1260-1264, 2002 (30).]
when healthy subjects breathed against an external elastic
load (28).
When ventilation is measured nonobtrusively and without
the use of a mouthpiece, as by means of inductive plethysmography, considerable variation in the average level of ventilation is evident among healthy subjects. For example, a
15-min nonobtrusive recording of resting breathing in 65
healthy subjects revealed a tidal volume of 383 ± 91 (SD)
ml (268). Equivalent nonobtrusive recordings revealed higher
tidal volumes in patients with stable COPD: 447 ± 139 mL
in 16 eucapnic patients and 476 ± 158 mL in 12 hypercapnic patients (268). The highest tidal volumes among patients
with various respiratory disorders were observed in 15 subjects with symptomatic but stable asthma: 679 ± 275 mL
(268). In addition to the substantial variation in average tidal
volume among subjects, each individual subject exhibited
considerable breath-to-breath variability in all breath components. Gross within-day, within-subject, breath-to-breath
variability in tidal volume, as reflected by coefficient of variation, was 33.0 ± 14.9% (SD) in 47 young healthy subjects
(21-50 years) and significantly higher in 18 healthy older
subjects (60-81 years), 44.0 ± 14.7% (274). The substantial
variability in breathing pattern between subjects, further magnified by the considerable breath-to-breath variability within
subjects, poses a problem in selecting settings during mechanical ventilation.
If tidal volume is set during volume-cycled assist-control
ventilation at the average value during unassisted breathing,
5-7 mL/kg, the wide breath-to-breath variation in ventilatory
demand means that around half of the delivered tidal volumes
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will be lower than the patient’s demand, which may lead to
dyspnea (308). It is possible that comfort will be attained only
when the set tidal volume approaches or exceeds the greatest
demand within the range of spontaneous breathing. If a higher
tidal volume were selected, such as 12-15 mL/kg, it is likely
that the breath-to-breath variation in demand will be satisfied
in virtually all patients. Most of the demand of the ventilatory
control system, however, would be satisfied with a lower volume setting. Younes, however, has speculated that the wide
variation in breathing pattern between subjects and also the
large variability on a breath-to-breath basis may explain why a
high tidal volume setting (12-15 mL/kg, as opposed a normal
value of 5-6 mL/kg) has been traditionally recommended during assist-control ventilation (308) (Fig. 30). More recently,
much lower tidal volumes have been employed, especially
in patients with ARDS, as randomized trials have revealed a
significantly lower mortality with a tidal volume of 6 mL/kg
as compared with a tidal volume of 12 mL/kg (1, 6).
PAV is a form of ventilator assistance in which the ventilator generates pressure in proportion to patient effort. While
receiving PAV, patients are able to achieve greater variation in breath components than with conventional ventilator modes. In 11 patients being ventilated for a variety of
reasons, Marantz et al. (164) altered the level of PAV from
near-maximal levels to the lowest tolerable level of assistance.
In this way, the constraint of abnormal respiratory mechanics
on the respiratory control system was progressively lessened
as the level of PAV was gradually increased. The most consistent finding was that variation in the level of PAV produced
no consistent effect on respiratory frequency, tidal volume, or
minute ventilation. At the highest and lowest level of assistance, respiratory frequency was respectively 25.0 ± 4.2 and
25.7 ± 3.9 breaths/min. Likewise, minute ventilation did not
change consistently between the highest and lowest level of
assistance: 12.8 ± 5.4 (SD) versus 11.6 ± 4.3 L/min. These
findings suggest that within an individual patient and for a
particular state there exists a unique set of values for tidal
volume, respiratory frequency and minute ventilation that are
largely independent of the mechanical load; if the level of
PAV is increased, patient effort is decreased to maintain the
desired ventilatory targets.
While the values of a breath component may be relatively constant and independent of load within a given patient, Marantz et al. (164) observed considerable variation in
the values of a breath component among the patients. Minute
ventilation, which reflects ventilatory demand, varied from
5.6 to 18.7 L/min among patients. At the highest level of PAV,
tidal volume ranged from 203 mL (3.4 mL/kg) to 844 mL
(9.4 mL/kg) among patients. The average tidal volume was
517 ± 217 mL (7.46 ± 3.25 mL/kg) at the highest level of PAV,
which was considerably less than the delivered tidal volume
while the patients had been receiving IMV or pressure support
before entry into the study. The patients’ tidal volume during
PAV was not correlated with any measure of respiratory mechanics or with the underlying disease. The only variable that
correlated with tidal volume was minute ventilation: r = 0.91.
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2.0
Flow
(L/s)
1.0
0.0
–1.0
–2.0
Esophageal pressure
(mmHg)
12
8
4
0
–4
–8
0
25
50
75
Time (s)
Figure 30 Variability of breathing. Time series of airflow and esophageal pressure in a patient with acute
respiratory failure secondary to an acute exacerbation of COPD who is being ventilated with pressure support
of 5 cmH2 O (PEEP, 0 cmH2 O). The esophageal-pressure tracing exhibits wandering values at end-expiration
and varying inspiratory excursions; these features are somewhat less evident on the flow tracing.
The strength of this correlation suggests that more than 80%
of the variability in tidal volume in ventilated patients is determined by alterations in ventilatory demand, presumably
arising from interindividual differences in ventilatory drive.
Because factors other than ventilatory demand accounted for
less than 20% of the variability in tidal volume, Marantz et al.
(164) went on to argue that receptor stimulation or malfunction secondary to a given underlying disease plays little role in
the regulation of tidal volume in ventilated patients; whether
this possibility, based on correlative data, can be generalized
remains to be determined.
As witnessed with PAV, another new ventilator mode also
achieves greater breath-to-breath variation in breath components than allowed with conventional modes. NAVA, which
delivers positive pressure in relation to a patient’s diaphragmatic electrical activity, is still in the early stages of clinical
application. In 12 patients with a moderate lung injury who
were being weaned from the ventilator, Schmidt et al. (230)
found that switching from pressure support to NAVA resulted
in no change in the mean values of breath components but
there were significant increases in the coefficients of variation
of tidal volume and mean inspiratory flow (V T /T I ). Similar
trends were observed with autocorrelation analysis: the lag
of V T /T I was lower at the highest setting of NAVA compared
with both pressure support and the lowest level of NAVA;
moreover, the autocorrelation coefficient of V T /T I and of respiratory frequency was lower at the highest setting of NAVA
than at the lowest level of NAVA. The observation that progressive unloading of the respiratory system with increasing
levels of NAVA produced an increase in breath-to-breath vari-
2902
ability of breathing and a decrease in the correlated fraction
is consistent with studies in healthy subjects during external
loading (28, 29) and in patients with restrictive lung disease
(30). At the present time, it is not known whether induced
changes in variability of breathing in ventilator-supported patients lead to improvements in patient outcome.
PAV and NAVA are not the only methods of increasing
the variability of breathing during mechanical ventilation. The
variation in breathing during mechanical ventilation with PAV
and NAVA is generated by the patient’s respiratory centers.
More recently, investigators have examined the effects of variation in breathing imposed by a ventilator, so-called “noisy
ventilation” (257, 261). Studies conducted in experimental
animals have revealed a number of benefits in response to the
deliberate imposition of some variability during mechanical
ventilation (257, 261). Noisy ventilation involves the deliberate imposition of a coefficient of variation in tidal volume
of up to 40%. In animal models of lung injury, noisy ventilation has been shown to improve oxygenation, reduce peak
inspiratory airway pressure, reduce elastance, and decrease
histological damage even when compared with the use of a
low tidal volume (11, 25, 92, 169, 250, 251). To date, noisy
ventilation has not been studied in human subjects.
Ventilator Weaning
When patients have recovered sufficiently from the illness that
precipitated the need for mechanical ventilation, attempts are
made to disconnect them from the machine. In the early days
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Comprehensive Physiology
of intensive care units and mechanical ventilation (from late
1950s to mid 1960s), physicians were worried about discontinuing the ventilator too abruptly; it was believed that patients
needed to slowly learn how to breathe on their own again. Consequently, the approach to the ventilator withdrawal was very
slow—just a minute or two of spontaneous breathing once or
twice a day (267). This gradualist approach was appropriately
called “weaning.” Today, it is recognized that the majority of
patients who demonstrate reasonable recovery of respiratory
function after a period of mechanical ventilation (patients
who perform well on weaning-predictor tests) will tolerate
the first trial of spontaneous breathing without a gradualist
weaning approach. Nevertheless, the short descriptor weaning is used in place of the more accurate but cumbersome term
“discontinuation of mechanical ventilation,” and attempts to
introduce other descriptors have not been successful.
Of patients who are deemed ready for a weaning trial,
about 20% to 30% will develop severe distress during the
first trial of spontaneous breathing and require the resumption of mechanical ventilation. If the trial is extended, these
weaning-failure patients will develop hypercapnia unless severe hypoxemia first intervenes. Because these patients develop acute respiratory failure over a relatively short period
of time (usually 15-90 min), they have become the most employed experiment of nature for studying the pathophysiology
of acute respiratory failure. Moreover, the patients who tolerate a weaning trial, and successfully sustain spontaneous
ventilation following extubation, provide a control group for
comparison. The mechanisms that cause weaning failure can
be divided into those occurring at the level of control of
breathing, mechanics of the lung and chest wall, the respiratory muscles, the cardiovascular system, and gas-exchange
properties of the lung.
Control of breathing
Patients who fail a trial of spontaneous breathing commonly
develop hypercapnia. This observation led many investigators to suspect that depression of respiratory motor output
was responsible. When respiratory motor output was directly
measured, however, it was found to increase between the onset
and end of a failed weaning trial as the patients were developing progressive hypercapnia. In the study of Tobin et al.
(277), patients developed acute severe distress accompanied
by an increase in PaCO2 , from 42 to 56 mmHg, and a fall
in pH from 7.43 to 7.35. Between the beginning and end of
the trial, which lasted 40 ± 11 min, the patients developed an
increase in mean inspiratory flow (V T /T I ): 265 ± 27 to 328 ±
32 mL/s (Fig. 31). No patient had a value of V T /T I below the
95% confidence limits of normal subjects. Subsequent studies
using the airway occlusion method (P0.1) as a measure of respiratory motor output revealed that respiratory motor output
is higher in weaning-failure patients than in weaning-success
patients (43, 173, 226, 227).
The major mechanism for acute hypercapnia in weaningfailure patients is a change in the pattern of breathing rather
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500
400
Success
Failure
300
VT
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100
0
0
1
2
3
Time (s)
Figure 31 The mean respiratory cycle during spontaneous breathing
in seven weaning-failure and ten weaning-success patients. The early
termination of inspiratory time in the weaning-failure patients leads to a
decrease in tidal volume. The decrease in inspiratory time, coupled with
a decrease in expiratory time, results in a faster respiratory frequency.
Bars represent 1 SE. [Adapted, with permission, from Tobin MJ, et al.
The pattern of breathing during successful and unsuccessful trials of
weaning from mechanical ventilation. Am Rev Respir Dis 134: 11111118, 1986 (277).]
than respiratory center depression. Patients who go on to fail a
weaning trial develop an almost immediate change in breathing pattern as soon as they are disconnected from a ventilator
(277) (Fig. 32). The dominant finding is a shortening of inspiratory time. For example, in the study of Tobin et al. (277),
inspiratory time was 0.8 ± 0.1 s in weaning-failure patients
versus 1.4 ± 0.3 s in weaning-success patients. At the level
of the respiratory centers, expiratory time is strongly coupled to inspiratory time (47). Consequently, expiratory time
was also shorter in the weaning-failure patients than in the
weaning-success patients: 1.2 ± 0.3 versus 2.5 ± 0.5 s. The
combined changes in inspiratory time and expiratory time led
to a marked increase in respiratory frequency: 33 ± 2 versus 21 ± 3 breaths/min. Because the rate of inspiratory flow
(V T /T I ) was equivalent in the two patient groups, the short
inspiratory time resulted in a lower tidal volume in the failure patients: 194 ± 23 versus 398 ± 56 mL. The decrease
in tidal volume was balanced by the increase in frequency,
and thus minute ventilation was equivalent in the two groups.
A decrease in tidal volume without an increase in minute
ventilation must result in higher overall dead-space ventilation (V D /V T ); indeed, the combined changes in tidal volume
and respiratory frequency accounted for 81% of increase in
PaCO2 observed in the weaning-failure patients. An attempt
to compensate for the low tidal volume through an increase
in frequency will produce an increase in work of breathing.
According to the model of Otis et al. (189), the increase in
work with rapid shallow breathing is exponential: work =
4035e (0.0017*f /V T ) , r = 0.90 (272) (Fig. 33).
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0.6
100
Start of trial
PaCO2 = 48
End of trial
PaCO2 = 73
Tidal volume (L)
Respiratory frequency
(breaths/min)
0.5
50
0.4
0.3
0.2
0.1
Tidal volume
(mL)
0
0.0
800
–20
400
–5
0
5
10
15
20
Figure 34 Two superimposed Campbell diagrams of work of
0
8
4
12
Minutes
16
20
Figure 32 A time-series, breath-by-breath plot of respiratory frequency and tidal volume in a patient who failed a weaning trial. The
arrow indicates the point of resuming spontaneous breathing. Rapid,
shallow breathing developed almost immediately after discontinuation
of the ventilator. [Adapted, with permission, from Tobin MJ, et al. The
pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 134: 1111-1118,
1986 (277).]
3.0
Work (Joules/min)
–10
Pes (cmH2O)
0
2.5
2.0
Work = 4035e (0.0017* f/VT)
r = 0.90
1.5
0
50
150
100
200
Frequency/tidal volume
(b/min/L)
250
Figure 33 The relationship between work of breathing and the
frequency-tidal volume (f/V T ) ratio for a constant alveolar ventilation of
4 L/min based on the model of Otis and collaborators (189). Work of
breathing is least for f/V T ratios of 37 to 59; it increases exponentially
as f/V T increases from 59 to 234/min/L. [Adapted, with permission,
from Tobin MJ, Laghi F and Brochard L. Role of the respiratory muscles
in acute respiratory failure of COPD: lessons from weaning failure. J
Appl Physiol 107: 962-970, 2009 (272).]
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breathing in a patient at the start and end of a trial of spontaneous
breathing. Over the course of the weaning trial, the patient developed
an increase in PaCO2 from 48 to 73 mmHg, but minimal change in
overall work of breathing, suggesting that the hypoventilation resulted
from either failure of respiratory motor output to increase during the
weaning trial or an inability of the respiratory controller to sense the
rise in PaCO2 .
Several groups of investigators have shown that rapid shallow breathing (high frequency, low tidal volume) is a characteristic finding in weaning-failure patients (227, 271, 285)
(Fig. 32). The degree of rapid shallow breathing can be quantified by calculating the ratio of respiratory frequency to
tidal volume (f /V T ) (302). The higher the ratio, the more
severe is the rapid, shallow breathing. An f /V T ratio of 100
breaths/min/L has been shown to be the best predictor of
weaning outcome (302), and has become part of routine diagnostic testing in ventilated patients.
While most patients who fail a weaning trial exhibit an
elevated respiratory motor output and also excessive mechanical load or insufficient respiratory muscle strength (or both),
a small proportion of weaning-failure patients display none
of these features. For example, Jubran and Tobin (127) observed that 2 of 17 (12%) weaning-failure patients developed PaCO2 values greater than 70 mmHg during a weaning
trial, and yet detailed measurements of their lung mechanics
and respiratory muscle function were within the range of the
weaning-success patients (Fig. 34). On the basis of exclusion,
depression of respiratory motor output was judged to be the
dominant reason for acute hypercapnia in these patients.
Respiratory mechanics
Physiological variables for quantifying lung mechanics can
be grouped under three major headings: resistance, elastance,
and gas trapping. The most detailed data on respiratory mechanics in patients being weaned from mechanical ventilation
comes from a study by Jubran and Tobin of 31 patients with
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R insp,L (cmH2O/L/s)
15
Edyn,L (cmH2O/L)
40
PEEPi (cmH2O)
Comprehensive Physiology
5
10
Failure
Success
*P < 0.003
5
0
*
0
2.5
*
0
0
Start
End
Figure 35 Inspiratory resistance of the lung (Rinsp,L ), dynamic lung
elastance (Edyn,L ), and intrinsic positive end-expiratory pressure (PEEPi )
in 17 weaning-failure patients and 14 weaning-success patients. Data
displayed were obtained during the second and last minute of a T-tube
trial, and at one third and two-thirds of the trial duration. Between
the onset and end of the trial, the failure group developed increases
in Rinsp,L (P < 0.009), Edyn,L (P < 0.0001), and PEEPi (P < 0.0001)
and the success group developed increases in Edyn,L (P < 0.006) and
PEEPi (P < 0.02). Over the course of the trial, the failure group had
higher values of Rinsp,L (P < 0.003), Edyn,L (P < 0.006), and PEEPi (P <
0.009) than the success group [Adapted, with permission, from Jubran
A and Tobin MJ. Pathophysiologic basis of acute respiratory distress in
patients who fail a trial of weaning from mechanical ventilation. Am J
Respir Crit Care Med 155: 906-915, 1997 (127).]
COPD undergoing a weaning trial (127). Over the course of a
trial of spontaneous breathing lasting 45 ± 8 min, 17 patients
developed acute distress and an increase in PaCO2 (from 45
to 58 mmHg), requiring the reinstitution of mechanical ventilation. The remaining 14 patients tolerated the trial and were
successfully extubated; these served as a control group.
At the start of the weaning trial, inspiratory lung resistance was markedly elevated, but not significantly different,
in the failure and success patients: 9.0 ± 1.7 versus 5.3 ± 1.1
cmH2 O/L/s (127) (Fig. 35). By the end of the trial, resistance
increased to 14.8 ± 2.0 cmH2 O/L/s in the failure patients, but
it did not change in the success patients. The mechanism of the
progressive increase in inspiratory resistance in the failure patients is not known, although bronchoconstriction consequent
to heightened airway reactivity is a possible candidate.
Dynamic lung elastance was higher in failure patients
than in success patients at the start of the trial: 21.2 ± 3.4
versus 9.9 ± 1.7 cmH2 O/L (127) (Fig. 35). At the end of
the trial, elastance increased to 34.1 ± 4.0 cmH2 O/L in the
failure patients and to 14.0 ± 2.0 cmH2 O/L in the success
patients. The elevated elastance at the start of the trial was
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probably secondary to frequency dependence of elastance.
The mechanism of the progressive increase in elastance over
the course of the trial is uncertain, but it may be related to
progressive dynamic hyperinflation (285) as discussed later.
PEEPi , an indirect measure of gas trapping, was higher
in the failure patients than in the success patients at the onset
of the trial: 2.0 ± 0.5 versus 0.7 ± 0.1 cmH2 O. By the end
of the trial, PEEPi increased to 4.1 ± 0.8 cmH2 O in the failure
patients and to 1.1 ± 0.2 cmH2 O in the success patients (127)
(Fig. 35).
Jubran and Tobin did not partition total PEEPi into the
component resulting from expiratory muscle contraction
and that resulting from an increase in end-expiratory lung
volume. This information was subsequently obtained by
the same group of investigators (191), who partitioned total
PEEPi into that resulting from expiratory muscle contraction
(abdominal muscles, expiratory rib-cage muscles, or both)
by calculating the rise in gastric pressure (Pga ) between
the onset of expiratory flow and the point of rapid decline
in esophageal pressure (Pes ), and the remaining portion,
suggesting an increase in end-expiratory lung volume. After
correcting for expiratory-muscle contribution, the remaining
portion of total PEEPi increased between the start and end
of the weaning trial in seven of the ten patients (191). These
data suggest that many weaning-failure patients develop
dynamic hyperinflation. Expiratory flow limitation (134)
and tachypnea, through a decrease in time available for
exhalation (277), are the most likely determinants of dynamic
hyperinflation. It should be recognized that it has not been
possible to obtain direct measurements of end-expiratory
lung volume in patients experiencing acute respiratory
failure, and the use of esophageal pressure to estimate this
entity is based on many assumptions (310).
Other investigators have also reported a worsening of
lung mechanics in weaning-failure patients. An innovative approach was employed by Vassilakopoulos et al. (285). They
first studied patients at the end of a T-tube trial. Then they
reinstituted ventilation in the assist-control mode, sedated the
patients, and hyperventilated them to abolish spontaneous
respiratory muscle activity. Later, they adjusted the ventilator settings to simulate a patient’s pattern of spontaneous
breathing, and measured lung mechanics under passive conditions. The investigators studied patients at two points in
time: shortly after they first failed a T-tube trial, and about 9
days later, shortly before they were successfully extubated.
Between the time of weaning failure and weaning success,
airway resistance decreased from 9.6 ± 3.4 to 7.9 ± 3.3
cmH2 O/L/s, static PEEPi decreased from 6.1 ± 2.5 to 3.8 ±
2.7 cmH2 O, and static respiratory compliance did not change.
The investigators also disconnected the patients from the ventilator (after first delivering some breaths simulating spontaneous breathing), and allowed them to exhale freely until
zero expiratory flow was reached. This point was taken as the
elastic equilibrium volume of the respiratory system, and the
increase in FRC secondary to gas trapping (PEEPi ) was taken
as the difference between inspired and expired volume. This
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Patient effort
The deterioration in lung mechanics during a failed weaning
trial leads to increased work of breathing. The increased respiratory work is made manifest by greater swings in esophageal
pressure (Fig. 36). In the study of Jubran and Tobin, pressuretime product was not different in the weaning-failure and
weaning-success patients at the onset of a spontaneous breathing trial: 255 ± 59 and 158 ± 23 cmH2 O.s/min (normal,
94 ± 12) (127). At the end of the trial, pressure-time product
increased more in the failure patients than in the success patients: 388 ± 68 versus 205 ± 25 cmH2 O.s/min. The increase
in effort in the failure patients resulted from worsening of
all elements of respiratory mechanics. Partitioning of the increase in pressure-time product at end of the trial revealed that
the fraction caused by PEEPi increased by 111%, that caused
by the non-PEEPi elastic component increased by 33%, and
the fraction caused by the resistive component increased by
42% (127).
In 60 patients being weaned from mechanical ventilation,
Jubran et al. (123) characterized the changes in esophagealpressure swings over the course of a trial of spontaneous
breathing (Fig. 37). The median time (plus interquartile range)
to reach ±10% of the average value of esophageal pressure during the last minute of the trial was 7.5 (4.2–14.8)
min in the weaning-failure patients and 5 (2–8.5) min in the
weaning-success patients (Fig. 38). In contrast, frequency-totidal volume ratio (f /V T ), a measure of rapid shallow breathing, reached ±10% of its final average value at 2 (1–2) min in
both the weaning-success and weaning-failure patients. The
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Flow
(L/s)
1.25
0
–1.25
50
Pes
cmH2O
volume was 327 ± 180 mL during weaning failure, and it fell
to 213 ± 175 mL at the time of weaning success.
The observation that weaning-failure patients display
more severely deranged lung mechanics than do weaningsuccess patients raises the question of whether the derangements might be detectable even before patients reattempt
spontaneous breathing (that is, while patients are still receiving full ventilator support). Jubran and Tobin (126) studied
lung and chest wall mechanics of patients before the onset
of a weaning trial. Inspiratory resistance was about 14 times
higher than that in healthy subjects but it was equivalent in
the failure and success patients: 13.9 and 13.0 cmH2 O/L/s,
respectively. Static elastance of the lung and the chest wall
were similar in the two groups (126). Dynamic elastance of
the lung was higher in the failure patients than in the success
patients, 28 ± 3 versus 17.8 ± 2 cmH2 O/L, and this was the
only measurement of passive mechanics that differentiated
the two groups. Dynamic PEEPi during passive ventilation
was equivalent in the groups. This picture contrasts with the
more severely deranged mechanics in failure patients than in
success patients during a weaning trial (127). The difference
indicates that something in the act of spontaneous breathing,
rather than an intrinsic abnormality in respiratory mechanics,
is responsible for the marked difference between failure and
success patients during a weaning trial.
Comprehensive Physiology
0
–50
0
2
4
0
Time (s)
2
4
6
Figure 36 Respiratory effort during a weaning trial. Recordings of
flow (inspiration directed upward) and esophageal pressure (Pes ) in a
patient with severe COPD who failed a weaning trial (left panel) and
in a weaning-success patient, who had been intubated because of an
opiate overdose (and had no lung disease) (right panel), 10 min into
a trial of spontaneous breathing. The weaning-failure patient exhibits
a steeper fall and greater excursion in esophageal pressure than did
the weaning-success patient—features that signify greater respiratory
motor output. Despite the threefold larger excursion in esophageal
pressure in the weaning-failure patient, peak inspiratory flow in this
patient is only twice as great as in the weaning-success patient, signifying more abnormal mechanics in the weaning-failure patient. The
duration of respiratory cycle was shorter in weaning-failure patient signifying tachypnea. The expiratory flow in the weaning-failure patient
demonstrates a supramaximal flow transient at the beginning of exhalation that is typical of expiratory flow limitation.
more gradual and progressive increase in esophageal pressure
over time may have resulted from a slow increase in PCO2 ,
as commonly occurs in weaning-failure patients (127, 277).
The relative constancy in f /V T may be related to the increases
in both inspiratory resistive and inspiratory elastic loads that
occur in weaning-failure patients. These loads have opposing
effects on breathing pattern. A resistive load slows respiratory
frequency while preserving tidal volume, thereby producing
a decrease in f /V T (29, 309). In contrast, an elastic load increases respiratory frequency accompanied by a decrease in
tidal volume, both of which will produce an increase in f /V T
(28, 208).
Respiratory muscles
Research into the mechanisms whereby abnormalities of
the respiratory muscles might contribute to weaning failure
has focused on inspiratory muscle strength and respiratory
muscle fatigue. Muscle strength has been assessed by measuring the pressure generated during a maximal inspiratory
effort against an occluded airway (143). Early investigators
reported that maximal inspiratory pressure (PI max) was lower
in weaning-failure patients than in weaning-success patients,
but later investigators reported no difference between the
two groups (84, 138, 226, 278, 317) The pattern of reporting
suggests the possibility of test-referral bias, whereby patients
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Flow (L/s)
0.8
0.4
0.0
–0.4
Pes (cmH2O)
10
0
–10
Paw (cmH2O)
–20
8
4
0
–4
10
0
30
20
Time (s)
25
250
20
200
f /VT, (breaths/min/L)
Pes swings (cmH2O)
Figure 37 Progressive increase in inspiratory effort in a weaning-failure patient. Flow (top panel), esophageal pressure (Pes , middle panel), and airway pressure (Paw , lower panel) in a patient who developed severe respiratory distress
while receiving continuous positive airway pressure (CPAP) of 5 cmH2 O. The patient had developed respiratory failure
(requiring mechanical ventilation) after developing a pulmonary embolus subsequent to undergoing lobectomy for lung
cancer. The swings in esophageal pressure became progressively more negative over the first 30 s of the trial.
15
10
5
150
100
50
0
0
10
20
30
0
0
40
Time (min)
10
20
30
40
Figure 38 Time-series plot of swings in esophageal pressure (Pes ; left panel) and frequencyto-tidal volume ratio (f/V T ; right panel) during a trial of spontaneous breathing in a weaningfailure patient. Black dots represent 1-min averages. The solid line indicates the average value
of Pes swings and f/V T of the final minute of the trial. The dashed lines indicate ±10% of the
final minute values of Pes swings and f/V T . The time taken to reach ±10% of the final value
was 14 min for Pes swings and 2 min for f/V T . [Adapted, with permission, from Jubran A,
et al. Weaning prediction: esophageal pressure monitoring complements readiness testing. Am
J Respir Crit Care Med 171: 1252-1259, 2005 (123).]
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with the lowest values of PI max were deliberately excluded
from the subsequently conducted studies (271). Another
consideration is the well-recognized difficulty of ensuring
reliable measurements of PI max, given its total dependence
on patient motivation and cooperation—an even greater
challenge in critically ill patients (143). Studies using phrenic
nerve stimulation, and specifically the technique of twitch
interpolation, revealed that patients being weaned from
mechanical ventilation typically make submaximal efforts
when PI max is being measured. Moreover, Laghi et al. (138)
found that six of nine weaning-failure patients had twitch
Pdi values below 10 cmH2 O. Healthy subjects have twitch
Pdi values of 35 to 39 cmH2 O, and stable patients with
COPD have values of 17 to 20 cmH2 O. Contrary to previous
thinking, these data indicate that weaning-failure patents
may have considerable muscle weakness.
Evidence has been accumulating for the presence of
ventilator-induced respiratory muscle injury as a mechanism
responsible for respiratory muscle weakness (273, 284). A
seminal study showed that 11 days of controlled mechanical
ventilation produced a 46% decrease in respiratory muscle
strength in baboons (8). Subsequent studies have revealed that
complete cessation of diaphragmatic activity with controlled
mechanical ventilation—alone (222) or in combination with
neuromuscular blocking agents (303)—results in injury and
atrophy of diaphragmatic fibers. Muscle fibers generate less
force in response to stimulation, not simply because of their
decreased bulk but even when normalized for cross-sectional
area. The decrease in diaphragmatic force ranges from 20%
to more than 50%. The alterations in muscle function occur
rapidly, within 12 h of instituting mechanical ventilation in
rats (168) and within one day in patients (119). These alterations increase as ventilator duration is prolonged (119, 204).
Oxidative stress appears to be the most proximal mechanism in the biochemical cascade that leads to ventilatorinduced muscle injury (203, 291). Oxidative stress decreases
contractility by causing protein oxidation and by promoting
protein catabolism (203). Other mechanisms that contribute
to muscle-protein loss include apoptosis (168) and decreased
protein synthesis (233).
Levine et al. (154) reported human data that support the
findings of the animal studies. They obtained biopsies of the
costal diaphragms from 14 brain-dead organ donors. These
patients exhibited diaphragmatic inactivity and had received
mechanical ventilation for 18 to 69 h. They also obtained
intraoperative biopsies of the diaphragms of eight patients
undergoing thoracic surgery for suspected lung cancer; these
control patients had experienced diaphragmatic inactivity and
mechanical ventilation for 2 to 3 h. Histologic measurements
revealed marked diaphragmatic atrophy in the brain-dead patients. Compared with the control group, the mean crosssectional areas of muscle fibers were significantly decreased
by more than 50%. Many of these findings have been corroborated by Jaber et al. (119), who also reported a progressive decrease in diaphragmatic contractility of mechanically
ventilated patients—the extent of which was correlated with
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the duration of ventilator support. In the study of Levine
et al. (154), the cross-sectional area of fibers of the pectoralis
major, a muscle not affected by mechanical ventilation, was
equivalent in the two groups. This finding indicates that the
diaphragmatic atrophy experienced by the brain-dead patients
was not part of some generalized muscle-wasting disorder.
Biochemical and gene-expression studies suggest that the
atrophy results from oxidative stress leading to muscle protein
degradation. Evidence of oxidative stress is indicated by a
23% lower concentration of glutathione in the diaphragms
of brain-dead patients than in controls (154). Evidence of
enhanced muscle protein degradation is indicated by a 100%
to 400% greater expression of calpain-1, 2, and 3 (119) and
150% greater expression of active caspase-3 in the braindead patients than in the controls (154). Calpains are calciumactivated proteases implicated in several aspects of skeletal
muscle injury and atrophy (119), and caspase-3 is an enzyme
that can dissociate proteins from the myofibrillar lattice, a
critical step in muscle proteolysis.
Muscle proteolysis typically involves the ubiquitinproteasome pathway, a cytosolic ATP-dependent protease system (143). In this system, proteins catabolized by the proteasome are first “tagged” with a small chain of ubiquitin
molecules. Tagging with ubiquitin is an ATP-requiring process that involves specific “ubiquitin ligases” such as atrogin1 and muscle ring finger-1 (MuRF-1) (143). In the study of
Levine et al. (154), the number of messenger RNA transcripts
for atrogin-1 and MuRF-1 were 200% and 590% higher, respectively, in the brain-dead patients than in the controls. In
the study of Jaber et al. (119), ubiquitinated proteins were
19% higher in the brain-dead patients than in the controls.
For years, researchers had believed that most if not all
weaning-failure patients develop respiratory muscle fatigue
by the completion of a failed weaning trial. This belief was
largely based on observations made by Cohen et al. (49) in a
study of 12 patients who exhibited difficulties during weaning. Seven patients developed a shift in the power spectrum
of the EMG signal recorded from the diaphragm, a finding
judged to signify muscle fatigue (32). In the study of Cohen
et al. (49), six of the seven patients also exhibited paradoxical motion of abdomen (inward displacement of abdomen
during inspiration) and four exhibited respiratory alternans
(phasic alternation between the contribution of the rib-cage
and abdominal compartments to tidal volume). The changes
in rib cage-abdominal motion were not observed in the five
patients who did not develop EMG changes. The investigators concluded that respiratory muscle fatigue was a common
cause of weaning failure and its presence could be detected
by finding paradoxical motion of abdomen.
Subsequent detailed recordings of rib cage-abdominal
motion revealed that when paradoxical motion of the abdomen
occurs in weaning-failure patients, it occurs immediately upon
disconnection from the ventilator and it displays no progression over time (270). In addition, mathematical computations
of the extent of abdominal paradox were no greater in failure patients than in success patients. In studies of healthy
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volunteers, fatigue was found to be neither a necessary nor
a sufficient condition for the development of abnormal rib
cage-abdominal motion (276). These data indicate that rib
cage-abdominal motion cannot be used for detecting respiratory muscle fatigue. The studies, however, did not exclude the
possibility that fatigue is common in weaning-failure patients.
Investigators have evaluated tension-time index as an index of fatigability. Studies in healthy volunteers have shown
that task failure becomes inevitable when subjects breathe
against an inspiratory load that causes the tension-time index
to rise above a threshold of 0.15 (18). In a number of studies (42, 127, 285), weaning-failure patients more commonly
had tension-time index values above 0.15 than did weaningsuccess patients. At completion of a weaning trial, other measures of inspiratory effort, such as pressure-time product,
were also markedly higher in weaning-failure patients, 388
± 68 (SE) cmH2 O.s/min, than in weaning-success patients,
205 ± 25 cmH2 O.s/min (normal, 94 ± 12 cmH2 O.s/min)
(127). Given that the high pressure-time product occurred in
conjunction with marked elevations in respiratory frequency,
37.1 ± 2.5 breaths/min, it is evident weaning-failure patients
experience workloads that are sufficient to induce task failure
and, possibly, respiratory muscle fatigue.
EMG power spectrum and tension-time index provide
only indirect evidence of fatigue, and do not provide direct
proof of its occurrence. The most direct method for detecting fatigue in patients is to stimulate the phrenic nerves and
measure the resulting change in Pdi .When employing this
technique in critically ill patients, it is especially challenging to ensure that successive twitches are all generated at
the same end-expiratory lung volume, to ensure a constant
degree of neural depolarization by the stimulator, and ensure that twitch potentiation (the transient increase in pressure that occurs with a recent forceful contraction) does not
occur (139, 140). Controlling for these factors, Laghi et al.
(138) studied 11 weaning-failure patients and eight weaningsuccess patients before and after a T-tube trial. Twitch Pdi
was 8.9 ± 2.2 H2 O before and 9.4 ± 2.4 H2 O after the trial in
the weaning-failure patients (Fig. 39). The respective values
in the weaning-success patients were 10.3 ± 1.5 and 11.2
± 1.8 cmH2 O. Not a single patient developed a decrease in
twitch Pdi . The absence of fatigue was surprising because
seven of the nine weaning-failure patients had a tension-time
index above the threshold reported to lead to task failure and
fatigue (0.15) (18).
One likely reason that patients did not develop fatigue is
because physicians reinstituted mechanical ventilation before
there was sufficient time for its development. The relationship
between the tension-time index and the length of time that a
load can be sustained until task failure follows an inversepower function. Bellemare and Grassino (18) expressed the
relationship as: time to task failure = 0.1 * (tension-time
index)−3.6 . The increase in the tension-time index over the
course of the weaning trial (138) and predicted time to task
failure (18) are shown in Figure 40. At the point that the
physician reinstituted mechanical ventilation, patients were
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After
Before
15
Pes
(cmH2O)
Pga
(cmH2O)
0
–15
40
20
0
Pdi
(cmH2O)
40
20
0
10
R-CMAP
(a.u.)
0
–10
10
L-CMAP
(a.u.)
0
–10
0
0.2
0.4
0
Time (s)
0.2
0.4
Figure 39 Esophageal pressure (Pes ), gastric pressure (Pga ), transdiaphragmatic pressure (Pdi ), and compound motor action potential
(CAMP) of the right and left hemidiaphragm after phrenic nerve stimulation before (left) and after (right) a T-tube trial in a weaning failure
patient. The end-expiratory value of Pes and the amplitude of the right
and left CAMPs were the same before and after the trial, indicating that
the stimulations were delivered at the same lung volume and that the
stimulations achieved the same extent of diaphragmatic recruitment.
The amplitude of twitch Pdi elicited by phrenic nerve stimulation was
the same before and after weaning. [Adapted, with permission, from
Laghi F, et al. Is weaning failure caused by low-frequency fatigue of the
diaphragm? Am J Respir Crit Care Med 167: 120-127, 2003 (138).]
predicted to be an average of 13 minutes away from task
failure. Moreover, the time to task failure was underestimated
because diaphragmatic recruitment during maximal voluntary
contractions was incomplete (138). In other words, patients
display clinical manifestations of severe respiratory distress
for a substantial time before they develop fatigue. In an intensive care setting, these clinical signs will lead clinicians
to reinstitute mechanical ventilation before fatigue has time
to develop. Other factors that might have protected the respiratory muscles from contractile fatigue include development
of dynamic hyperinflation because susceptibility to fatigue
is greater when a fatiguing protocol is conducted at optimum
muscle length rather than when a muscle is shortened (88), and
activation of extradiaphragmatic muscles of respiration (191).
In a study of 19 patients being weaned from mechanical
ventilation (191), all but one of the 11 weaning-failure patients exhibited expiratory muscle activity (the exception being a patient with paraplegia). Expiratory muscle activity—as
quantified by the expiratory rise in Pga —was absent in all but
three of eight weaning-success patients, and its magnitude
was trivial in the remainder (Fig. 41). At the onset of the
trial, the expiratory rise in Pga was equivalent in the failure
and success groups, 0.9 ± 0.5 and 0.1 ± 0.1 cmH2 O, respectively (P = 0.3). At the end of the trial, the expiratory rise in
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6
50
Expiratory rise in Pga (cmH2O)
Predicted time to task failure (min)
60
40
30
20
10
0.3
0.2
Tension-time 0.1
index
0.0
2
0
0
10
20
30
40
50
Duration of spontaneous breathing
trial (min)
Figure 40 Interrelationship between the duration of a spontaneous
breathing trial, tension-time index of the diaphragm, and predicted
time to task failure in nine patients who failed a trial of weaning from
mechanical ventilation. The patients breathed spontaneously for an average of 44 min before a physician terminated the trial. At the start of
the trial, the tension-time index was 0.17, and the formula of Bellemare
and Grassino (18) (see text for details) predicted that patients could
sustain spontaneous breathing for another 59 min before developing
task failure. As the trial progressed, the tension-time index increased
and the predicted time to development of task failure decreased. At
the end of the trial, the tension-time index reached 0.26. That patients
were predicted to sustain spontaneous breathing for another 13 min
before developing task failure clarifies why patients did not develop a
decrease in diaphragmatic twitch pressure. In other words, physicians
interrupted the trial on the basis of clinical manifestations of respiratory distress, before patients had sufficient time to develop contractile
fatigue. [Adapted, with permission, from Laghi F, Tobin MJ: Disorders
of the respiratory muscles. Am J Respir Crit Care Med 2003; 168:10
(143).]
Pga increased to 4.4 ± 1.1 cmH2 O in the failure group (P =
0.0005), whereas it did not change, 0.1 ± 0.1 cmH2 O, in the
success group (P = 0.4). Compared with the success group,
the failure group exhibited larger increases in expiratory rise
in Pga (P = 0.004). In the failure group, expiratory muscle
activity accounted for 53 ± 4% of total PEEPi throughout the
weaning trial.
In patients with COPD experiencing acute respiratory failure, heightened activation of the expiratory muscles represents an automatic component of the response of the respiratory system to very high levels of ventilatory stimulation
(183,301,305). Consistent with this viewpoint is the observed
correlation between expiratory muscle activation and respiratory motor output, estimated as the rate of change in Pes :
r = 0.57 (0.12-0.82), P = 0.02 (191). Thus, irrespective of
the underlying ventilatory defect (77), expiratory muscle recruitment appears to be part of the normal response of the
respiratory centers to increased ventilatory demands (77,143).
In healthy subjects, expiratory muscle recruitment helps
inspiration because the active reduction in end-expiratory lung
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4
Last minute
First minute
Spontaneous breathing trial, time sextiles
Figure 41 Expiratory rise in gastric pressure (Pga ) during the course
of a weaning trial in failure ( ) and success patients ( ). Between the
onset and the end of the trial, increases in expiratory rise in Pga (P =
0.0005) occurred in failure patients but not in the success patients. Over
the course of the trial, failure patients had higher values of expiratory
rise in Pga (P = 0.004) than success patients. Bars represent ± SE.
[Modified, with permission, from Parthasarathy S, Jubran A, Laghi F
and Tobin MJ. Sternomastoid, rib-cage and expiratory muscle activity
during weaning failure. J Appl Physiol 103: 140-147, 2007 (191).]
volume stores elastic energy in the diaphragm and abdomen.
At the end of exhalation, the expiratory muscles relax and
the release of stored energy causes intrathoracic pressure to
fall and inspiratory flow to start before the diaphragm begins to contract (143). When stable, about 60% of patients
with COPD have expiratory flow limitation (72), which hinders the expiratory muscles from lowering lung volume and,
thus, patients cannot benefit from this action of the expiratory
muscles. In the patients of Parthasarathy et al. (191), expiratory muscle contraction was, if anything, associated with
an increase, rather than a decrease, in end-expiratory lung
volume. The expiratory muscles are effective in assisting inspiration in the upright posture, but they may be less effective
in semirecumbent patients. Even when it is beneficial, expiratory muscle contraction naturally imposes a cost in energy
expenditure (4). When expiratory muscle contraction is of no
potential benefit, as in patients with expiratory flow limitation, it may be detrimental and contribute to the development
of acute respiratory failure.
In the study of Parthasarathy et al. (191), sternomastoid
EMG activity, measured with fine-wire electrodes, was evident in 83 ± 9% of all the breaths in the weaning-failure
group and in 19 ± 10% of all breaths in the weaning-success
group (P = 0.002) (Fig. 42). Sternomastoid activity became
evident within the first minute of the trial in 8 of the 11 failure
patients and 1 of the 8 success patients. By the end of the
trial, sternomastoid activity was noted in all failure patients
but in only three of the success patients, and this activity was
modest. The immediate increase in sternomastoid activity in
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First minute
2
Flow (L/s)
Last minute
40% of trial
duration
1
0
–1
Pes (cmH2O)
–2
10
0
–10
EMGscm
(arb units)
–20
2
1
0
–1
–2
0
2
4
6
8
0
2
4
6
8
0
2
4
6
8
Time (s)
Figure 42 Representative tracings of flow, Pes , and EMGscm in a weaning-failure patient.
Recordings were obtained during the first minute of the weaning trial, 40% of trial duration,
and last minute of the trial. Phasic inspiratory activity of the sternomastoid muscle was evident
within the first minute of the trial, and it increased progressively over the course of the trial. Note
that phasic activity of the sternomastoids persists into expiration. [Adapted, with permission, from
Parthasarathy S, Jubran A, Laghi F and Tobin MJ. Sternomastoid, rib-cage and expiratory muscle
activity during weaning failure. J Appl Physiol 103: 140-147, 2007 (191).]
the failure patients probably results from increased respiratory motor output in response to a combination of decreased
capacity of the respiratory muscles to generate pressure (138)
and an increase in mechanical load that occurs early during
the weaning trial. In addition to increased sternomastoid activity, weaning-failure patients displayed greater inspiratory
rib-cage muscle contribution to tidal breathing throughout the
trial than did the success patients (Fig. 43).
A striking feature of the weaning-failure patients is the
timing at which different muscle groups become active (191).
The sequence begins with activity of the diaphragm and with
greater activity of inspiratory rib-cage muscles than is the
case in the success patients; recruitment of sternomastoids and
rib-cage muscles is near maximum within 4 min of trial commencement, whereas the expiratory muscles are not recruited
until quite late in the trial [at 17-20 min (191)]. The existence
of a hierarchy of respiratory muscle activation is supported
by the known delayed activation of the sternomastoid muscles
(111) and expiratory muscles in healthy volunteers (145,300)
and in ambulatory patients with COPD (53).
In addition to extradiaphragmatic muscle recruitment, another factor that may protect the diaphragm of weaning-failure
patients from long-lasting fatigue is the activation of neural
pathways designed to inhibit inspiratory muscle recruitment
in the face of potentially fatiguing loads. This possibility is
supported by studies conducted in laboratory animals wherein
inspiratory loading causes respiratory failure and acidosis be-
Volume 2, October 2012
fore force output decreases or substrate is depleted in the
diaphragm (2, 181, 211, 224). These observations suggest that
central (57, 255) and reflex mechanisms (109, 249) affect the
breathing pattern (210) and α-motoneuron firing rates (167)
in response to loading. Two neural pathways may convey information from the respiratory muscles to the central nervous
system (57, 197). One pathway transmits information from
mechanoreceptors [Golgi tendon organs and muscle spindles
(109, 159)] in the dorsal column, and relays it to the brainstem and thalamus before reaching the sensimotor cortex
(159, 320). This pathway may participate in proprioceptive
control of the respiratory muscles, integrating movements
originating in the motor cortex (255). The second pathway
consists of vagal (2,159) and possibly phrenic nerve afferents
[group IV phrenic afferent fibers (109)] that reach the amygdala after relaying in the brainstem and then projecting to
the mesocortex [cingulated gyrus (159)]. This pathway may
deal with respiratory nociception (51, 255), such as dyspnea
[through the relay in the amygdala (20)], and the ventilatory
response to carbon dioxide [through the relay in the brainstem,
ventral cerebellum, and limbic system (102)] (51,255). In addition to these two pathways projecting to the central nervous
system, there is evidence for the existence of a spinal pathway
responsible for phrenic-to-phrenic reflex inhibition (249). The
net effect of these reflex pathways may be to inhibit the inspiratory muscles in the face of potentially fatiguing loads,
thereby protecting them from irreversible damage at the cost
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Weaning success
–30
Start
End
–20
ΔPes (cmH2O)
–10
0
Weaning failure
–40
–30
–20
–10
0
–30
–15
0
15
–30
–15
0
15
ΔPga (cmH2O)
Figure 43 Plots of tidal changes in esophageal pressure (Pes ) against tidal
changes in gastric pressure (Pga ) in a weaning-success patient and a weaningfailure patient. At the start of a weaning trial, the success patient (top left panel)
exhibited swings in esophageal pressure that became markedly more negative
between the onset (closed symbol) and the end of inspiration (open symbol); in
contrast, gastric pressure increased only slightly. Therefore, the slope of the Pes Pga plot at the onset of weaning (top left panel) was much greater than the slope
recorded in healthy subjects during resting breathing, where the tidal change in
gastric pressure is often greater than the tidal change in esophageal pressure.
The steep Pes -Pga plot (top left panel) indicates a greater-than-usual contribution
of the rib-cage muscles to tidal breathing than that of the diaphragm. Between
the onset (top left panel) and the end of weaning (top right panel), the slope
of the Pes -Pga plot changed very little, indicating a constant contribution of the
diaphragm and rib-cage muscles to tidal breathing over the course of the weaning trial. In the case of the weaning-failure patient, the inspiratory swings in
esophageal pressure and gastric pressure had a similar pattern at the start of
the trial to that in the success patient (bottom left panel). At the end of the trial,
the failure patient exhibited a markedly negative slope in the Pes -Pga plot, signifying a further increase in inspiratory rib-cage muscle recruitment that was out
of proportion to diaphragmatic recruitment.
of CO2 retention. Finally, an increase in CO2 during loading may also protect the respiratory muscles by decreasing
production of reactive oxygen species (253).
Cardiovascular performance
Although the respiratory muscles may not develop fatigue,
they have to overcome a huge workload. Thus, they depend
on an efficient transport of oxygen by the cardiovascular system. Aware of this fact, several researchers have examined
cardiovascular performance during weaning. Lemaire et al.
(151) studied 15 patients with severe COPD who were difficult to wean (seven of whom had documented ischemic
heart disease). During unassisted breathing the patients developed evidence of cardiovascular stress including increases
in transmural pulmonary artery wedge pressure, cardiac in-
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dex, and left- and right-ventricular end-diastolic volume.
The investigators attributed the increase in left-ventricular
end-diastolic volume to augmentation of venous return (secondary to low pleural pressure during spontaneous breathing
and central translocation of blood volume secondary to peripheral vasoconstriction) and increased left-ventricular afterload (secondary to markedly negative pleural pressure swings
and increased catecholamine release).
Jubran et al. (125) continuously recorded cardiovascular
performance and mixed venous oxygen saturation in eight
weaning-failure and 11 weaning-success patients over the
course of trials of spontaneous breathing that lasted about
40 min. Immediately before the trial, mixed venous oxygen
saturation was equivalent in the two groups. On discontinuation of the ventilator, saturation fell progressively in the
failure patients (to 51.5 ± 7.9% at end of trial), whereas
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it did not change in the success patients. Right- and leftventricular afterload increased in the failure patients—most
likely because the negative swings in intrathoracic pressure
were more extreme during the course of spontaneous respiration. At the completion of the trial, the level of oxygen
consumption was equivalent in patients who could be weaned
and in those who could not. How the cardiovascular system
met oxygen demands differed in the two groups (125). In the
weaning-success patients, oxygen demands were met through
an increase in oxygen delivery, mediated by the expected
increase in cardiac output on discontinuation of positivepressure ventilation. In the weaning-failure patients, oxygen
demands were met through an increase in oxygen extraction,
and these patients had a relative decrease in oxygen delivery (125). The greater oxygen extraction caused a substantial
decrease in mixed venous O2 saturation, contributing to the
arterial hypoxemia that occurred in some patients (125).
In an investigation of similar design, Zakynthinos et al.
(317) studied 12 weaning-success and 18 weaning-failure patients during a spontaneous breathing trial. Half of the failure
patients increased their oxygen consumption and this increase
was met mainly by an increase in oxygen extraction. The remaining half of the failure patients did not exhibit an increase
in oxygen consumption; instead, increase in oxygen delivery
was accompanied by a decrease in oxygen extraction. These
studies (125, 151, 317) demonstrate variability in circulatory and global tissue oxygenation responses during weaning
failure.
In these investigations (125,151,317), all weaning-failure
patients developed respiratory distress, suggesting that they
developed increases in respiratory motor output. The response
of the respiratory centers, however, was not uniform. During a
weaning trial, the patients of Lemaire et al. (151) experienced
a decrease in the negative swings in intrathoracic pressure. In
contrast, Jubran et al. (125) recorded an increase in the negative swings in intrathoracic pressure. Many patients in these
investigations developed acute or acute-on-chronic alveolar
hypoventilation. It is not known how the respiratory centers
integrate afferent information from the cardiovascular system, respiratory system and peripheral muscles in generating
neural volleys to the respiratory muscles.
Gas exchange
A primary goal of mechanical ventilation is to improve gas
exchange, and accordingly one expects some deterioration in
gas exchange with the resumption of spontaneous breathing.
The most detailed study of gas exchange during weaning is
that conducted by Beydon et al. (23). They studied eight patients with COPD who were considered ventilator dependent
(although the patients were able to sustain at least 1-3 h of
spontaneous breathing). When switched from controlled ventilation, patients developed an increase in frequency, fall in
tidal volume (without change in minute ventilation), and an
increase in PaCO2 (41 to 49 mmHg). Using the multiple inert gas technique, the investigators found that the distribution
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of ventilation to regions of ventilation-perfusion (V̇A / Q̇) relationships above 100 (i.e., dead space) increased from 39 ± 8%
during controlled ventilation to 46 ± 7% during spontaneous
breathing. Perfusion of low V̇A / Q̇ regions was higher during spontaneous breathing than during controlled ventilation
(15 ± 11 vs. 6 ± 8%). The investigators also performed isotope scans, which revealed a decrease in V̇A / Q̇ ratios between
the apex and the base of the lungs. This observation indicated
that the low V̇A / Q̇ units identified by the inert-gas technique
were located at the lung bases. The major determinant of the
V̇A / Q̇ abnormalities was the size of tidal volume: it correlated
with perfusion in the low V̇A / Q̇ range, the decrease of V̇A / Q̇
ratios in the bases, and widening of the isotopic craniocaudal
gradient. The maldistribution of V̇A / Q̇ ratios during spontaneous breathing was improved by controlled ventilation but
not by pressure support of 10 cmH2 O.
Torres et al. (281) used the multiple inert-gas technique
to study eight patients with COPD who were apparently successfully weaned. Measurements were first obtained during
assist-control ventilation (tidal volume 700 mL, frequency 12
breaths/min). On discontinuation of the ventilator, the patients
developed rapid shallow breathing (relative to ventilator settings) and acute respiratory acidosis (increase in PaCO2 from
49 to 59 mmHg, decrease in pH from 7.42 to 7.36). Spontaneous breathing caused an overall worsening of ventilationperfusion inequality: the fraction of cardiac output distributed
to low V̇A / Q̇ (< 0.1) areas increased from 9.4 to 19.6%
and the dispersion of ventilation distribution increased. Despite the deterioration in V̇A / Q̇ relationships, the expected
fall in PO2 was prevented by an increase in cardiac output
(4.7 to 6.7 L/min) and increase in mixed venous PO2 (37 to
42 mmHg). A largely similar pattern of gas exchange was
reported by Ferrer et al. (82), who studied seven patients with
COPD that were not yet ready to tolerate complete discontinuation of mechanical ventilation.
Extubation
Virtually no pathophysiologic studies have been conducted on
patients who develop such severe respiratory distress following the removal of an endotracheal tube that they require reintubation and the reinstitution of mechanical ventilation. Two
factors make it especially challenging to conduct research
in this setting. The first is instrumentation. The recording of
swings in intrathoracic pressure, as reflected by esophageal
pressure, is relatively easy, but of limited value on its own.
The derivation of most physiologic indices, such as pulmonary
resistance, compliance and intrinsic PEEP, requires a simultaneous measurement of airflow. The use of a mouthpiece or
face mask for recording airflow is particularly difficult in a
recently extubated dyspneic patient, and is likely to distort the
very variables an investigator wishes to measure. The second
challenge is the timing. Weaning failure almost invariably
occurs within the first hour of attempted spontaneous breathing. The time course for the development of postextubation
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cardiorespiratory distress extends over a longer span, and
many patients do not develop distress until many hours after
extubation. Consequently, investigators and their instruments
have typically long left the scene by the time the problem
becomes manifest.
Management of weaning
Discontinuation of mechanical ventilation needs to be carefully timed. Premature discontinuation places severe stress on
the respiratory and cardiovascular systems, which can impede
a patient’s recovery. Unnecessary delays in ventilator discontinuation can lead to a host of complications and several
measurements are used to aid decision making. The level
of oxygenation must be satisfactory before one attempts
to discontinue mechanical ventilation. Yet in many patients with satisfactory oxygenation, such attempts fail. The
use of traditional predictors of the success or failure of
attempts—maximal inspiratory pressure, vital capacity, and
minute ventilation—frequently yield false-positive or falsenegative results (266).
A more reliable predictor is the ratio of respiratory frequency to tidal volume (f /V T ) (302). The higher the ratio, the
more severe the rapid, shallow breathing and the greater the
likelihood of unsuccessful weaning. The reliability of f /V T ratio as a predictor of weaning outcome has been evaluated by
at least 29 groups of investigators (271). When data from the
studies were entered into a Bayesian model with pretest probability as the operating point, the reported positive-predictive
values were significantly correlated with the values predicted
by the original report on f /V T (302), r = 0.86 ( P < 0.0001);
likewise, reported negative-predictive values were correlated
with the values predicted, r = 0.82 (P < 0.0001) (271). The
average sensitivity of 0.87 indicates that f /V T is a reliable
screening test for successful weaning.
Once the recorded values on weaning-predictor tests suggest that a patient has a reasonably good chance of tolerating
the discontinuation of mechanical ventilation, the next step is
to undertake a formal weaning trial. Two approaches involve
the use of a T-tube circuit, whereby the patient either proceeds
immediately to a trial of spontaneous breathing lasting for up
to two hours or trials begin briefly (lasting only 5-10 min) and
the duration is gradually extended (weaning in the literal sense
of the work). Two other approaches involve a gradual reduction in the level of ventilator assistance. When IMV is used
for this purpose, the number of ventilator-assisted breaths is
gradually decreased in response to patient tolerance. When
pressure support is used, the level of pressure is gradually
decreased (266).
Until the early 1990s, it was widely believed that all weaning methods were equally effective, and physician judgment
was regarded as the critical determinant. Results of randomized controlled trials, however, indicate that the period of
weaning is as much as three times as long with IMV as with
trials of spontaneous breathing (34, 75). In a study involving
patients who experience respiratory difficulties during wean-
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ing, trials of spontaneous breathing halved the weaning time
as compared with pressure support (75); in another study, the
weaning time was similar with the two methods (34). Performing trials of spontaneous breathing once a day is as effective
as performing such trials several times a day (75)—but much
simpler. In a subsequent study, half-hour trials of spontaneous
breathing were as effective as 2-h trials in patients undergoing
their first weaning attempt (73).
When patients are able to sustain spontaneous ventilation
without undue discomfort, they are extubated. About 10% to
20% of such patients require reintubation (34, 75). Mortality among patients who require reintubation is more than six
times as high as mortality among patients who can tolerate
extubation (73). The reason for the higher mortality is unknown; it is not clearly related to the development of new
problems after extubation or to complications of reinserting
the tube. Indeed, the need for reintubation may simply be a
marker of a more severe underlying illness.
Several investigators have studied the usefulness of noninvasive ventilation as a means of making the process of weaning and extubation more expeditious and effective. At least
three groups of investigators have reported that the institution of noninvasive ventilation in certain patients (in particular those with COPD) is beneficial if instituted at the point
when patients have just failed a trial of spontaneous breathing
(81, 97, 179). In contrast, two groups of investigators have
reported that noninvasive ventilation is not beneficial in postextubated patients when instituted after they already have
clinical manifestations of respiratory distress. In the latter
two studies, however, the level of ventilator assistance, pressure support of 5 cmH2 O (131) or delivered tidal volume of as
little as 5 mL/kg (76), may have been inadequate to truly test
the efficacy of noninvasive ventilation in this circumstance.
Coda
The respiratory control system plays a fundamental role in
the three topics covered in this article: ventilatory failure,
mechanical ventilation, and ventilator weaning. Abnormalities in respiratory mechanics and pulmonary gas exchange
contribute to the development of ventilatory failure, but it is
the performance of the respiratory controller that determines
whether or not a patient will be able to sustain spontaneous
ventilation without requiring ventilator assistance. While a patient is being supported by mechanical ventilation, abnormalities in respiratory mechanics and gas exchange again influence
the selection of ventilator settings, but the most challenging
component of ventilator management—achieving satisfactory
interaction between the patient and the machine—depends
crucially on knowledge of the respiratory control system. Indeed, new ventilator modes introduced with the specific intent
of improving patient-ventilator synchronization, such as PAV
and NAVA, operate through modulation of respiratory motor
output on a breath-by-breath basis. Finally, when patients fail
a trial of weaning from mechanical ventilation, abnormalities
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of respiratory muscle function, cardiovascular performance
and respiratory mechanics are all involved, but the physiological hallmark of weaning failure—rapid shallow breathing—is
a manifestation of altered respiratory motor output.
Despite the fundamental importance of control of breathing in every aspect of acute respiratory failure and ventilator
management, it is the component of pulmonary physiology
that poses the greatest challenge to clinicians and with which
they feel the greatest unease. At least two factors contribute
to this unsatisfactory state of affairs. One is the lack of direct
methods for monitoring the major sensory inputs to the respiratory control system (mechanoreceptor and vagal stimuli,
and so on) and the absence of a simple measure of respiratory
motor output, in contrast with the ready availability of methods for monitoring gas exchange and respiratory mechanics at
a patient’s bedside. The second, and more fundamental, factor
is the complexity of the physiological mechanisms involved
in the respiratory control system and the likelihood that our
knowledge has progressed considerably less in this field than
in other areas of respiratory pathophysiology.
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