Respiratory Physiology & Neurobiology 240 (2017) 17–25

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Respiratory Physiology & Neurobiology

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Determinants of cough effectiveness in patients with respiratory

muscle weakness
Franco Laghi a,b,∗ , Veeranna Maddipati a,b , Timothy Schnell a,b , W. Edwin Langbein b ,
Martin J. Tobin a,b
a
Loyola University of Chicago Stritch School of Medicine, Maywood, IL, United States
b
Hines Veterans Affairs Hospital, Hines, IL, United States

a r t i c l e i n f o a b s t r a c t

Article history: Experiments were undertaken to mechanistically define expiratory-muscle contribution to effectiveness
Available online 16 February 2017 of cough while controlling glottic movement. We hypothesized that electrical abdominal-muscle stimu-
lation in patients with respiratory-muscle weakness produces effective coughs only when glottic closure
Keywords: accompanies coughs. In ten spinal-cord-injury patients, esophago-gastric pressure and airflow were
Tracheostomy recorded during solicited-coughs, coughs augmented by abdominal-muscle stimulation, and passive
Glottis
open-glottis exhalations. During solicited-coughs, patients closed the glottis initially; five were flow-
Spinal cord injury
limited, five non-flow-limited. Stimulations during solicited-coughs or open-glottis exhalations elicited
Neuromuscular electrical stimulation
Abdominal muscles similar driving pressures (changes in gastric pressure; p < 0.001). Despite high driving pressures, stimula-
tions induced flow-limitation only when patients transiently closed the glottis – not during open-glottis
exhalations. That is, transient glottic closure enabled transmission of abdominal (driving) pressure to the
thorax during cough, while impeding dissipation of intrathoracic pressure. In conclusion, transient glottic
closure is necessary to render cough effective in patients with respiratory-muscle weakness, indicating
that failure to close the glottis contributes to ineffective cough in weak tracheostomized patients and
patients with bulbar disorders.
© 2017 Elsevier B.V. All rights reserved.

1. Introduction
Cough plays a major role in problems experienced by patients
with a wide variety of respiratory diseases (Dicpinigaitis et al.,
2012), especially patients with neuromuscular disorders (Laghi
and Tobin, 2003). Our understanding of the integrated physiology
of cough, however, is rudimentary. Cough is a complex respira-
tory movement involving mucus, and coordinated recruitment of
inspiratory muscles, expiratory muscles and the glottis (Hasani
et al., 1994; Lasserson et al., 2006; Polkey et al., 1998; Smith et al.,
2012). The goal of this coordinated activity is to generate high
intrathoracic pressure when the glottis closes briefly during a cough
(Knudson et al., 1974; Ross et al., 1955). High intrathoracic pres-
sure is necessary to induce dynamic airway compression – a key
∗ Corresponding author at: Division of Pulmonary and Critical Care Medicine,
Hines VA Hospital (111N), 5th Ave & Roosevelt Rd, Hines, IL 60141, United States.
E-mail addresses: flaghi@lumc.edu (F. Laghi), maddipativ15@ecu.edu
(V. Maddipati), timothy.schnell@gmail.com (T. Schnell), langbein@comcast.net
(W.E. Langbein), mtobin2@lumc.edu (M.J. Tobin).
factor in achieving effective cough (Estenne et al., 1994). This com-
bination (high intrathoracic pressure and transient compression
of the airway) facilitates the achievement of a flow of air at high
linear velocity through the airways (Knudson et al., 1974; Kulnik
et al., 2016). The high velocity of air transfers kinetic energy to
intraluminal secretions, shearing them off the bronchial wall and
carrying them towards the mouth (Ross et al., 1955; Sivasothy et al.,
2001). Transient airway compression also promotes development
of turbulent expiratory flow, which creates additional shear forces,
contributing to the dislodgement of secretions (King et al., 1985;
Zahm et al., 1991).
In patients with airway obstruction, forced expectoration while
the glottis is open − so-called huffing − is as effective as cough
in clearing radioactive particles (Hasani et al., 1994; Sutton et al.,
1983) and expelling mucus (Hasani et al., 1994). The effective-
ness of this open-glottis maneuver likely rests on the achievement
of high transpulmonary pressure (Langlands, 1967), which gen-
erates a flow of air at high linear velocity through the airways.
High transpulmonary pressure cannot be achieved by expiratory
muscle contraction in patients with respiratory muscle weakness

http://dx.doi.org/10.1016/j.resp.2017.02.005
1569-9048/© 2017 Elsevier B.V. All rights reserved.
18 F. Laghi et al. / Respiratory Physiology & Neurobiology 240 (2017) 17–25
(Laghi and Tobin, 2003). This consideration raises the possibility
that the effectiveness of cough in patients with muscle weakness
may be critically dependent on transient closure of the glottis. Glot-
tic closure prevents dissipation – within the thorax – of abdominal
pressure generated by expiratory muscle contraction (the driving
pressure for cough).
Isolating and defining the precise contribution of expiratory
muscle contraction to the effectiveness of cough while concur-
rently controlling movement of the glottis is impossible in healthy
subjects. To overcome this obstacle, we took advantage of an
experiment of nature and employed external stimulation of the
expiratory muscles in patients with spinal-cord injury. Incremental
stimulation of paralyzed expiratory muscles in patients able to vol-
untarily close their glottis provides a unique opportunity to unravel
the mechanistic contribution of abdomino-thoracic pressure in
determining whether a cough is effective or not. Stimulations were
delivered during a solicited cough (when the glottis is closed tran-
siently), and during a passive exhalation (when the glottis is open).
We defined the effectiveness of cough in operational terms: that
expiratory muscle contraction (in response to external stimula-
tion) generated an abdominal pressure (the driving pressure for
cough), which, following transmission to the thorax, was sufficient
to induce dynamic airway compression. Various methodologies
have been employed to determine whether dynamic airway com-
pression occurs during cough, such as radiography (Ross et al.,
1955), video-endoscopy (Estenne et al., 1994), and pressure-flow
relationships (a plot of peak expiratory flow against correspond-
ing esophageal pressure during a cough) (Estenne et al., 1994). The
development of a plateau on a flow tracing (of a pressure-flow
curve) signifies expiratory flow limitation, and occurs only as a
result of dynamic airway compression (Estenne et al., 1994).
The goal of this study was to define mechanistically the con-
tribution of expiratory muscle contraction to the effectiveness of
cough while concurrently regulating glottic movements. Specifi-
cally, we hypothesized that stimulation of the abdominal muscles
in patients with respiratory muscle weakness produces an effective
cough only when there is accompanying (transient) glottic closure.
2. Methods
(See online supplement for additional details)
2.1. Patients
Ten patients with spinal-cord injury were recruited (Table 1).
Patients were selected if their injury resulted in motor impairment
above the seventh thoracic level based on clinical estimation of the
neurological impairment (McBain et al., 2013). Exclusion criteria
included need for mechanical ventilation or tracheostomy, abdom-
inal pathology that could have interfered with electrode placement
and stimulation, and presence of implanted electronic devices such
as cardiac pacemakers, defibrillators and intrathecal pumps. The
study was approved by the local human studies subcommittee.
Written informed consent was obtained from all patients.
2.2. Experimental setup
2.2.1. Flow and pressure measurements
Airflow was measured at the mouth with a heated pneumota-
chometer connected to a differential pressure transducer. Volumes
were obtained by electronic integration of the flow signal.
Esophageal (Pes) and gastric (Pga) pressures were separately
measured with balloon-tipped catheters coupled to pressure trans-
ducers (Mador et al., 1996). Airway pressure (Paw) was measured
at the mouthpiece using a third pressure transducer
2.2.2. Electrical stimulation of the abdominal muscles
Stimulations of the abdominal muscles were delivered by means
of surface electrodes. Electrodes were applied using an ante-
rior configuration and anterolateral configuration as previously
described (Gollee et al., 2008; Kandare et al., 2002; Langbein et al.,
2001) (Fig. 1). We tested two different configurations to determine
whether four electrodes (anterior configuration) would suffice to
achieve expiratory flow limitation or whether eight electrodes
(anterolateral configuration) would be needed to achieve that goal.
An electrical stimulator was connected to the anterior elec-
trodes. A second stimulator was connected to the anterolateral
electrodes (Fig. 1). Both stimulators were programmed to gener-
ate trains of electrical impulses with a 250 ␮s pulse width, at a
frequency of 50 Hz for duration of 1 s (Butler et al., 2011). Dur-
ing anterolateral stimulations, the two stimulators were linked to
deliver the stimulations simultaneously.
Stimulations were triggered once 300 milliseconds of absent
inspiratory flow (zero flow or expiratory flow) had elapsed from
the manual activation of a handheld switch controlled by an inves-
tigator.
The minimum current used with the anterior configuration (4
electrodes) and anterolateral configuration (8 electrodes) was that
which caused sufficient abdominal-muscle recruitment to pro-
duce a 4 cmH2 O rise in Pga (threshold stimulation) while patients
relaxed at end-expiratory lung volume with nose clipped and
mouthpiece occluded.
2.2.3. Electromyogram (EMG) abdominal muscles
To assess whether electrical stimulations were properly timed,
one pair of surface electrodes was applied over the external oblique
(Laghi et al., 2014) (Fig. 1).
2.3. Experimental protocol
Patients were studied while supine with the head of the bed
raised 30◦ from the horizontal position. After placement of all trans-
ducers and electrodes, patients were instructed to carry out the
following maneuvers.
2.3.1. Maximal expiratory efforts
Patients were instructed to perform at least five maximal expi-
ratory efforts against a valve that could be closed by turning a tap.
Maximal expiratory pressure was measured at total lung capacity
(TLC).
2.3.2. Unassisted solicited coughs
To determine whether expiratory flow limitation was achieved
during unassisted cough, patients performed a series of 12–23
solicited coughs of varying intensity commencing from TLC
(Estenne et al., 1994). After each cough, patients were told how
strong the next cough should be (Estenne et al., 1994). A 1-to-
2 min period of resting breathing elapsed between two successive
solicited coughs.
2.3.3. Solicited coughs combined with electrical stimulations of
abdominal muscles
To determine whether stimulations combined with solicited
coughs could induce expiratory flow limitation, patients performed
a series of forceful solicited coughs commencing from TLC while
concurrently receiving stimulations using the anterior (10–15
coughs) and anterolateral electrode configuration (9–15 coughs).
Stimulator current (mA) was set between 20 and 100% of the cur-
rent range, starting from the threshold stimulation to the maximum
output achievable by the stimulator(s) (100 mA) (Lee et al., 2008).
 F. Laghi et al. / Respiratory Physiology & Neurobiology 240 (2017) 17–25 19

Table 1
Patients’ characteristics.

Patient Age Months since Injury Level and Maximal expiratory pressure Expiratory flow limitation Reason for Injury
(years) ASIA grade (percent predicted)a

1 46 269 C 5–7, A 33.7 (+) MVA

2 39 77 C 5–7, A 25.8 (+) MVA
3 62 395 C 5–7, A 28.1 (+) MVA
4 66 137 C 5–7, C 45.0 (+) Post-Surgical
5 39 17 T4-T5, C 56.7 (+) Trauma

6 48 66 C 5–6, A 33.6 (−) MVA

7 37 140 C 5–6, A 28.7 (−) Diving accident
8 67 8 C 5–7, B 34.2 (−) Epidural Abscess
9 43 71 C 5, D 35.1 (−) Assault
10 26 99 T 4–6, A 54.3 (−) MVA

Abbreviations;: ASIA: American Spinal Cord Injury Association classification (A = complete spinal cord injury (SCI); B = incomplete SCI with only some sensory function
preserved; C = incomplete SCI with <50% motor function preserved; D = incomplete SCI with >50% motor function preserved; E = SCI with normal sensory and motor function);
C: cervical spine; T: thoracic spine; (+) = expiratory flow limitation present; (−) expiratory flow limitation absent; MVA: motor vehicle accident
a
Predicted values from Wilson et al (Thorax. 1984;39:535-8).

Fig. 1. Photograph of a representative healthy subject (left panel) and schematic representation (right panel) of anterior and anterolateral stimulating electrodes and elec-
tromyography electrodes.
The anterior electrodes were applied over the rectus abdominis below the costal margin and above the pubic symphysis, each approximately 2–3 cm from the midline. The
anterolateral electrodes were placed over the intersection of the lower costal margin and the mid-axillary line, and above the anterior superior iliac spine. Electromyography
(EMG) electrodes were applied over the left external oblique muscle.

2.3.4. Stimulations from TLC with open glottis were used to construct pressure-flow curves (Estenne et al., 1994).
To determine whether stimulation of the abdominal muscles As described by Estenne et al. (Estenne et al., 1994), the presence of
could induce expiratory flow limitation in the absence of transient a flow plateau during the three conditions was assessed by visual
glottic closure, patients were instructed to passively exhale from inspection by two independent investigators (VM and FL).
TLC while concurrently receiving stimulations using the anterior
(10–17 passive exhalations) and anterolateral electrode configura-
2.4.2. Maximal Pga and Pes during exhalation
tion (10–22 passive exhalations).
Maximal increase in Pga and Pes reached during the three
experimental conditions were calculated as the maximum positive
2.4. Measurements excursion in the Pga and Pes signals subtracted from the corre-
sponding values recorded during the preceding end-exhalation
The change in Pes (Pes) and Pga (Pga) recorded during unas- (Butler et al., 2011).
sisted solicited coughs, during solicited coughs combined with
electrical stimulations, and when stimulations were combined with
2.5. Statistical analysis
passive exhalations were computed as the Pga and Pes at peak
expiratory flow and as the maximal Pga and Pes during exha-
Data recorded during the three experimental conditions were
lation (Fig. 2). These computation strategies give information on
compared by one-way analysis of variance (ANOVA) with repeated
two different aspects of cough physiology. One gives information
measures. When ANOVA revealed a significant effect, protected
on expiratory flow limitation, and the other on maximal force of
Fisher’s LDS post-hoc multiple comparison testing was performed
expiratory muscle contraction.
(Hussain et al., 2011).

2.4.1. Pga and Pes at peak expiratory flow

The values of Pga and Pes at peak expiratory flow were cal-
culated as the positive excursion in the Pga and Pes signals at peak
exhalation subtracted from the corresponding values recorded dur-
ing the preceding end-exhalation (Estenne et al., 1994). The Pes at
peak expiratory flow and the accompanying peak expiratory flow
3. Results
Patient characteristics are summarized in Table 1. Most had
complete spinal-cord injury. As expected, maximal expiratory pres-
sure values were reduced in all patients.
20 F. Laghi et al. / Respiratory Physiology & Neurobiology 240 (2017) 17–25
Fig. 2. Flow, esophageal pressure (Pes), gastric pressure (Pga), and electromyogram
of the external oblique muscle (EMG) in a patient during a solicited cough combined
with electrical stimulation of abdominal muscles.
The change in Pes (Pes) and Pga (Pga) during a solicited cough, whether com-
bined with electrical stimulation or not, was calculated as the change in respective
pressure associated with peak expiratory flow (vertical line) and as the maximal
change in pressure during exhalation. Inset shows Pes (upper tracing) and Pga (lower
tracing) and the points used in making calculations. The uppermost serrated hori-
zontal lines (on the right) are the maximum positive Pes and Pga during exhalation.
The second highest serrated horizontal lines (on the left) are drawn at the point in
time corresponding to peak expiratory flow (vertical line). The lowermost horizontal
lines represent Pes and Pga at the end of exhalation of the preceding breath.
Similar calculations were performed when stimulations were combined with pas-
sive exhalations.
3.1. Unassisted solicited coughs
When a voluntary cough was solicited, all patients closed
the glottis initially. (Glottic closure was identified in operational
terms: no significant airflow despite positive intrathoracic pres-
sure). After 0.28 ± 0.03 s, the glottis opened and expiratory flow
commenced. Expiratory flow peaked 0.11 ± 0.01 s later (Fig. 3). Five
patients did not achieve a clear-cut flow plateau as expiratory pres-
sure increased. These patients were classified as non-flow limited
(Fig. 4). Four of the five remaining patients achieved a clear-cut
flow plateau as expiratory pressure increased. These patients were
classified as flow limited. In the remaining patient (patient 5), the
peak Pes and the expiratory flow recorded during the most vig-
orous solicited coughs overlapped with the corresponding values
during assisted coughs. Accordingly, patient 5 was grouped in the
flow-limited group.
The level of spinal cord injury was equivalent in the non-flow-
limited and in the flow-limited patients (Table 1). Similarly, the
volume of air inhaled before the solicited coughs was equivalent
in the two groups of patients (data not shown). These data suggest
that flow-limitation did not occur because flow-limited patients
started their solicited coughs from a smaller lung volume than did
non-flow limited patients.
Expiratory flows and pressures during solicited coughs are
summarized in Table 2. Flow and pressures were equivalent in
flow-limited and non-flow limited patients (data not shown).
After the commencement of expiratory flow, 8 of the 10 patients
experienced subsequent partialor complete obstruction to flow in
50 ± 10% of forceful solicited coughs (Fig. 5). This flow obstruction
occurred 0.47 ± 0.12 s after the first peak in expiratory flow.
3.2. Stimulations from TLC with open glottis
In 79% of stimulations (delivered at 80% output or more),
patients were able to maintain the glottis open upon being
instructed to passively exhale from TLC. Expiratory flow peaked
0.23 ± 0.02 s after commencement of exhalation.
Stimulations from TLC (using 4 and 8 electrodes) with open glot-
tis generated maximal Pga values greater than the corresponding
pressures during unassisted solicited coughs (Table 2, Table E1).
Maximal Pes elicited by stimulations with open glottis using 4
electrodes was smaller than maximal Pes during solicited (unas-
sisted) coughs (Table E1). In contrast, maximal Pes elicited using
8 electrodes was not different maximal Pes during unassisted
solicited coughs (Table 2).
Stimulation using 4 electrodes and 8 electrodes from TLC with
open glottis achieved lower peak expiratory flows than peak flow
during unassisted solicited coughs (Table 2, Table E1). These stim-
ulations with open glottis produced expiratory flow limitation in
only three patients (patient 1, 3, and 5), all of whom were flow-
limited during unassisted coughs (Fig. 4).
After commencement of expiratory flow, 7 of the 10 patients
requested to passively exhale from TLC experienced subsequent
(partial or complete) obstruction to flow in 43 ± 11% of stim-
ulations. Four patients had 1–3 episodes of flow obstruction
that spanned the entire duration of stimulation (Fig. 5); in all
other patients, partial or complete obstruction to flow occurred
0.78 ± 0.19 s after the first peak in expiratory flow.
3.3. Solicited coughs combined with electrical stimulations
Electrical stimulations were accurately timed with the start
of solicited coughs as documented by the onset of the stimulus
artifact in the external oblique EMG signal. Electrical stim-
ulations using either the 4- or the 8-electrode configuration
combined with solicited coughs augmented maximal Pga by
24.9 ± 5.7 cmH2 O and 47.5 ± 8.9 cmH2 O and maximal Pes by
11.8 ± 5.3 and 31.8 ± 7.7 cmH2 O, respectively (Fig. 3).
Upon a request to generate a voluntary cough during the deliv-
ery of a stimulation, all patients closed the glottis initially. After
0.26 ± 0.03 s, the glottis opened and expiratory flow commenced.
Expiratory flow peaked 0.13 ± 0.01 s later.
The combination of solicited cough and electrical stimulation
increased peak expiratory flow by 0.5 ± 0.2 L/s using the 4-electrode
configuration and by 0.7 ± 0.2 L/s using the 8-electrode configu-
ration (Table 2, Table E1). Stimulations combined with solicited
coughs produced no increase in expiratory flow in the five patients
who were already flow-limited during unassisted (solicited) coughs
(data not shown). In the five patients who were non-flow lim-
ited during unassisted coughs, peak expiratory flow increased from
5.1 ± 0.6 L/s to 6.1 ± 0.5 L/s (p = 0.009) with 4 electrodes and to
6.3 ± 0.5 L/s (p = 0.018) with 8 electrodes. Stimulation with the 4-
electrode configuration achieved flow limitation in four of the
five non-flow limited patients. In contrast, stimulation with the
8-electrode configuration achieved flow limitation in all non-flow
limited patients (Fig. 4).
 F. Laghi et al. / Respiratory Physiology & Neurobiology 240 (2017) 17–25 21

Table 2
Peak expiratory flows and pressures recorded during unassisted and assisted solicited coughs and during passive exhalation combined with stimulations.

Electrical stimulations with anterolateral electrode

configuration (8 electrodes)

Unassisted solicited Stimulations combined Stimulations combined ANOVA

coughs with passive exhalation with solicited coughs (p)

Peak expiratory flow, l/s 5.2 ± 0.4 4.2 ± 0.5 5.9 ± 0.4 <0.001

Pes at peak expiratory flow, cm H2 O 28.7 ± 2.7 13.4 ± 3.6 44.7 ± 6.6 <0.001
Maximal Pes during exhalation, cm H2 O 36.6 ± 4.1 30.7 ± 5.8 68.3 ± 8.6 <0.001
<0.001
Pga at peak expiratory flow, cm H2 O 20.7 ± 2.4 47.2 ± 5.1 55.6 ± 8.3 <0.001
Maximal Pga during exhalation, cm H2 O 23.2 ± 2.5 64.5 ± 8.4 70.7 ± 9.5 <0.001

Abbreviations: ANOVA = Analysis of variance. Pes and Pga at peak expiratory flow = positive excursion in the esophageal and gastric pressure signals at peak exhalation
subtracted from the corresponding values recorded during the preceding end-exhalation. Maximal Pes and maximal Pga during exhalation = maximum positive excursion
in the esophageal and gastric pressure signals subtracted from the corresponding values recorded during the preceding end-exhalation (see text for details). Values are
means ± standard error.

Fig. 3. Flow, esophageal pressure (Pes), gastric pressure (Pga), and electromyogram of the external oblique muscle (EMG) in a patient during a solicited cough (left) and
during electrical stimulation of abdominal muscles combined with a solicited cough (right).
During the unassisted cough (left), change in Pga (Pga) – calculated by subtracting Pga at end-exhalation from Pga at peak expiratory flow – was 2.7 cm H2 O. The corresponding
Pga during electrical stimulation combined with a solicited cough (right) was 56.4 cm H2 O. The larger Pga was accompanied by a larger Pes – 52.9 v. 9.3 cm H2 O (Pes
was calculated by subtracting Pes at end-exhalation from Pes at peak expiratory flow) – and a greater peak expiratory flow (5.0 v. 3.1 L/sec).
22 F. Laghi et al. / Respiratory Physiology & Neurobiology 240 (2017) 17–25

Fig. 4. Peak expiratory flow vs. change in esophageal pressure (Pes) at peak expiratory flow in a representative patient (Patient # 2) during unassisted coughs (left), electrical
stimulations combined with solicited coughs (center), and electrical stimulations with open glottis (right).
Failure to achieve a plateau in peak flow during either unassisted solicited coughs (left) or electrical stimulations combined with passive exhalations and open glottis (right)
using 4 electrodes (closed squares) or 8 electrodes (open squares) indicates the absence of expiratory flow limitation and, thus, absence of dynamic airway compression.
Achievement of a plateau in peak flow − despite an increase in Pes − during solicited coughs combined with electrical stimulations (center) using 4 electrodes (closed
circles) or 8 electrodes (open circles) indicates achievement of expiratory flow limitation and, thus, the presence of dynamic airway compression.

4. Discussion

The major finding of this study is that the effectiveness of cough

in patients with muscle weakness is critically dependent upon tran-
sient closure of the glottis.

4.1. Expiratory flow limitation during external stimulation

It was possible to induce expiratory flow limitation when

Fig. 5. Expiratory flow during solicited coughs combined with electrical stimula-
tions.
Upper panel: This pattern was seen with nearly half of solicited coughs combined
with electrical stimulations. There is an early peak (black arrow) followed by a
smooth decline lasting about 2 s.
Left lower panel: Seventeen percent of solicited coughs combined with electrical
stimulation produced an early peak in expiratory flow (black arrow) followed by
a sudden and incomplete cessation of flow (open arrow), signifying partial glottic
closure.
Center lower panel: Thirty-one percent of solicited coughs combined with electrical
stimulation produced an early peak in expiratory flow (black arrow) followed by
a sudden and complete cessation of flow (open arrow), signifying complete glottic
closure
Right lower panel: On one occasion, glottic closure spanned the entire duration of
stimulation. (The duration of stimulation is indicated by the serrated horizontal
line.)
Similar patterns in expiratory flow were recorded during solicited coughs and during
exhalations from total lung capacity (see text for details).
After the commencement of expiratory flow, 9 of the 10 patients
experienced subsequent (partial or complete) obstruction to flow
in 49 ± 12% of coughs involving a combination of external stim-
ulation and voluntary cough. One patient had a single episode of
obstruction to flow that spanned the entire duration of stimulation
(Fig. 5); in all other patients, partial or complete flow obstruction
occurred 0.59 ± 0.12 s after the first peak in expiratory flow.
3.4. Safety
Stimulations caused no side effects such as skin redness, burns
or autonomic dysreflexia. Two patients experienced transient
inconsequential lower extremity spasms.
abdominal-muscle stimulation was combined with a solicited
cough whereas it was not possible when stimulation was combined
with passive exhalation. Two mechanisms explain this finding.
Transient closure of the glottis at the start of a solicited cough, when
combined with external stimulation, fosters a rise in pleural pres-
sure (Yanagihara et al., 1966) and, upon glottic opening, dynamic
narrowing of airways and expiratory flow limitation. In the absence
of glottic closure, abdominal pressure generated by external stim-
ulation will be dissipated (rather than being transferred to the
thorax), and, thus, will not provide effective driving pressure for
cough. The inadequacy of driving pressure is indicated by the lesser
maximal Pes achieved by stimulation combined with exhalation
than the maximal Pes achieved by stimulation combined with
solicited cough: 30.7 ± 5.8 v. 68.3 ± 8.6 cmH2 O (p = 0.001) (Table 2).
This difference in maximal Pes occurred despite the similar driv-
ing pressure (maximal Pga) generated by stimulation combined
with passive exhalation and stimulation combined with a solicited
cough: 64.5 ± 8.4 and 70.7 ± 9.5 cmH2 O, respectively (p = 0.16).
That is, generation of an effective cough depended on the glot-
tis closing at the start of a solicited cough (whether assisted or
unassisted).
A decrease in chest-wall compliance consequent to voluntary
activation of upper chest-wall muscles (unaffected by spinal-cord
injury) (Estenne et al., 1994; McBain et al., 2013) also contributes
to achievement of expiratory flow limitation when stimulation is
combined with solicited cough. Lowered chest-wall compliance
will also promote transmission of abdominal pressure (driving
pressure for cough) to the thorax (McBain et al., 2013). The con-
tribution of glottic closure and decreased chest-wall compliance to
the generation of expiratory flow limitation (and effective cough) is
reflected in the ratio of maximal Pes-to-maximal Pga (McBain
et al., 2013). This ratio quantifies the extent to which abdominal
pressure is transmitted to the thorax. A ratio of less than 1.0 indi-
cates imperfect transmission and low driving pressure for cough. A
ratio of 1.0 indicates complete transmission of abdominal pressure
to the thorax. A ratio of greater than 1.0 also indicates complete
transmission, but, in addition, contraction of expiratory muscles
 F. Laghi et al. / Respiratory Physiology & Neurobiology 240 (2017) 17–25
other than abdominal muscles (Estenne and De, 1990), resulting in
a greater driving pressure for cough.
The combination of stimulation and passive exhalation achieved
a Pes-to-Pga ratio of 0.50 ± 0.08; a ratio of less than 1.0 indicates
that abdominal pressure is not being effectively transmitted to the
thorax and also that pressure is being dissipated within the thorax.
The loss of pressure within the thorax results from escape of air
through the upper airways (and open glottis). Rib-cage paradox
is another factor contributing to abdominal-pressure loss in the
thorax (Estenne and De, 1990).
The combination of stimulation and solicited cough achieved
a Pes-to-Pga ratio of 1.05 ± 0.13 (p = 0.005). A ratio close to 1.0
signifies two phenomena: that abdominal pressure was being effec-
tively transmitted to the thoracic cavity and that pressure was not
being dissipated within the thorax.
By preventing loss of air through the airways, glottic closure
enables the buildup of pressure within the thorax as elevated
abdominal pressure is transmitted across the diaphragm (Polkey
et al., 1999). Provided the glottis remains closed, transmural airway
pressure (pressure within the airways minus pressure surrounding
the airways) will be positive as it is the same as recoil pressure
of the lung (Wilson and Hyatt, 1991). When the glottis suddenly
opens, it permits escape of air and, consequently, airway pressure
drops. Because pressure surrounding the airways is high, and con-
tinues to rise (Langlands, 1967), transmural pressure falls (Wilson
and Hyatt, 1991). It is this decrease in transmural pressure (pro-
vided it is sufficiently large) that gives rise to dynamic airway
compression and expiratory flow limitation. Another contributor
to the decrease in transmural pressure is the Bernoulli effect: as
air flowing through the narrowed airway increases, lateral intra-
luminal pressure decreases (Macklem and Wilson, 1965). Dynamic
airway compression and expiratory flow limitation will delay lung
empting, thus impeding the dissipation of intrathoracic pressure
during a cough.
4.2. Glottal dynamics during unassisted and assisted voluntary
coughs
When a voluntary cough was solicited from patients, all closed
the glottis initially. This closure (irrespective of whether a volun-
tary cough on its own or in combination with external stimulation)
lasted about 300 milliseconds. Approximately half a second after
opening the glottis, nearly all patients experienced subsequent
(partial or complete) obstruction to flow in about half the coughs.
Likely mechanisms for this flow obstruction include reflex contrac-
tion of the glottis (Green and Neil, 1955) and Bernoulli effect (Von
and Isshiki, 1965; Yanagihara et al., 1966). This obstruction did
not occur until one-third of cough duration had already elapsed.
This finding raises the following considerations. Glottic closure
occurred with the same frequency when a solicited cough was com-
bined with external stimulation as when cough was solicited in the
absence of stimulation. Glottic closure did not occur until relatively
late in the cough duration and, thus, did not impede development of
expiratory flow limitation. This contrasts with use of epidural stim-
ulation to generate cough. Employing this technique, DiMarco et al.
(DiMarco et al., 2009a) observed that “reflex glottic closure was a
frequent occurrence resulting in inaccurately low airway pressure
measurement.” Frequent occurrence of glottic closures subsequent
to the initial closure may benefit patients: a single episode of exter-
nally generated expiratory muscle contraction induces more than
one episode of dynamic airway compression.
4.3. Clinical implications
When managing cough problems in patients with neuromus-
cular disorders, clinicians commonly think in terms of expiratory
23
muscle weakness (Harraf et al., 2008; Laghi and Tobin, 2003;
Nicot et al., 2006). When such weakness is present, clinicians
commonly prescribe insufflator-exsufflator devices to assist cough
(Andersen et al., 2016; Chatwin et al., 2003; Senent et al., 2011). In
weak patients with bulbar dysfunction, Andersen et al. (Andersen
et al., 2016), recently reported that these devices induce laryngeal
adduction, rendering them ineffective. Our experiments expand on
Andersen’s observations (Andersen et al., 2016) by investigating
the central contribution of glottal dynamics to the effectiveness of
cough.
Maximal pleural pressure recorded during anterolateral stim-
ulations combined with solicited coughs (68.3 ± 8.6 cmH2 O) was
approximately half the value in healthy subjects (146.0 ± 32.6
cmH2 O)(Lavietes et al., 1998) and approximately half the airway
pressure in spinal-cord injury patients receiving thoraco-lumbar
epidural stimulation (137 ± 28 cmH2 O) (DiMarco et al., 2006;
DiMarco et al., 2009a; DiMarco et al., 2009b). Despite being some-
what low, elicited pressures are likely to be clinically useful for the
following reasons. McBain et al. (McBain et al., 2015) reported that
an intrathoracic pressure of about 50 cmH2 O achieves dynamic air-
way compression in patients with high-cervical injury, which is less
than the pressure recorded during our assisted coughs (68.3 ± 8.6
cmH2 O). Moreover, patients with muscular dystrophy, who typi-
cally generate maximum expiratory pressures of < 45 cmH2 O, have
ineffective coughs (Szeinberg et al., 1988).
The combination of anterolateral stimulation and an automatic-
trigger system is a non-surgical, affordable method of augmenting
cough and easy to use in a supine patient. This technique might be
useful in re-conditioning the expiratory muscles to improve effec-
tiveness of stimulated coughs (McBain et al., 2013). The only other
report of similar findings is a recent study by McBain et al. (McBain
et al., 2015). These investigators positioned electrodes in the pos-
terolateral aspect of the abdominal wall and manually triggered
a set of stimulations while patients sat on a wheelchair. We, in
contrast, positioned electrodes on the anterolateral aspect of the
abdominal wall (Gollee et al., 2008; Kandare et al., 2002) because
anterolateral electrodes are less cumbersome than posterolateral
electrodes. This point has practical implications even in bed-bound
patients. External stimulation has potential for avoiding the limita-
tions of conventional cough-assist techniques (Mustfa et al., 2003)
that are expensive, not necessarily effective (Andersen et al., 2016),
time-consuming and occasionally lead to complications (Kinney
et al., 1996; Suri et al., 2008).
5. Summary and conclusion
In summary, voluntary cough in patients with muscle weakness
typically generates an intrathoracic pressure that is insufficient to
induce dynamic airway compression, and, consequently, inabil-
ity to induce a high-pressure gradient within the airways. In the
absence of such a gradient, expiratory flow limitation will not
occur and patients will not be able to develop a flow of air at high
speed during cough. Accordingly, the kinetic energy in the air being
exhaled will not be sufficient to clear intraluminal secretions, and,
thus, the cough will be ineffective. Through the use of transcu-
taneous stimulation of the abdominal muscles, we were able to
induce expiratory flow limitation in these patients. Flow limitation
was achieved only when stimulation was combined with a volun-
tary cough solicited from a patient. Solicitation of a voluntary cough
induced transient closure of the glottis at the start of the cough and
also lowered chest-wall compliance. The combination of these two
activities − together with the development of dynamic airway nar-
rowing − prevented the loss of abdominal pressure being generated
by expiratory muscle activation, and enabled the transmission of
abdominal pressure (the driving pressure for cough) to the thorax.
24 F. Laghi et al. / Respiratory Physiology & Neurobiology 240 (2017) 17–25
In conclusion, transient closure of the glottis renders cough more
effective in patients with respiratory muscle weakness.
Authorship
F.L., and W.E.L. contributed to the design of the experiments,
their execution. F.L., VM and TS contributed to the analysis of
data, literature search, and to the preparation of the manuscript.
MJT contributed to data interpretation, and critically revised the
manuscript for important intellectual content. All authors reviewed
and contributed to the final manuscript.
Acknowledgments
The authors thank Dr. Robert Jaeger for his advice on neuro-
muscular stimulation of abdominal muscles in spinal cord injury
patients, Ms. Linda Fehr for setting up the trigger system for neu-
romuscular electrical stimulation, Ms. Christine Jelinek for her
assistance with logistics and supplies, and the patients who took
part in the project. Dr. Laghi’s has received research grants from the
National Institutes of Health, VA Research Service, Liberate Medi-
cal LLC, and the National Science Foundation. Drs. Langbein has
received research grants from the RR&D VA Research Service. Dr.
Tobin receives royalties from McGraw-Hill for two books published
on critical care medicine.
This work was supported by research grants from the Veterans
Administration Research Service. The funding agencies had no role
in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.resp.2017.02.005
. Abdominal muscle training can enhance cough after spinal cord injury.
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