INVITED REVIEW SERIES:

NON-INVASIVE VENTILATION
SERIES EDITORS: AMANDA PIPER AND CHUNG-MING CHU

NIV in amyotrophic lateral sclerosis:

The ‘when’ and ‘how’ of the matter
CAPUCINE MORELOT-PANZINI,1,2 GAËLLE BRUNETEAU3,4 AND JESUS GONZALEZ-BERMEJO1,2

1
INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Sorbonne Université, Paris, France; 2Service
de Pneumologie et Réanimation Médicale du Département R3S, AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix,
Paris, France; 3Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris,
France; 4Département de Neurologie, Centre Référent SLA, APHP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris,
France

ABSTRACT speech, mastication and swallowing) and respiratory

Non-invasive ventilation (NIV) has become an essential muscles. Onset of the disease is usually observed dur-
part of the treatment of amyotrophic lateral sclerosis ing the sixth decade. The prevalence of the disease var-
(ALS) since 2006. NIV very significantly improves sur- ies slightly from one country to another; for example,
vival, quality of life and cognitive performances. The from 3 to 5 cases per 100 000 inhabitants in Europe
initial NIV settings are simple, but progression of the and the USA, respectively, with an annual incidence of
disease, ventilator dependence and upper airway 1–2 new cases per 100 000 inhabitants.1 Although
involvement sometimes make long-term adjustment of about 5–10% of patients report a family history of the
NIV more difficult, with a major impact on survival. disease,2 ALS appears to occur sporadically in the
Unique data concerning the long-term adjustment of majority of cases. Multiple pathophysiological pro-
NIV in ALS show that correction of leaks, management cesses that have not yet been fully elucidated are
of obstructive apnoea and adaptation to the patient’s involved in ALS. It is generally accepted that ALS has a
degree of ventilator dependence improve the prognosis. multifactorial origin resulting from the interaction of
Non-ventilatory factors also impact the efficacy of NIV genetic and environmental factors, and the pathophysi-
and various solutions have been described and must be
ology of ALS could involve a multistep process.3 Since
applied, including cough assist techniques, control of
1999, it has been confirmed that in the great majority
excess salivation and renutrition. NIV in ALS has been
considerably improved as a result of application of all of cases ALS is complicated by respiratory failure sec-
of these measures, avoiding the need for tracheostomy ondary to diaphragmatic dysfunction, resulting in dys-
in the very great majority of cases. More advanced use pnoea and impaired sleep, with subsequent severe
of NIV also requires pulmonologists to master the asso- suffering. ALS also impairs cough function, resulting in
ciated end-of-life palliative care, as well as the modali- frequent episodes of bronchial congestion and infec-
ties of discontinuing ventilation when it becomes tion. The characteristic feature of ALS is its rapid and
unreasonable. severe course: the median survival is 3 years from
onset of the first symptoms and 6 months after onset of
diaphragmatic dysfunction, in the absence of treat-
Key words: amyotrophic lateral sclerosis, drainage, postural, ment.4 Respiratory involvement of ALS is the leading
non-invasive ventilation, palliative care, sleep apnoea, cause of death. The impact on the patient’s family is
obstructive. devastating, as a result of the combined motor deficit
and respiratory failure and the rapid course of the dis-
INTRODUCTION ease, for which no curative treatment is available. Two
molecules, riluzole and edaravone, have been shown to
Amyotrophic lateral sclerosis (ALS) is a degenerative be effective in the treatment of ALS. Riluzole, which
motoneuron disease that induces rapidly progressive inhibits presynaptic glutamate release,5 prolongs
paralysis of the limbs, bulbar muscles (controlling median survival by 3 months.6 Edaravone, which has
antioxidant properties, also decreases the functional
impairment related to the disease, although its effect
Correspondence: Jesus Gonzalez-Bermejo, Service de remains limited and is only observed in some
Pneumologie et Réanimation Médicale du Département R3S, patients.7,8 Since 2006, a consensus has been reached
AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, F-
among pulmonologists and neurologists that ventila-
75013 Paris, France. Email: [email protected]
Received 5 September 2018; invited to revise 18 September tory assistance relieves dyspnoea, improves sleep,
2018 and 8 February 2019; revised 30 January and 9 February improves quality of life and prolongs survival.9 Cough
2019; accepted 13 February 2019 assistance,10 especially by means of mechanical
© 2019 Asian Pacific Society of Respirology Respirology (2019)
doi: 10.1111/resp.13525
2 C Morelot-Panzini et al.

devices, improves patient comfort and limits infectious accessory muscles, NIV allows a dramatic reduction of
episodes. energy expenditure (−7% of daily resting energy
However, management of ALS patients by pulmonol- expenditure),24 as well as ‘cortical resting’ via decreased
ogists is not limited to prescription of mechanical ven- premotor cortex activity.25
tilation. From 2006 to the present time, not only has it
been demonstrated that non-invasive ventilation (NIV)
is difficult to adjust in this setting, but also that NIV CRITERIA FOR INITIATION OF NIV
must be integrated into multidisciplinary management,
taking into account progression of the disease and the All studies published since 1993 have proposed NIV in
patient’s living conditions outside of hospital. The ALS patients with daytime or nocturnal hypoventilation. As
patient’s family plays a predominant role in supportive discussed below, only a few studies have proposed the
care and everyday management of treatment, including so-called early ventilation prior to onset of
end-of-life palliative care. hypoventilation.
From a database comprising more than 600 patients,
Georges et al.26 showed that in more than 80% of cases
PATHOPHYSIOLOGY OF RESPIRATORY NIV was initiated at a stage of daytime hypoventilation
INVOLVEMENT AND INDICATION FOR NIV with a median PaCO2 of 48 mm Hg. However, all
guidelines27 recommend that the indication for NIV be
Progressive degeneration of phrenic motoneurons based on pulmonary function parameters, nocturnal
results in diaphragmatic muscle impairment.11,12 In the oximetry or even plasma bicarbonate, although these
early 2000s, the role of diaphragmatic weakness as the recommendations are not contradictory. As shown in
major cause of poor sleep and impaired quality of life Table 1, all of these measurements at the proposed
in ALS patients was confirmed,4,13 although this effect cut-off values can raise the suspicion of hypoventilation
was first described in 1979.14 Diaphragmatic dysfunc- with varying degrees of sensitivity. More recently, dia-
tion initially affects REM sleep, when accessory respi- phragm ultrasound has been shown to detect those at
ratory muscles are impaired, and then extends to high risk of hypoventilation.28,29 In view of the nature
involve all phases of sleep with the subsequent pro- and rapid progression of ALS, three-monthly assess-
gression of the disease. Arnulf et al. reported that ments are necessary to determine the appropriate time
some patients are able to use their accessory muscles to initiate NIV. However, three-monthly assessments of
during REM sleep, as a result of an as yet unexplained PCO2 are not practical due to the painful and invasive
phenotypic change.4 These authors also demonstrated nature of arterial blood gases and/or the cost of percu-
a dramatic reduction of survival due to diaphragmatic taneous measurements. The measurements shown in
involvement (217 vs 620 days), providing a major Table 1 are minimally invasive, inexpensive and can be
physiological argument in favour of the use of NIV in performed on an outpatient basis by non-pulmonology
ALS,4 and confirming results of earlier trials.15–18 Fol- teams after a short training phase. The best examina-
lowing these studies, diaphragmatic involvement of tion at present to detect hypoventilation is the sniff
ALS and the benefit provided by NIV have been the test30 with a sensitivity of 97% for a sniff
subject of numerous publications and considerable <40 cm H2O. This is much better than that of vital
improvements in therapy that will be reviewed in this capacity (VC), which has a sensitivity of only 58% for a
article. value <50%. More reliable measurements are obtained
with a mask rather than a mouthpiece, especially for
patients with bulbar disease.31 Measurement of the fall
BENEFICIAL EFFECTS OF NIV in VC between sitting and supine positions increases
the sensitivity of the test to 90%.32 Two studies have
From the first non-controlled studies published in recently confirmed the value of diaphragm ultrasound,
199315 to the randomized controlled trial published in with a good correlation between diaphragm thickening
2006,19 many studies have shown that NIV significantly fraction with VC and PaCO2 measurement, although no
improves survival, quality of life and cognitive perfor- cut-off value has yet been defined to suspect hypoven-
mance in ALS despite disease progression.13,15–18,20,21 tilation.28,29 This technique would be an attractive
The survival gain as a result of NIV has been estimated option for pre-NIV follow-up, but diaphragm ultra-
to be 7 months.19 Ten years later, with improvement of sound is rarely available outside of highly specialized
the quality of NIV and multidisciplinary management, centres.
NIV now provides a median improvement in survival The cut-off value for CO2 adopted to define hypo-
of more than 13 months.22 This improvement is even ventilation in ALS is PCO2 > 45 mm Hg on arterial
observed in patients with bulbar muscle involvement blood gases during spontaneous breathing, while rest-
(muscles controlling speech, mastication and swallow- ing in a seated position for at least 15 min. There is no
ing), considered to be poor candidates for NIV in recommendation at the present time concerning the
2006,19 with a survival gain of 19 months over those best time of day to perform arterial blood gases
with non-bulbar phenotypes.22 Progressive improve- (on waking, in the morning or in the evening at
ment of survival of ALS patients over the years has bedtime).33
been clearly shown to be due to the introduction of The value of nocturnal transcutaneous carbon diox-
NIV after 200623 (Fig. 1). ide (PtcCO2) in ALS has also been recently
Recent physiological studies have further refined our emphasized,34 but particular attention must be paid to
knowledge of the benefit of NIV in ALS. By resting the technical difficulties of PtcCO2 and its reliability in
© 2019 Asian Pacific Society of Respirology Respirology (2019)
NIV in amyotrophic lateral sclerosis 3

Onset of 151 272 291,3 744 Months

disease
No NIV

NIV but
persistent OA

NIV but persistent leaks

NIV with no leaks and no OA

Figure 1 Illustration of the differ-
ent expected survival times
depending of the quality of
mechanical ventilation. These sur- NIV with no leaks and no OA + IN/EXsufflator +?
vival times are only examples,
extrapolated from selected latest Tracheostomy + invasive mechanical venlaon
publications in amyotrophic lat-
eral sclerosis patients.

certain circumstances (drift and aberrant values). Con- to avoid hospitalization and all outpatient approaches
comitant analysis of the pulse oxymetry (SpO2) signal are highly appreciated by patients and are associated
allows detection of aberrant values. The PtcCO2 cut-off with health cost savings.41 Sheers et al. showed that
value to propose NIV has not been unequivocally outpatient initiation of NIV can save time and conse-
defined at the present time, but a 10-mm Hg increase quently improve patient survival.43
of PtcCO2 above 50 mm Hg for more than 10 min is
classically used to define nocturnal hypoventilation.33
A currently unresolved question concerns the value Presentation of NIV
of NIV before hypoventilation occurs, the so-called Mechanical ventilation is an important step in the life
‘early’ NIV. This approach was initially proposed in of ALS patients. It can be a feared and traumatic step
Duchenne’s myopathy in 1994, before being ceased fol- for the patient and their family, with many associating
lowing demonstration of excess mortality in the ‘early ventilation with tracheostomy and end of life. Patients
NIV’ group.35 However, several arguments suggest that must be clearly informed about this treatment modal-
early ventilation could reduce the respiratory decline in ity. Mitsumoto and Rabkin45 proposed the following to
ALS and decrease respiratory work.24 A large retrospec- describe therapy to the patient: ‘Many assistive devices
tive study36 and three small series have demonstrated can greatly help your breathing, which left unassisted
an improvement in survival for patients initiating NIV may decrease your energy levels and impede your sleep
with VC > 80% predicted,37–39 although this effect was at night. One such device is a noninvasive positive pres-
not confirmed when sham NIV was used in the control sure ventilator. It includes an easy-to-use mask that fits
group.39 In practice, patients with only minimal respira- on your face. It should increase energy and provide bet-
tory symptoms, essentially presenting features of motor ter sleep’. It could be added that ‘this treatment will also
disability, are unlikely to continue long-term NIV if the relieve your breathlessness, while you are using ventila-
therapy is initiated prior to exhibiting hypoventilation. tory assistance, but probably also when you are breath-
Jacobs et al. reported an adherence of about 3 h per ing on your own’.24
day with early NIV.39 A large randomized controlled
trial on this subject40 was terminated due to insufficient
Choice of equipment and settings
recruitment. One of the hypotheses proposed for the
excess mortality observed in the 1994 Duchenne study No particular mode of ventilation has been demon-
was under-use of NIV in the early NIV group when strated to be superior. No difference in terms of effi-
patients reached the stage of hypoventilation. Recent cacy has been demonstrated between volume assist-
data showing poor adherence to early NIV would tend control ventilation, in which the patient receives a pre-
to support these results.39,40 defined volume of gas, and pressure assist-control ven-
tilation, in which partial pressure assistance is
provided.46
The disadvantage of volume assist-control ventilation
HOW SHOULD ALS PATIENTS BE is the rigid feeling of ventilation and the absence of
VENTILATED? compensation for leaks. The two main theoretical
advantages are that it allows the patient to perform air
Site of initiation of NIV stacking to assist airway clearance and it is able to
NIV can be initiated in any setting experienced in NIV. overcome obstruction to airflow. This is the preferred
No site of NIV initiation has been demonstrated to be mode in invasive ventilation. Some highly experienced
superior to another, with home,41 ambulatory care42,43 teams effectively use this mode for NIV,46 probably with
and even telemonitoring44 all reporting successful good efficacy for obstructive events (see below). The
establishment of NIV. The current trend, especially in main advantages of pressure assist-control ventilation
view of the major motor disability of these patients, is are that it is more comfortable for the patient and,
Respirology (2019) © 2019 Asian Pacific Society of Respirology
4 C Morelot-Panzini et al.

Table 1 Simple tests suitable for general clinic or bedside use to identify and monitor respiratory muscle weakness
and the possibility of hypoventilation in patients with ALS and to introduce NIV27,30,52

Measurement Thresholds and comments

VC Threshold: between <80% and <50%

Simple and readily accessible measurement able to be performed routinely at bedside, in
clinics or patient’s home
Erect to supine fall in VC > 20% indicative of diaphragmatic weakness
Provides sensitive thresholds for predicting survival at 6 months (sensitivity of 58%)
Is a late predictor of respiratory failure compared to MIP
MIP Threshold: <40 cm H2O to < 60 cm
A value >80 cm H2O excludes significant inspiratory muscle weakness
MIP <40 cmH2O widely used to identify those at risk of hypoventilation
May be difficult for some patients to perform and is affected by leaks in those with orofacial
muscle weakness
Reliant on patient effort
Wide range of normal values. Percent of the normal is more appropriate (i.e. 40–60%
predicted)
SNIP Threshold: <40 cm H2O
Normal values >70 cm H2O (males) and 60 cm H2O (females)
SNIP <40 cm H2O more sensitive (than VC or MIP) in identifying ALS patients at risk of
hypoventilation
Both MIP and SNIP assess global inspiratory muscle function rather than specific diaphragm
strength
Wide range of normal values. Percent of the normal would be more pertinent (i.e. <40%)
Diaphragmatic ultrasound Threshold and conditions of the measurement not standardized
Nocturnal pulse oximetry Threshold: % time spent <90%, >5% or 10%
Measurement is not useful where the patient has lung disease or is using supplemental
oxygen

ALS, amyotrophic lateral sclerosis; MIP, maximum inspiratory pressure; NIV, non-invasive ventilation; SNIP, sudden nasal inspira-
tory pressure; VC, vital capacity.

more importantly, it compensates for leaks. Pressure Low-level inspiratory pressure support is generally suf-
assist-control ventilation is the preferred mode for NIV, ficient when initiating NIV. Semi-controlled pressure
even in ventilator-dependent patients. modes (spontaneous modes with back-up frequency) are
Survival differences in favour of pressure assist- preferred, being more effective in ALS than spontaneous
control ventilation have been observed in large patient modes.51 Ventilator settings can then be adjusted to
cohorts with a follow-up of 10 years (+13 months ensure sufficient inspiratory assistance to obtain normal
under pressure-controlled ventilation22 vs +10 months daytime and nocturnal PaCO2. Initial settings are pro-
under volume-controlled ventilation47), although other posed in Table 2 and must be adjusted during the first
factors including regional and cultural differences minutes of ventilation to meet the patient’s needs and
probably account for this finding. symptoms. Ventilator settings are then continuously
All commercially available masks can be used. adjusted over the first hours and days of ventilation with
Nasal ventilation allows for more natural humidifica- 3– 5 days usually needed to achieve optimal settings. The
tion, permits speech and induces a lower rate of efficacy of ventilation should be evaluated at 1 month
obstructive apnoea48 (see below). Ventilation with a and then reviewed every 3 months.52 An illustration of
single-limb circuit with intentional leak requires a the settings usually required to ensure optimal NIV is pre-
mask leak during expiration and has the advantages sented in Table 1. These settings should not constitute an
of allowing a wider choice of mask and the use of objective per se and should be adapted on the basis of
simpler circuits.49 Expiratory valve ventilation requires good quality monitoring of NIV (see below).
the use of a no-leak mask. A higher error rate (85%
in active circuit vs 30% in passive circuit, P < 0.001)
with the same efficacy has recently been reported Adaptation of NIV in ventilator-dependent
with the use of expiratory valve circuits in ALS patients
patients treated by invasive ventilation (i.e. more Although the definition of a ventilator-dependent
advanced disease50). patient differs from one country to another (patient
Harnesses and masks fitted with security systems can ventilated for more than 16 h per day to more than
also be useful in motor-disabled patients, especially 20 h per day, depending on the country, and even
ALS patients, when the mask needs to be removed in remains unclear in the ISO standards53), special mea-
an emergency. Adaptation by an occupational therapist sures must be taken in the individuals.
should be considered when a suitable mask is not Pressure assist-control ventilation does not need to be
available50 (Fig. 2). changed to volume assist-control ventilation in ventilator-
© 2019 Asian Pacific Society of Respirology Respirology (2019)
NIV in amyotrophic lateral sclerosis 5

Table 2 Proposal for setting NIV in ALS patients

Setting To start Target

Mode Pressure mode and assisted-controlled mode

Pressure support 4–6 10–12
(cm H2O)
EPAP (cm H2O) Non-bulbar patient
4 4
Bulbar patient
4 6–14 or automatic EPAP
Back-up RR 14 16–20
(cycles/min)
Rise time 200 Minimal to 400 ms
(ms)
Inspiratory trigger Medium sensitivity
Expiratory trigger Medium sensitivity (50% of the peak flow)
Inspiratory time (s) Ti min − Ti max: 0.8–1.6
or
Fixed Ti: 1.3–1.6 (calculated for an I/E ratio to ½ with the back-up RR set)

ALS, amyotrophic lateral sclerosis; EPAP, expiratory positive airway pressure; I/E ratio, inspiratory time/expiratory time ratio; NIV,
non-invasive ventilation; RR, respiratory rate; Ti, inspiratory time.

dependent patients. A semi-controlled mode51 with back- This technique cannot currently be recommended as
up rate is sufficient, even in 24-h-a-day ventilator- an alternative or complement to NIV in ALS.
dependent patients. The security of ventilation, the pres-
ence of alarms and batteries, the dimensions, simplicity
(or complexity) and noise are not better, at the present Adjustment of ventilator settings and
time, with either pressure assist-control or volume assist- monitoring of the quality of NIV
control ventilators. However, risk reduction measures In 2011, the difficulty of long-term NIV in ALS was first
must be undertaken: raised.62 Following the publication of guidelines for
• The provision of two life support ventilators53 is NIV quality monitoring based on nocturnal
recommended. recordings,63 Atkeson et al. applied this approach to
• The patient must have several types of masks avail- ALS patients and observed a high rate of patient/venti-
able (e.g. a nasal mask or a nostril mask) in order to lator asynchrony.62 Poor quality of nocturnal NIV is
change pressure points and to allow eating or talking associated with poorer survival52,64 (Fig. 1). Leaks are
for several hours a day. the leading cause of failure of NIV, in more than half of
• A check list of parameters that should be monitored the cases52 and must be monitored at each follow-up
several times a day is very useful to avoid deteriora- visit. Ventilator software allows very simple verification
tion or death due to technical or logistic problems. of leaks, from data card downloads or by teletransmis-
An example of such a check list is provided in the sion. Correction of leaks is now fairly simple as a result
online supplement. of the large range of masks available on the market.
• Other daytime NIV techniques must be considered After correcting any leaks, the main problem remains
in highly ventilator-dependent patients in addition to obstructive apnoea, which also negatively impacts sur-
mask ventilation. vival when it is not corrected.64 Obstructive apnoea in
• Mouthpiece ventilation54 has been recently tested in ALS can be due to various causes, but pharyngolaryngeal
ALS and can be proposed to ventilator-dependent muscle impairment obviously predisposes to upper air-
patients who still retain good orofacial muscle con- way collapse. Schellhas et al.48 confirmed the presence of
trol.55 Severe bulbar involvement (ALS functional rat- obstructive apnoea during NIV in ALS patients and sug-
ing scale (ALSFRS) score between 0 and 3) identifies gested the use of an oronasal mask as an additional
those unsuited for this technique.55 cause. Corrective measures of these obstructive events
• Handheld ventilators designed for COPD have been have been proposed by various teams.48,64–66 An increased
recently used in a very preliminary trial in five ALS positive expiratory pressure is clearly the best treatment
patients, with interesting prospects provided certain but is not always effective nor well tolerated by the
technical improvements can be made.56 patient. Various steps of treatment adjustment can be
• Intermittent abdominal compression ventilation57 is considered48,64 and are summarized in Table 3. When all
also available in a few centres, but has never been of these corrective measures fail, Sayas Catalan et al.67
studied in ALS. proposed a more detailed analysis of the cause of
Implanted phrenic nerve stimulation initially raised obstruction by videolaryngoscopy during NIV. Finally,
great hopes in ALS,58 but has unfortunately been some authors have reported the efficacy of a cervical col-
shown to be dangerous, causing deterioration of the lar65,66 or a mandibular advancement device in addition
disease in two randomized controlled trials,59,60 even in to ventilation.48,64 Unfortunately, mandibular advance-
patients with primarily upper motoneuron disease.61 ment may be difficult to apply due to excess salivation
Respirology (2019) © 2019 Asian Pacific Society of Respirology
6 C Morelot-Panzini et al.

Table 3 Possible measures to reduce apnoeas and ALS. The absence of cough, when left untreated, is
hypopnoeas persisting with NIV. Following tolerance and associated with marked excess mortality.68 Chatwin
efficacy of waveforms of the ventilator software48,64–66 et al. reviewed all of the currently available airway
clearance techniques and essentially recommended
Steps Desire effect Tool three-monthly monitoring of cough peak expiratory
(1) FIT MASK Decrease pressure Switch to nasal
flow (CPEF).69 This very simple measurement can even
on facial mask (without
be performed with an asthma flow meter. A mechani-
structures chin strap) in
cal aid is used when CPEF < 270 L/min.
Several methods can be useful, but an insufflator–
patients without
exsufflator is the most effective method,10 even in bulbar
buccal weakness
Decrease facial Switch to nasal
patients,70 although it is obviously more difficult. Setting
pressure and mask (with chin
adjustments, available on modern insufflator–exsuffla-
prevent leakage strap)
tors, can be proposed in severe bulbar ALS patients:
• Ensure triggering on every insufflation.
Prevention of air Optimization of
• Decrease inspiratory flow.
leakage and drop oronasal mask
in the EPAP fitting
• Decrease inspiratory pressure.
(2) Increase Improvement of Increase fixed EPAP
• Increase inspiratory time.
EPAP upper airway (from 4 to
Flexible pharyngolaryngoscopy while using the
insufflator–exsufflator device should also be considered
patency 14 cm H2O)
in case of failure of setting adjustments.70
Improvement of Automatic EPAP
upper airway from 8 to
patency with 14 cm H2O† Congestion due to excess salivation
better tolerance
Excess salivation can be a specific cause of failure of NIV
(3) Shorten Reducing time Switch to a mode
in ALS. Various drugs can be used (atropine, scopolamine
expiratory window for with Ti max
and belladonna tincture), but salivary gland radiotherapy
time end-expiratory setting
has been shown to be very effective and should be pro-
upper airway Decrease Ti max
posed to these patients,71 even in patients already treated
collapse and/or fixed Ti
by NIV.72 Botulinum toxin injection into the salivary glands
from 1.6 to 1 s
is difficult to perform and only has a temporary effect.
(4) Increase Increasing pressure Volumetric mode
inspiratory during inspiration Automatic IPAP
pressure can open closed devices with short Undernutrition secondary to swallowing
upper airway rise time disorders and the need for gastrostomy
(5) Positional Reduction of Avoidance of the
Swallowing disorders, requiring as feeding gastrostomy,
treatment positional apnoea supine sleep
can occur after commencing NIV. Various solutions
position
have been proposed including endoscopic gastrostomy
(6) Mandibular Anterior Cervical collar
with NIV support,73 but this is difficult to perform in
action displacement of Mandibular
patients with severe bulbar lesions who are be unable
the jaw advancement
to control mouth leaks during NIV, or percutaneous
device (poorly
endoscopic gastrostomy with NIV support73–76 which
tolerated)
can sometimes be impossible in the presence of very
†
The automatic algorithms (for EPAP or pressure support) are advanced diaphragmatic dysfunction with intrathoracic
very different between the devices. In case of failure of one stomach. Surgical gastrostomy may sometimes be nec-
device, other devices must be tested. essary under brief general anaesthesia with intubation
EPAP, expiratory positive airway pressure; IPAP, inspiratory and rapid extubation followed by NIV support.
positive airway pressure; NIV, non-invasive ventilation; Ti, inspi-
ratory time.
TRACHEOSTOMY IS NOT
and/or the patient’s motor disability making insertion of SYSTEMATICALLY THE NEXT STEP
the device more difficult. AFTER NIV
Other causes can also be responsible for failure of
NIV, including claustrophobia, mask-induced skin Tracheostomy has been shown to markedly improve
lesions and rhinitis, with solutions the same as those survival, as recently highlighted by Stephen Hawking’s
used in other diseases. very long-term survival,77 with quality of life considered
to be satisfactory by patients78,79 although less so by
caregivers80 (Fig. 1).
NON-VENTILATORY CAUSES OF
The technical and financial feasibility of this
FAILURE OF NIV IN ALS approach may be important determinants of tracheos-
tomy placement in some countries, with the likelihood
Bronchial congestion secondary to impaired of the patient being able to return to their place of resi-
cough dence following the tracheostomy an important factor
Concomitant impairment of the diaphragm, expiratory in decision-making. For example, tracheostomy with
muscles and airways makes cough very ineffective in ventilatory assistance is fully reimbursed in Japan
© 2019 Asian Pacific Society of Respirology Respirology (2019)
NIV in amyotrophic lateral sclerosis 7

Figure 2 Chin strap adaptation by the occupational therapist for ALS patients. ALS, amyotrophic lateral sclerosis; NIV, non-invasive
ventilation; OA, obstructive apnoea.22,52,64,79

where the tracheostomy rate is 27%; partially reim- activity, psychological fatigue and lack of motivation.82
bursed in France where 5% of patients are tracheoto- According to one study, patients may experience dis-
mized; and no reimbursement in the USA where the tress and pain during the last month of life and often
tracheostomy rate is 3%. Similarly, there is no reim- receive suboptimal treatment.82 Symptomatic treat-
bursement in the United Kingdom.45 ments for dyspnoea such as opioids should be readily
This lack of reimbursement can lead to problematic available, even fairly early in the course of the disease,
and inextricable situations for the families of ALS patients. if dyspnoea is not fully relieved by NIV. A strong corre-
Some patients and their families nevertheless request tra- lation between dyspnoea and pain has been described
cheostomy and they must be informed as completely as in patients who are effectively relieved by NIV. Reliev-
possible about the consequences of this decision, ideally ing dyspnoea by NIV in patients with ALS having respi-
as early as possible, to avoid performing tracheostomy in ratory failure is associated with decreased pressure
an acute setting when the patient and the family have not pain thresholds.83
had time to discuss this option. Mitsumoto and Rabkin45
have proposed various examples of the way in which tra-
cheostomy can be presented to patients and families. Discontinuation of NIV
Improvement of the quality and efficacy of NIV, even Although ventilatory support can meaningfully extend
in ventilator-dependent patients, and limited discussions life, the patient sometimes requests cessation of NIV
regarding provision of ventilation other than with NIV when allowed by local legislation. However, discontinua-
probably explain the very low rate of tracheotomized tion of NIV will inevitably be accompanied by severe
patients in Western countries. The situation appears to be symptoms, or even true acute respiratory distress. This
changing in Japan,81 where the almost automatic transi- type of situation must be anticipated, which necessitates
tion from NIV to tracheostomy has been declining over rigorous and carefully appropriate drug treatment.
recent years with patients who have used NIV for more As in any situation of end-of-life dyspnoea, opioids and
than 6 months being less inclined to request tracheos- benzodiazepines, possibly associated with the administra-
tomy (Fig. 2). tion of oxygen, effectively relieve the symptoms induced
by discontinuation of ventilatory support. It is only com-
mon sense to initiate these treatments before discontinu-
ing ventilatory support, which can be legitimately
PALLIATIVE CARE AND temporarily resumed if the doses administered are insuf-
DISCONTINUATION OF NIV ficient to relieve the patient’s symptoms and promote
patient comfort. It is important to ensure the continuous
Dyspnoea and end of life presence of a doctor or a nurse in the patient’s room after
End of life is accompanied by a number of symptoms: stopping ventilatory support, to allow a rapid response
dyspnoea, weakness, physical fatigue, decreased when the doses need to be increased to reassure the
Respirology (2019) © 2019 Asian Pacific Society of Respirology
8 C Morelot-Panzini et al.

family about the significance of any respiratory pauses or 5 Cheah BC, Vucic S, Krishnan AV, Kiernan MC. Riluzole, neuropro-
agonal gasps, which, despite their spectacular nature, tection and amyotrophic lateral sclerosis. Curr. Med. Chem. 2010;
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6 Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V.
does not occur rapidly, a doctor or nurse should fre-
Dose-ranging study of riluzole in amyotrophic lateral sclerosis.
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7 Yeo CJJ, Simmons Z. Discussing edaravone with the ALS patient:
Acknowledgement an ethical framework from a U.S. perspective. Amyotroph. Lateral
The authors thank Anthony Saul for his help with English style Scler. Frontotemporal Degener. 2018; 19: 167–72.
and grammar. 8 Brooks BR, Jorgenson JA, Newhouse BJ, Shefner JM, Agnese W.
Edaravone in the treatment of amyotrophic lateral sclerosis: effi-
cacy and access to therapy – a roundtable discussion. Am.
Disclosure statement J. Manag. Care 2018; 24: S175–86.
J.G.-B. perceived honoraria from Synapse Biomedical for educa- 9 Heiman-Patterson TD. NIPPV: a treatment for ALS whose time has
tional activities to launch phrenic nerve stimulation in Europe, come. Neurology 2006; 67: 736–7.
from 2007 to 2012, and for an expertise about new generation of 10 Senent C, Golmard J-L, Salachas F, Chiner E, Morelot-Panzini C,
painless stimulators in July 2012. He perceived honoraria from Meninger V, Lamouroux C, Similowski T, Gonzalez-Bermejo J. A
home ventilator manufacturers for expertise of new generation comparison of assisted cough techniques in stable patients with
of ventilators and educational activities (Resmed, Philips, Breas severe respiratory insufficiency due to amyotrophic lateral sclero-
and Lowenstein). sis. Amyotroph. Lateral Scler. 2011; 12: 26–32.
11 Pinto S, Geraldes R, Vaz N, Pinto A, de Carvalho M. Changes of
the phrenic nerve motor response in amyotrophic lateral sclerosis:
The Authors longitudinal study. Clin. Neurophysiol. 2009; 120: 2082–5.
G.B. (neurologist), J.G-B and C.M-P (pneumologists) are students 12 Similowski T, Attali V, Bensimon G, Salachas F, Mehiri S, Arnulf I,
of Professors Meininger and Similowski, respectively, creators of Lacomblez L, Zelter M, Meininger V, Derenne JP. Diaphragmatic
the first French network of ALS centers in 1999 and one of the first dysfunction and dyspnoea in amyotrophic lateral sclerosis. Eur.
to study the involvement of the diaphragm in ALS. The three phy- Respir. J. 2000; 15: 332–7.
sicians pursued their work in Paris, France, with a triple orientation: 13 Bourke SC, Shaw PJ, Gibson GJ. Respiratory function vs sleep-
clinical care, research and teaching at the Sorbonne University. J. disordered breathing as predictors of QOL in ALS. Neurology 2001;
G-B is specialized in home mechanical ventilation and diaphragm 57: 2040–4.
pathology. He currently directs a pulmonary rehabilitation centre. 14 Minz M, Autret A, Laffont F, Beillevaire T, Cathala HP,
C.M-P, specialist of the field of dyspnoea and neuromuscular dis- Castaigne P. A study on sleep in amyotrophic lateral sclerosis. Bio-
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and muscle in the UMRS974 Laboratory at the Paris Center of 16 Aboussouan LS, Khan SU, Meeker DP, Stelmach K, Mitsumoto H.
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17 Kleopa KA, Sherman M, Neal B, Romano GJ, Heiman-Patterson T.
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Movement Sleep; RR, respiratory rate; SNIP, sudden nasal MND/ALS patients: survival rates in a controlled trial. J. Neurol.
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of CO2; PtcCO2, transcutaneous carbon dioxide; Ti, inspiratory time; 19 Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ,
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