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\begin{document}

\title{An Overview of Noninvasive Ventilation in Cystic Fibrosis}



\author[1]{AESHA JOBANPUTRA}%
\author[1]{Sugeet Jagpal}%
\author[1]{Paula Marulanda}%
\author[1]{MAYA RAMAGOPAL}%
\author[1]{TEODORO SANTIAGO}%
\author[2]{Sreelatha Naik}%
\affil[1]{Rutgers Robert Wood Johnson Medical School}%
\affil[2]{Geisinger Wyoming Valley Medical Center}%


\vspace{-1em}



  
  \date{June 15, 2024}


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\selectlanguage{english}
\begin{abstract}
Noninvasive ventilation (NIV) use was initially reported in cystic
fibrosis (CF) in 1991 as a bridge to lung transplantation, and over the
decades the use of NIV has increased in the CF population. Individuals
with CF are prone to various physiologic changes as lung function
worsens, and they may benefit from NIV for advanced lung disease. As
life expectancy in CF has been increasing due to advances such as highly
effective modulator therapy, people with CF are now subject to the same
co-morbidities that may benefit from NIV as their age matched cohorts.
NIV can improve gas exchange, quality of sleep, exercise tolerance and
augment airway clearance in CF, and it is important that CF providers
are comfortable with this therapeutic modality. In this review, we will
summarize the physiologic basis for NIV use in CF, describe indications
for initiation of NIV, and postulate a practical approach for CF
clinicians to take fin monitoring patients on NIV. We will discuss
aspects unique to people with CF and the use of NIV. We hope that this
serves as a resource for CF providers, especially those of us who do not
have dedicated training in sleep medicine, as we continue to care for
our patient population.%
\end{abstract}%



\sloppy


\textbf{Title:} An Overview of Noninvasive Ventilation in Cystic
Fibrosis

\textbf{Authors:} Aesha Jobanputra MD\textsuperscript{1}, Sugeet Jagpal
MD\textsuperscript{1}, Paula Marulanda RT\textsuperscript{1}, Maya
Ramagopal MD\textsuperscript{2}, Teodoro Santiago\textsuperscript{1},
Sreelatha Naik MD\textsuperscript{3}

\begin{enumerate}
\tightlist
\item
  Division of Pulmonary, Critical Care and Sleep Medicine, Rutgers the
  State University of New Jersey, New Brunswick, NJ
\item
  Division of Pediatric Pulmonary Medicine and Cystic Fibrosis Center,
  Robert Wood Johnson University Hospital, New Brunswick, NJ
\item
  Division of Pulmonary, Critical Care and Sleep Medicine, Geisinger
  Wyoming Valley Medical Center, Wilkes-Barre, PA
\end{enumerate}

\textbf{Corresponding Author:} Sreelatha Naik MD

\textbf{Email Address:}snaik1@geisinger.edu

\textbf{Address:} Geisinger Wyoming Valley Medical Center

1000 East Mountain Blvd. VMB, 1\textsuperscript{st} Floor; Pulmonary
Medicine Wilkes-Barre, PA 18711

\textbf{Disclosures:} The authors have no relevant
disclosures.\textbf{Funding:} none\textbf{Keywords:} noninvasive
ventilation, sleep apnea, cystic fibrosis, hypercarbic respiratory
failure\textbf{Abbreviated Title:} Noninvasive ventilation in Cystic
Fibrosis

\textbf{Introduction~}

Noninvasive ventilation (NIV)~use~was initially~reported in~cystic
fibrosis (CF)~in 1991~as a bridge to lung transplantation, and since
then, the knowledge base for earlier NIV support of chronic respiratory
failure in CF has grown.\textsuperscript{1-3} Given the ability of NIV
to reverse or~stabilize~hypoxia, reduce~hypercapnia~and reduce
respiratory muscle fatigue, it is not surprising that many CF
providers~have~reached~for this intervention in patients with advanced
lung disease. Concomitantly, it is evident from PortCF~registry data
that NIV use is increasing over the years despite consistent
improvements in lung function attributed to the introduction of highly
effective modulator therapy, indicating that NIV is being prescribed to
patients without advanced lung disease as well.\textsuperscript{1,4} The
PortCF registry currently simply asks if NIV was used by the patient in
the past year, but does not ask for the diagnosis that prompted the use,
so we are unable to currently report which diagnoses outside of advanced
lung disease are prompting NIV use in CF patients.

In the~last few decades, epidemiologic trends have demonstrated that
improvements in home mechanical ventilation technology and widespread
initiation of chronic NIV has resulted in improved clinical
outcomes~regardless of disease severity in obstructive lung
disease.\textsuperscript{2}~NIV~is often utilized in the acute setting
of CF exacerbations, as it improves hypoxia~and~decreases work of
breathing.\textsuperscript{5}~In CF with chronic hypercapnic respiratory
failure, use of nocturnal NIV improves sleep related hypoventilation as
compared to oxygen use alone.\textsuperscript{6,7} In the earliest study
of long-term NIV use in bronchiectasis in 1994, no reduction in
hospitalizations was demonstrated, but this was disproven as more
research was done and reduction in hospitalizations has been noted in
subsequent studies.\textsuperscript{8} In addition, there is increasing
evidence that NIV use may augment airway clearance in
CF\textsuperscript{2} and improve survivorship in hypoxic patients when
compared to oxygen alone.\textsuperscript{9}

In a 2018 survey done by Franco et al, 68 CF centers responded to
questions related to sleep. Respondents reported that guidelines
regarding sleep testing would be valuable, indicated frustrations with
current approved indications for NIV, reported varying levels of comfort
with prescribing therapies for sleep disturbance, and stated that
educational resources regarding sleep and CF would be well
received.\textsuperscript{10}

It is clear that NIV use will have a place as an adjunct for CF care
itself as well as to treat comorbidities that CF patients develop with
continued improvements in lifespan.~Therefore, it is important for CF
providers to understand the role of this therapy and prescribe it when
indicated for patients with CF. In this review, we will describe the
role of NIV in the CF population, benefits and risks to this modality,
and introduce a practical approach to initiation of NIV. We will also
review clinical indications for NIV other than CF in order to provide a
better perspective for NIV use.

\textbf{Physiology~of Respiratory Failure In CF}

Nocturnal hypoventilation occurs prior to daytime respiratory failure in
CF due to several factors. Firstly, there is increased in work of
breathing from reduced respiratory function during sleep combined with
altered respiratory mechanics during sleep that act to limit minute
ventilation.\textsuperscript{11,12} While, a decrease in minute
ventilation would normally elevate CO\textsubscript{2} tension, the
ventilatory response to CO\textsubscript{2} is decreased during sleep,
making this compensatory response weak and allowing for
hypercapnia.\textsuperscript{13} Finally, there is the influence of the
sleep state itself. During REM sleep, inhibition of spinal motor neurons
causes atonia of most skeletal muscles. Although the diaphragm is spared
from paralysis in REM sleep, accessory muscles of respiration, such as
the chest wall muscles that are needed by patients with lung disease to
maintain normal ventilation, are
paralyzed.\textsuperscript{14}Consequently, hypoventilation is first
seen in REM sleep.

In 2002, thirty two~CF patients with FEV1 \textless{} 50\%~were
extensively monitored for respiratory physiologic changes longitudinally
as disease progression occurred.\textsuperscript{12} A key clinical
finding in this study was an alteration of breathing pattern to more
rapid shallow breathing as pulmonary disease progressed, as well as an
observed increased load on respiratory muscles and a decrease in dynamic
compliance during resting breathing.\textsuperscript{12} There was
little change in the resistive work of breathing, pointing against
bronchospasm as the main cause for the increased
load.\textsuperscript{12}~ Hart et al speculated that the declining FEV1
in these patients was due to increased inflammatory changes and
destruction of lung parenchyma itself, resulting in reduced~elasticity
and compliance, increasing the load.\textsuperscript{12} Rapid shallow
breathing combined with the increased respiratory load has been
demonstrated to contribute to inefficient clearance of carbon dioxide,
further contributing to hypoventilation and subsequent
hypoxia.\textsuperscript{15}~~As physiologic changes leading to
hypoventilation begin in sleep, intervention at this early point of the
cascade of hypoventilation may be helpful in preventing
progression.\textsuperscript{11} NIV is a treatment modality that could
be helpful in preventing the pathophysiology in CF, primarily by
maintaining ventilation during sleep.

\textbf{Benefits of NIV for CF patients~}

The use of NIV in patients with respiratory failure in CF has been shown
to improve physiologic parameters throughout both sleep and wake states.
NIV increases tidal volumes, reduces respiratory rate and
reduces~respiratory~muscle fatigue.\textsuperscript{1,12,16} It may
prevent sleep-induced hypoxia even without modification of sleep quality
and efficiency, and improves alveolar ventilation during all sleep
states.\textsuperscript{6}~Even~short-term~treatment with NIV, such as
with~40-minute periods, there are notable acute improvements overall in
tidal volume, minute ventilation, and improved oxygenation in patients
with respiratory failure from CF.\textsuperscript{17}

NIV used only nocturnally improves clinical outcomes including improved
hypoxia and hypercapnia at rest, improved sleep quality, and increased
respiratory muscle strength.\textsuperscript{12,16} Improved dyspnea,
decreased hypoxemia and decreased hypercapnia during exertion and
increased exercise tolerance are also seen in patients using NIV
nocturnally, potentially allowing patients to take part in the exercise
regimens prescribed by their CF care team.\textsuperscript{18,19} NIV
also supported recovery from a severe respiratory exacerbation that
resulted in hypercapnia.\textsuperscript{20} Long term treatment with
nocturnal NIV also minimizes the longitudinal decline in lung
function\textsuperscript{21,22} and prevents progression of respiratory
failure. These findings have led to the consideration of the use of
nocturnal NIV in patients with frequent exacerbations or in those
exhibiting a decline in lung function.\textsuperscript{23}Significantly,
a prospective randomized controlled trial showed improved survivorship
in those treated with long-term nocturnal NIV over those treated with
nocturnal oxygen alone.\textsuperscript{9}

NIV~has also been postulated to improve airway
clearance\textsuperscript{24} and has been recommended by recent
guidelines in airway clearance for CF
patients.\textsuperscript{25}~~Patients with cystic fibrosis are
dependent on airway clearance~therapies, and NIV can potentially augment
airway clearance.\textsuperscript{24,26}~~The use of NIV allows
a~patient to increase functional residual capacity (FRC) with greater
ease than a positive expiratory pressure (PEP) device, improving
compliance and decreasing work of breathing.\textsuperscript{27}~In this
same study, chest physiotherapy combined with NIV or CPAP was by patient
report less tiring than mask positive expiratory pressure (PEP)
therapy.\textsuperscript{27}~~During NIV treatment, a patient maintains
a constant positive airway pressure with the goal to decrease
inspiratory work, reduce respiratory rate, increase tidal
volumes,~improve oxygenation and
decrease~hypercapnia.\textsuperscript{26}~In a study on adult CF
patients looking at the addition of NIV for airway clearance, there was
a significant reduction in ventilatory inhomogeneity as~measured by lung
clearance index (LCI).\textsuperscript{26} This indirectly demonstrates
less~inflammation and mucus plugging in the patients with additive NIV
treatment.\textsuperscript{26}~Importantly, this finding can be
replicated in patients with acute exacerbations, and the addition of
NIV~during chest physiotherapy also preserves inspiratory muscle
strength and improves expiratory muscle strength.\textsuperscript{24}

Standford et al looked at a~one-year~period following the addition of
NIV to~airway clearance techniques (ACT)~and demonstrated statistically
significant improvements in ease of patient report of airway clearance
and reduced effort during ACT.\textsuperscript{28}~This study analyzed
objective measures such as lung function and frequency of use of IV
antibiotics, as well as patient reported measures of fatigue and
breathlessness.\textsuperscript{28}~Patients reported significant
improvement in fatigue and breathlessness, which would lead to improved
quality of life.\textsuperscript{28}

Given the high~preexisting~treatment burden in CF patients, patient
reported benefit is~important in helping decide best therapies~and help
with adherence.\textsuperscript{28}~It is encouraging that there is both
a physiologic benefit to NIV use as well as studies documenting patient
perceived efficacy. The definitive benefit in augmenting airway
clearance is worth noting for all CF clinicians.

\textbf{Risks of NIV~in CF Patients~}

NIV is well-tolerated by most patients, but it is important to be aware
of potential harms of NIV use.\textsuperscript{29}~ATS guidelines have
listed several contraindications to NIV including inability to protect
the airway and effectively clear respiratory
secretions.\textsuperscript{30}~Guidelines suggest proceeding with
caution~when considering NIV~in patients with extensive gastric
distention, ileus, nausea or vomiting, and
GERD.\textsuperscript{29,31,32}~GERD is one of the most common
gastrointestinal manifestations of CF.\textsuperscript{33}~It is
interesting to note that CFTR modulators~are not only improving lung
function in CF patients, but are also credited with the observed decline
in GERD.\textsuperscript{34}~Another gastric consequence of using NIV is
gastric insufflation, which can compress the lungs, decreasing
compliance and increasing mean airway pressures.\textsuperscript{35}This
combination of events can lead to increased aspiration, and may
contribute to the 5\% increase in aspiration pneumonia seen in NIV
patients.\textsuperscript{29} Care should be taken to reduce~the risk of
gastric consequences including aspiration by timing use of NIV away from
mealtimes and having the head of bed raised when
possible.\textsuperscript{36}~Timing the use of NIV can also allow for
breaks for the patient to effectively clear airway secretions.

Barotrauma has also been described in~obstructive lung diseases,
which~includes CF, in the setting of NIV use.\textsuperscript{37}~Known
steps to minimize barotrauma include using pressure control ventilation
in patients with low lung compliance, keeping peak inspiratory pressure
as low as possible, avoiding auto-PEEP, and preventing
patient-ventilator asynchrony.\textsuperscript{29} Using settings to
minimize barotrauma and monitoring for barotrauma is essential when
using NIV in obstructive lung disease.

Special precautions also need to be taken~with NIV to prevent
hemodynamic consequences~in patients with chronic right ventricular
dysfunction and lung hyperinflation from obstructive lung
disease.\textsuperscript{29} Both~careful use of PEEP and cautious
delivery of low tidal volumes can help~mitigate these adverse
events.\textsuperscript{38} With the advanced lung disease guidelines
suggesting monitoring for hypercapnia and cardiac function in CF
patients as lung function declines, it will be easier for CF clinicians
to also consider these data prior to initiation of
NIV.\textsuperscript{39}

\textbf{Special Considerations}

\emph{CF Exacerbations and Hospitalizations}

A~prospective randomized controlled study evaluated~comprehensive
in-patient care to the same care with the addition of NIV during airway
clearance treatments~during in-patient admissions for CF exacerbation in
patients with moderate to severe disease.\textsuperscript{40}~This study
reported that the lung function (FEV1) was higher at discharge in the
NIV group relative to the usual care group.\textsuperscript{40}~~It
should be noted that the average daily NIV use in the intervention group
was only a total of 95 minutes, but still resulted in a measurable
difference in lung function.\textsuperscript{40}~ As described earlier,
use of NIV to augment~chest physiotherapy has been shown to improve
inspiratory and expiratory muscle strength, time with oxygen saturation
less than 90\% during sleep, and daytime
dyspnea.\textsuperscript{24}~~Both of these~studies support use of NIV
for airway clearance during inpatient care, and noninvasive ventilation
may have a role for ventilatory support as well.\textbf{~  }
Understandably, no randomized controlled trials of NIV for hypercapnia
in CF exacerbations have been performed. In an observational study
showed that among 16 ICU patients with severe CF respiratory
exacerbation who had NIV prescribed in an effort to avoid invasive
mechanical ventilation, NIV was successful in preventing invasive
ventilation in 50\% of those patients.\textsuperscript{41}~In~patients
with emphysema, a better studied obstructive lung disease, NIV use
during acute exacerbations with suspected hypercapnia has been proven to
improve length of stay, reduce need for intubation and reduce
in-hospital mortality.\textsuperscript{42}

In a survey of hospitals in France, the most common indication for NIV
use in CF was hypercapnia greater than 45 mmHg during an acute
exacerbation.\textsuperscript{43}~ Survey results demonstrated that FEV1
and hypercapnia during sleep were not factors for initiating NIV, and
NIV was not continued outside the setting of an
exacerbation.\textsuperscript{43}~However, there is some data to support
that hypercapnia during exacerbations may persistent after resolution of
exacerbation.\textsuperscript{44}~In a study of 19~CF patients~admitted
for acute exacerbation, 26.3\% of patients
(n=5)~had~PaCO\textsubscript{2} greater than 50
mmHg.\textsuperscript{44} In this hypercapnic group of patients, median
PaCO\textsubscript{2} was 58.5 mmHg on admission, decreased to 51.7 mmHg
on day 7, and 46 mmHg at treatment completion, which was still not
normal.\textsuperscript{44}~Median CO\textsubscript{2} at day 45 on
out-patient arterial blood gas was still 46.7mmHg in the individuals
with hypercapnic respiratory failure.\textsuperscript{44} This small
study demonstrates that~hypercapnia during in-patient admissions may
predict moderate persistent hypercapnia even after discharge, suggesting
some value to chronic nocturnal use of NIV post the immediate
exacerbation.\textsuperscript{44}

\emph{Advanced CF Lung Disease}

Hypercapnia is~a feature of~advanced CF lung disease (ACFLD)~as it
is~among the factors associated with increased mortality in~CF,
particularly when PaCO\textsubscript{2} is greater than 45
mmHg.\textsuperscript{45}~In a study of 10 patients with severe CF who
had a lung transplant, the baseline PaCO\textsubscript{2} was 63.75 mmHg
and FEV1 was 15.4\%.\textsuperscript{46}~ Utilization of nasal
noninvasive ventilation for 6-8 hours per night reduced the PaCO2 to
56.25 mmHg at 3 months and 48.00 mmHg at 6 months.\textsuperscript{46}~
In this small study, 4 patients died, 3 were transplanted and 3 remained
on NIV at the end of the study.\textsuperscript{46}~ A larger
retrospective study of 47 patients with severe CF with hypercapnia also
showed that NIV reduced PaCO\textsubscript{2} from 50 mmHg at initiation
of NIV to 45.9 mmHg at 1 year, 45.0 mmHg at 2 years and 49.6 mmHg at 3
years.\textsuperscript{22}~ In addition, in this cohort, while FEV1 fell
by 212 mL in the year prior to NIV initiation, it rose by 18 mL after 1
year and by 43 mL at 3 years after NIV Initiation.\textsuperscript{22}~
Median time on NIV prior to death or transplantation was 16 months with
NIV.\textsuperscript{22}~ In summary, the impact of NIV is impactful
across all spectrum of CF disease from mild nocturnal hypoventilation to
more severe disease with daytime hypercapnia.

\textbf{Indications for NIV}

Use of home NIV~in chronic respiratory failure~is~associated with
improved survivorship\textsuperscript{47,48},~reduced
hospitalizations\textsuperscript{47},~and~improved quality of
life.\textsuperscript{48,49}~While these benefits were initially noted
among patients with neuromuscular disorders, use has expanded other
etiologies of hypoventilation, including CF.\textsuperscript{49}

NIV~has~been used in acute and chronic respiratory failure in CF
patients.\textsuperscript{50}~CF Foundation Consensus Guidelines from
2020 recommend that individuals with advanced CF lung disease (ACFLD)
are screened annually for hypercapnia to determine need for home
NIV.\textsuperscript{39} NIV was suggested for those with:
paCO\textsubscript{2} [?] 55 mmHg or paCO\textsubscript{2} 50-54 mmHg and
nocturnal hypoxemia, or paCO\textsubscript{2} 50-54~mmHg and more than
two hospitalizations in the previous year for hypercapnic respiratory
failure.\textsuperscript{39}

One of the most common indications for use of positive airway pressure
(PAP) therapy is obstructive sleep apnea (OSA). Continuous positive
airway pressure (CPAP) therapy was first described to be therapeutic in
treatment of OSA back in 1980s.\textsuperscript{51} PAP continues to be
the most effective therapy in decreasing the severity OSA based on
objective measurements such as apnea-hypopnea index (AHI) and nadir
oxygen desaturations.\textsuperscript{52} However, CPAP may not be
effective in treatment of certain OSA populations, such as those who
require higher therapeutic pressures or develop treatment-emergent
central sleep apnea or complex sleep apnea.\textsuperscript{53} This
patient population may require management with NIV such as bilevel
positive airway pressure (BPAP) or adaptive servo ventilation
(ASV).\textsuperscript{53,54}

NIV has also been~used for management of treatment-emergent~central
sleep apnea, central sleep apnea related to other medical conditions
such as heart failure or high altitude, central apnea related to
medication or substance use, or primary central sleep
apnea.\textsuperscript{55} Often these disorders are characterized by
presence or absence of~hypercapnia~(paCO\textsubscript{2}~[?]~45
mmHg).\textsuperscript{56}~Primary central sleep apnea, nocturnal
hypoventilation associated with neuromuscular disease or underlying lung
disease often present with
elevated~paCO\textsubscript{2}.\textsuperscript{56} Meanwhile,
treatment-emergent apnea, central sleep apnea associated with heart
failure or high altitude, and central apnea associated medication and
substance use may present with normal paCO2
levels.\textsuperscript{56}~First line treatment for management of
central sleep apnea related to heart failure and medication or substance
use to optimize the underlying medical condition and discontinue the
offending agent if feasible, respectively.\textsuperscript{57}~If
despite the intervention, central or complex sleep apnea continues,
different types NIV can be utilized depending on the underlying
condition.\textsuperscript{56}

Obesity hypoventilation syndrome (OHS) is another~well-known~indication
for NIV use.~OHS is defined by hypoventilation during wakefulness
(paCO\textsubscript{2} \textgreater{} 45 mmHg), presence of obesity (BMI
\textgreater{} 30 kg/m\textsuperscript{2}), and~absence of other
conditions that may lead to hypoventilation such as underlying lung
disease, pulmonary vascular disease, chest wall disorder, medication
use, neuromuscular disease, congenital or idiopathic central alveolar
hypoventilation syndrome.\textsuperscript{55}~Of note, 80\% - 90\% of
patients with OHS have comorbid OSA.\textsuperscript{55} Patients with
concurrent severe OSA may respond with CPAP treatment alone.~ However,
those without concomitant OSA and primarily nocturnal hypoventilation,
defined by PaCO2 \textgreater{} 55 mmHg for \textgreater{}10 minutes or
an increase in PaCO\textsubscript{2} \textgreater{} 10 mmHg~when awake
PaCO2 \textgreater{} 50 mmHg for \textgreater{} 10 minutes,~may require
treatment with NIV.\textsuperscript{56}

In addition, neuromuscular diseases such as amyotrophic lateral
sclerosis (ALS), muscular dystrophies, myopathies, and spinal muscular
atrophies are also indications for the use of NIV. In fact, use of NIV
in ALS patients have demonstrated survival
advantage.\textsuperscript{48,58-60} It has been demonstrated that NIV
improves outcomes in those with predominantly limb-onset ALS compared to
those with primarily bulbar symptoms.\textsuperscript{60,61} Several
studies show positive impact on quality of life in these patients with
improvement in energy, vitality, shortness of breath, daytime
somnolence, depression, concentration, sleep quality, and physical
fatigue.\textsuperscript{48,62-64} Although there are no robust data to
determine when to initiate NIV in ALS patients, the occurrence of
orthopnea, sniff nasal pressure \textless{} 40 cm H\textsubscript{2}O,
maximal inspiratory pressure \textless{} -60 cm H\textsubscript{2}O,
abnormal nocturnal oximetry, or vital capacity \textless{} 50\%
predicted have been suggested.\textsuperscript{65} In other
neuromuscular disorders, NIV initiation has been recommended with the
development of nocturnal hypoventilation.\textsuperscript{66-68}

In summary, the major indications for the use of NIV include advanced
obstructive lung diseases such as COPD and CF, central sleep apnea,
obesity hypoventilation syndrome, and neuromuscular disorders. Figure 1
summarizes the requirements for the approval of home NIV by major
insurance carriers.

\textbf{Types of Noninvasive Ventilators~and Masks}

Various types of~ventilators are used in a hospital setting~and an
outpatient~setting.~ Invasive ventilators that are used in the intensive
care units (ICUs)~are~connected to an endotracheal or tracheostomy
tube.~These ventilators traditionally have separate inspiratory and
expiratory limbs, which prevent a patient from rebreathing exhaled
air~and~allow for measurements of inspiratory pressures and exhaled
minute ventilation.\textsuperscript{69}~Meanwhile, the noninvasive
ventilators (NIV) used in the outpatient setting are often smaller and
only have single limb with an exhalation port.~~However, more recently,
these distinctions are starting to blur. For example, ResMed Astral 150
and Philips Trilogy Evo, now also have dual-limb circuits available.

The simplest form of noninvasive ventilation, utilized in both the
in-patient and home setting, is bilevel positive pressure ventilation
(BPAP), which typically has inspiratory positive airway pressure (IPAP)
and expiratory positive airway pressure (EPAP)
settings.\textsuperscript{69} The difference between the IPAP and EPAP
is the amount pressure support that is delivered and will dictate the
tidal volumes a patient gets depending on the compliance of their
lung-chest wall unit.\textsuperscript{69} There are two different modes
on this type of device: spontaneous or
spontaneous/timed.\textsuperscript{69} With the spontaneous mode, each
breath is patient triggered, whereas with the spontaneous/timed mode,
breaths can be patient triggered but a ventilator breath is also
delivered at a specific time
interval.\textsuperscript{69}Spontaneous/timed mode allows the device to
provide a rate (back up rate) when patient is unable to initiate a
breath and is a form of pressure control
ventilation.\textsuperscript{69}

Even more sophisticated ventilators, utilized both in the in-patient and
home setting, have advanced modes capable of adjusting inspiratory
pressures to target tidal volume. One example of such ventilator mode
would be volume assured pressure support (VAPS) where the minimum and
maximum pressure support (minPS and maxPS, respectively) is set with
minimum and maximum expiratory positive airway pressure (minEPAP and
maxEPAP, respectively) to assure that the patient receives the targeted
tidal volumes.\textsuperscript{69} The pressures are automatically
adjusted to assure the target volume is delivered to the
patient.\textsuperscript{69} Volume control is another advanced mode of
ventilation that is infrequently used and is reserved mainly for
mouthpiece ventilation.\textsuperscript{69}

Advantages and disadvantages of these modes are discussed in Table 1
below. However, it should be noted that most studies evaluating use of
NIV in CF have utilized some form of BPAP with or without backup rate
(Table 2). Further studies are needed to determine the efficacy of VAPS
NIV in hypercapnic CF.

It is also very important to assure that the patients are well fitted
and comfortable with the mask that they are prescribed. Choosing a mask
should be a joint decision between the provider and the patient. Studies
have reported that one of best predictor of PAP adherence is early
usage.\textsuperscript{70,71} Mask selection and comfort can have
significant impact on the early experience and
usage.\textsuperscript{65} Therefore, it is vital that patients are
allowed to participate in choosing the right mask for themselves. There
are a variety of different masks available in different styles and
sizes. Some of the nasal mask interfaces in include nasal pillow, with
nasal prongs that are placed inside the nose, and a nasal mask, which
covers the entire nose.\textsuperscript{69} There are also oronasal
masks, which cover the entire nose and mouth, and hybrid masks which
cover the mouth, but lie below the nostrils without fully covering the
nose.\textsuperscript{69} In addition, there is a total face mask, which
fits over the entire face.\textsuperscript{69} There are advantages and
disadvantages to each type of mask. For instance, the nasal masks are
associated with decreased risk for aspiration, aerophagia, and have
reported to be more comfortable.\textsuperscript{69,72} Meanwhile, masks
with oral interfaces are better at controlling air-leak through the
mouth.\textsuperscript{69,72} It is important to spend time trialing and
selecting a mask to patient's satisfaction as studies have demonstrated
that patients who are well-adapted to their initial mask have better
adherence than those that need to exchange masks.\textsuperscript{73} A
multidisciplinary CF team, with the appropriate education, is uniquely
poised to help with the unique aspects of promoting adherence to NIV.

\textbf{Initiating NIV}

In initiating home NIV for in chronic hypercapnic respiratory failure
CF, important considerations are: 1) when to initiate NIV, 2) what
device or settings to choose, and 3) how to initiate NIV. Indications
for initiating NIV are described above, specifically as described in the
CF Foundation Guidelines for Advanced CF Lung Disease, as well as other
comorbidities patients may have such as OSA, OHS, and neuromuscular
weakness. For patients with COPD, current
CMS~reimbursement~guidelines~for E0470 devices (BPAP) suggest NIV in
patients with paCO\textsubscript{2}~[?] 52 mmHg with time with oxygen
saturation~[?] 88\% for~[?] 5 minutes on 2 LPM oxygen or the patient's
daytime flow (whichever is higher), with documentation of clinical
exclusion of obstructive sleep apnea.\textsuperscript{74}~ BPAP ST
devices (E0471) may be obtained if paCO\textsubscript{2} remains~[?] 52
mmHg and time with oxygen saturation~[?] 88\% for~[?]5 minutes on bilevel S
device with 2 LPM oxygen on the patient's daytime flow (whichever is
higher).\textsuperscript{74} No CMS guidelines are currently present~for
guidance in obtaining more advanced devices.

Table 1 describes common modes of noninvasive ventilation, and Table 2
summarizes studies that observed use of home NIV in CF patients,
modes~and~settings utilized.~ BPAP S and BPAP S/T were most frequently
used.~ One study by~Fauroux~et al evaluated the role of backup rate
while in pressure support mode (similar to~BPAP) or volume control mode,
both without end-expiratory pressure.\textsuperscript{75} In this study,
back up rates served to reduce respiratory effort and tachypnea,
surrogates of degree of respiratory rest.\textsuperscript{12} No
randomized controlled trials have evaluated the efficacy of novel modes
of NIV such as volume assured pressure support (VAPS) in hypercapnic CF
patients.~ A meta-analysis in hypercapnic COPD showed that VAPS was not
superior to pressure support mode in improving pH, PaCO2 or
oxygenation.\textsuperscript{76}

\textbf{Practical Considerations for Ordering NIV}

When ordering NIV, it is important to provide all the needed
documentation to avoid insurance denial or delay in set up.~Appropriate
records include office~or hospital~notes, supporting diagnostic and
laboratory tests as well as a prescription that includes settings,
supplies,~diagnosis~and~length of need as well as demographic
information. When choosing a durable medical equipment
(DME)~provider,~it is important to~consider if the patient~has other
medical equipment~such as a nebulizer~or oxygen. Choosing the~same
provider~for NIV may~avoid conflict when NIV needs to be used in
combination with~oxygen. Also, choosing a DME in network with the
patient's health insurance will minimize out of pocket expenses for
the~patient.~Having one DME provider also streamlines things for a
patient, much in the same way as having the same specialty pharmacy for
CF medications.

BPAP S or ST may be the mode chosen to initiate therapy both in the
in-patient setting and for home NIV. Traditionally, in an in-patient
setting, NIV is adjusted to target work of breathing,~pH~or
paCO\textsubscript{2}.\textsuperscript{77} For patients with hypercapnic
COPD, the American Thoracic Society recommends normalization of awake
arterial CO\textsubscript{2} tension.\textsuperscript{78} While similar
treatment goals have not been established in hypercapnic CF, it is
recommended that NIV be initiated for elevated
CO\textsubscript{2}tension.\textsuperscript{39}~Establishing a goal of
reducing awake paCO\textsubscript{2} to approach eucapnia may be a
reasonable goal.\textsuperscript{77} In addition to evaluation of
arterial blood gases, review of data from NIV may be helpful to
determine if treatment targets are met.~ Common targets in NIV learned
from other~disease states are ensuring that sufficient tidal volumes are
being delivered, and that there is sufficient ventilatory
rest.\textsuperscript{79,80}

Cloud systems monitoring home NIV use can provide data on usage, average
leak, residual apnea-hypopnea index (AHI), pressures used, tidal
volumes, and respiratory rate. Diagnostic and adherence reports can be
accessed by creating an account at\emph{www.airview.resmed.com}
and\emph{www.careorchastrator.com}for ResMed and Respironics,
respectively. The patient demographics and equipment information is
uploaded by the DME company and linked to the provider's account.

In some patients, NIV can worsen work of breathing and these patients
must be identified rapidly in order to seek guidance from sleep boarded
physicians\textsuperscript{77}. It is important that CF providers review
any downloads that cause concern with an expert in this field. A
download report can be first looked at for hours of compliance nightly,
followed by checking for leaks, then assessing tidal volumes, and
finally for residual AHI. Residual respiratory events, patient
ventilator asynchrony and upper airway obstructive events negatively
impact patient-related outcomes, health related quality of life, and
survival\textsuperscript{81}. It is important that NIV be systematically
monitored by the CF team and if needed by a sleep physician for these
residual events.

\textbf{Managing and Counseling Patients on NIV}

\emph{Adherence~}

CF is known to have a high treatment burden, and adherence to
chronically prescribed therapies is not ideal, with chest physical
therapy adherence rates documented between 40-47\% and dietary
recommendation adherence rates ranging from 16-20\%
.\textsuperscript{82,83} Rates of non--adherence to NIV treatment
regimens can vary for many reasons and routine clinical assessment for
respiratory symptoms, sleep quality, and NIV side effects can allow
clinicians to troubleshoot for issues early on in therapy and promote
adherence. \textsuperscript{84,85} In addition, taking into account
treatment burden as a whole and personalizing treatment plans may help
CF patients.

Researchers have attempted to identify patient characteristics that my
predispose to lower adherence to NIV. DiFeo~et al evaluated patient
characteristics such as obesity, race, gender, presence of developmental
delay/hyperactivity, parental factors, and PAP-related~factors such as
pressure, nasal symptoms on PAP adherence in
children.\textsuperscript{86} Their analysis revealed that maternal
education was the greatest predictor of PAP use for mean hours per night
for children.\textsuperscript{86} Family and social support is
also~predictive~of success with CPAP~adherence ,~but not as strong as
maternal education.\textsuperscript{86} It is reasonable to assume that
family and social support would also predict success in adults, and
telemonitoring in the future may also help with adherence in
adults.\textsuperscript{80}

The type of PAP device used does not affect adherence, although mask
type may be a determining factor with a lower compliance noted for
full-face masks compared to nasal~masks.\textsuperscript{87} Majority of
the studies that address specific barriers to~adherence in children
have~focused on the concerns of the patients' family
alone.\textsuperscript{88}~Simon and colleagues developed a 31-item
psychometric questionnaire (ABCQ) to evaluate both child and family
barriers to CPAP adherence~.\textsuperscript{89} In adults with low
adherence, it is suggested that clinicians first determine whether the
patient has the appropriate mask interface for their facial size, assess
for claustrophobia, check for leaks, and ask about adverse events such
as dry mouth and aerophagia\textsuperscript{90}. Switching mask size,
increasing heated humidification, using oral moisturizer rinses, and
changing the settings are all possible measures that can be taken to
improve adherence.\textsuperscript{90}

\emph{Maintaining NIV}

Bacterial contamination of home nebulizers of people with CF has been
documented, and infection control guidelines for CF state that durable
home nebulizers should be cleaned, disinfected, and air dried after each
treatment\textsuperscript{91}. Heat or cold disinfectant methods can be
followed, as permitted by the manufacturer\textsuperscript{91}.
Distilled water is not recommended for cleaning of equipment as
contamination with B. cepacia can occur during
manufacturing\textsuperscript{91}. The guidelines do not specifically
address NIV, but it is reasonable to assume that following manufacturer
guidelines is prudent.

Proper cleaning of NIV-related equipment important in maintenance of
equipment as well as preventing infection in users. Daily cleaning of
mask can be done with mild detergent and warm water, mask cleaning wipes
or spray mask cleaner.\textsuperscript{92} The humidifier chamber needs
to be emptied and refilled daily with distilled water.~ The remainder of
the supplies such as headgear,~tubing~and reusable sponge filter can
also be cleaned weekly using mild soap and warm
water.\textsuperscript{92} Although manufacturer guidelines for NIV may
include some suggestions regarding vinegar, vinegar is not recommended
in CF as it has inadequate coverage against S. aureus and other
potential CF pathogens\textsuperscript{91}. Other commercial
disinfecting methods include UV light devices like~Lumin~and~Paptizer,
and Ozone devices like Sleep 8, Virtu clean, Zoey and So Clean.
{[}www.thoracic.org{]}~However, none of these devices are FDA approved
and manufacturer's warranty excludes damages caused by these
devices.\textsuperscript{93}

\emph{Counseling}

Education on disease progress and the need for medical equipment have
shown promise as a strategy for improving patient
adherence.\textsuperscript{94} It is important to review the process of
obtaining NIV, the benefits,~contraindications, what to expect during
setup, equipment~maintenance, cleaning, supply replacement schedule, and
adherence or usage requirements. It is also important to counsel
patients on when to call the clinical team versus the durable medical
equipment company. In patients with more severe disease, it may be
important to discuss the incorporation of NIV into their routines, such
as medication, feeding and airway clearance therapy schedules. In
addition, the optimal time to start NIV should be a co-decision between
the provider and the patient as early usage pattern does establish
overall adherence pattern.\textsuperscript{70,71}

\textbf{Conclusion}

Noninvasive ventilation (NIV)~use~was initially~reported in~cystic
fibrosis (CF)~in 1991~as a bridge to lung transplantation, and evidence
for use in chronic respiratory failure in CF outside of lung
transplantation continues to grow.\textsuperscript{1-3} NIV can increase
tidal volume, reduce respiratory rate, and reduce~respiratory~muscle
load both while it is being used and also continually in patients using
NIV intermittently.\textsuperscript{12} In addition, NIV can improve gas
exchange, quality of sleep, augment airway clearance, and allow for
improved exercise tolerance.\textsuperscript{12}

It is important for CF providers to know when NIV should be initiated in
CF patients, what device and settings to choose in initial prescribing,
and what to monitor in patients on this modality. In addition, non-sleep
boarded CF providers may benefit from understanding the basics of
reviewing a PAP download and consulting with a sleep physician when
indicated, especially when the expected benefit is not readily apparent.

Future studies are needed to investigate even earlier intervention with
NIV in CF considering its salutary effects in preserving lung function.
The entire CF team should be utilized, especially respiratory
therapists, to help counsel patients on the importance of adherence, the
proper methods of cleaning, and how to fit this therapy into their
individual care plan. This review can serve as a resource for CF
providers in recognizing hypercarbic respiratory failure, recognizing
the impact of NIV, and potentially for initiation of
NIV.\textbf{Acknowledgements} ~ The authors thank Dr. Rose Franco MD for
her collaboration. The authors also thank the Cystic Fibrosis Foundation
for the grant support of the Rutgers-Robert Wood Johnson Medical School
pediatric and adult Cystic Fibrosis programs (CC 154).

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