sensors

Article
A Low-Cost Breath Analyzer Module in Domiciliary
Non-Invasive Mechanical Ventilation for Remote
COPD Patient Monitoring †
Antonio Vincenzo Radogna 1, * , Pietro Aleardo Siciliano 1 , Saverio Sabina 2 ,
Eugenio Sabato 3,4 and Simonetta Capone 1, *
1 Institute for Microelectronics and Microsystems, National Research Council (CNR-IMM), Campus Ecotekne,
Str. Prov. Lecce-Monteroni km 1.2, 73100 Lecce, Italy; pietro.siciliano@le.imm.cnr.it
2 Institute of Clinical Physiology, National Research Council (CNR-IFC), Campus Ecotekne, Str. Prov.
Lecce-Monteroni km 1.2, 73100 Lecce, Italy; sabina@ifc.cnr.it
3 “A. Perrino” Hospital, Pulmonology Ward, 72100 Brindisi, Italy; sabatoeugenio@gmail.com
4 Institute for Research on Population and Social Policies, (CNR-IRPPS), 72100 Brindisi, Italy
* Correspondence: antonio.radogna@le.imm.cnr.it (A.V.R.); simonetta.capone@cnr.it (S.C.)
† This paper is an expanded version of “Radogna, A.V.; Capone, S.; Di Lauro, G.A.; Fiore, N.; Francioso, L.;
Casino, F.; Siciliano, P.; Sabina, S.; Sabato, E. A smart device for supporting mechanical ventilo-therapy” in
Proceedings of the IEEE International Conference on IC Design and Technology (ICICDT 2018), Otranto,
Italy, 4–6 June 2018.




Received: 15 November 2019; Accepted: 17 January 2020; Published: 24 January 2020


Abstract: Smart Breath Analyzers were developed as sensing terminals of a telemedicine architecture
devoted to remote monitoring of patients suffering from Chronic Obstructive Pulmonary Disease
(COPD) and home-assisted by non-invasive mechanical ventilation via respiratory face mask. The
devices based on different sensors (CO2 /O2 and Volatile Organic Compounds (VOCs), relative
humidity and temperature (R.H. & T) sensors) monitor the breath air exhaled into the expiratory line
of the bi-tube patient breathing circuit during a noninvasive ventilo-therapy session; the sensor raw
signals are transmitted pseudonymized to National Health Service units by TCP/IP communication
through a cloud remote platform. The work is a proof-of-concept of a sensors-based IoT system with
the perspective to check continuously the effectiveness of therapy and/or any state of exacerbation of
the disease requiring healthcare. Lab tests in controlled experimental conditions by a gas-mixing
bench towards CO2 /O2 concentrations and exhaled breath collected in a sampling bag were carried
out to test the realized prototypes. The Smart Breath Analyzers were also tested in real conditions
both on a healthy volunteer subject and a COPD suffering patient.

Keywords: COPD; exhaled breath; noninvasive ventilation; sensors; patient monitoring

1. Introduction
Chronic respiratory failure is a serious pathological condition characterized by reduced efficiency
of respiratory function; the lungs are not able to ensure adequate oxygenation of the arterial blood
(hypoxemia) and/or to prevent CO2 retention (hypercapnia) [1]. The main condition that commonly
leads to chronic respiratory failure is Chronic Obstructive Pulmonary Disease (COPD), an umbrella
term used to describe progressive and not fully reversible lung disease involving emphysema (damage
to the air sacs in the lungs), chronic bronchitis (long-term inflammation of the airways), and refractory
(non-reversible) asthma [2]. The primary cause of COPD is cigarette smoking and/or exposure to
tobacco smoke; other causes include air pollution, infectious diseases, and genetic conditions [3].
COPD represents an important public health challenge and it is a major cause of chronic morbidity and

Sensors 2020, 20, 653; doi:10.3390/s20030653 www.mdpi.com/journal/sensors

Sensors 2020, 20, 653 2 of 20

mortality throughout the world. Indeed, it is currently the 4th leading cause of death in the world but
it is projected to be the 3rd leading cause of death by 2020 due to population ageing [4]. The impact of
COPD on National Health Services (NHSs) in terms of cost and patient management is huge. The most
critical issue is preventing the recurrence of acute exacerbations of COPD (ECOPDs), i.e., the episodes
of worsening of symptoms, due to various factors, the most common being respiratory tract infections,
which lead to hospitalization and increased mortality [5–7].
Noninvasive ventilation (NIV) refers to the integrated therapeutic treatment based on mechanical
ventilators that assist (or substitute) breathing, using either pressure or volume control, with the
help of a respiratory face mask; such ventilatory support improves pulmonary gas exchange and rest
compromised respiratory muscles sufficiently to recover from the fatigued state [8,9]. This therapy
has markedly increased over the past two decades in COPD treatment in replacement for invasive
ventilation (endotracheal tube or tracheostomy tube), becoming a fundamental beneficial tool in patient
management at home [10–13].
However, NIV administration in home setting gives rise to other problems related to domiciliary
complex care of vulnerable patients under constant risk of sudden respiratory decompensation, as
well as to health service management. Hypoxemia in COPD patients is due to ventilation/perfusion
(V/Q) mismatch resulting from progressive airflow limitation and emphysematous destruction of the
pulmonary capillary bed [14]; supplemental oxygen therapy is often used to manage hypoxemia but
prolonged treatments are debated for the risks related to an inappropriate administration [15–17].
Patients with end-stage COPD frequently develop chronic hypercapnic respiratory failure associated
with end-of-life; long-term NIV to treat chronic hypercapnic respiratory failure is still controversial in
severe Chronic Obstructive Pulmonary Disease (COPD) patients [18].
The organization and cost of services for long-term domiciliary NIV assistance of patients are
charged to NHSs; accurate individual titrations and frequent specialized technical support for adjusting
ventilator setting and patient-ventilator asynchrony are required in order to optimize ventilation and
minimize side effects. Patients and their families often feel alone in coping with daily ventilo-therapy
without any medical monitoring. There is no integrated program of intervention on the territory aimed
at ensuring proper patient assistance in the different COPD stages (mild, moderate, severe, end-stage)
and supporting clinical decision-making in the successful management of domiciliary NIV [19].
Arterial-blood gas (ABG) test, measuring the amounts of arterial CO2 and O2 , is the gold standard
technique, but it is relatively invasive [20]. There is a growing interest in applying non-invasive
technologies that could measure physiological parameters, as end-tidal CO2 (capnography) and blood
oxygen saturation level SpO2 (oximetry) [21–23]. However, for domiciliary NIV, capnograph is an
optional module of the mechanical ventilator, not included in the kit supplied to home assisted
COPD patients. On the other side, most common oximeters do not allow SpO2 monitoring because
they have no communication port or data storage and generally they are not provided to patients.
There is, hence, the need to develop telemedicine systems for a remote monitoring of respiratory
variables and patient surveillance under NIV [24–27]. The most diffused telehealth services are based
on tele-assistance (teleconsultation, videoconference, etc.), but the most needed are those based on
sensor technologies for monitoring the main physical variables of interest. Anyway, at present in
both approaches home care programs controlled by telemonitoring are relatively rare [28–32]. The
cost-benefit balance for telehealth technologies is debated; clinicians express negative generic advices
and are generally skeptical about the effectiveness of such technologies, whereas patients were broadly
in favor of devices that feel them supported in manage their disease [33]. A survey of the available
technologies for the remote monitoring of Chronic Obstructive Pulmonary Disease (COPD) patients
together with the future challenges are given by Tomasic et al. [34].
In this work we report the development of a low-cost breath analyzer implementable as external
and independent module to almost any type of modern ventilator via compatible connections to
expiratory line of bi-tube breathing circuit. We extended the description of the developed device
presented at International Conference on IC Design & Technology held on 4th–6th June 2018 at Otranto,
Sensors 2020, 20, 653 3 of 20

Italy (ICICDT 2018) [35]. The module allows continuous remote measurements of exhaled CO2 , O2 ,
and Volatile Organic Compounds (VOCs), as well as relative humidity and temperature (R.H. & T)
during an NIV therapy session. A bundle of significant variables of exhaled breath are monitored. The
module can be exploited to check continuously the status of hypoxemia and/or hypercapnia, avoiding
invasive frequent blood draws needed for standard hemogasanalysis. As novelty, the information on
the current health status, carried by exhaled VOCs, is traced through chemoresistive gas/VOC sensors.
The aim is to develop a system complementary to long-term domiciliary NIV for remote patient
monitoring. The temporal tracings of all the sensor signals are sent to an ICT platform (OMNIACARETM
eResults srl, Italy) [36] allocating a cloud storage. The clinicians can visualize the sensor tracks by
connecting to the configured platform, use this auxiliary information to assess outpatient health
condition, and be supported in making clinical decision for a successful management of domiciliary NIV.

2. Materials and Methods

2.1. Rationale
In the initial stage of the device design, the authors collaborated with specialist doctors;
pulmonologists were asked to describe the main problems of home management of COPD patients
and to express what were the not yet satisfied needs of technological innovation from a medical
point of view. By these interactions and on the basis of physiological/clinical considerations, the
main specifications of the device and the physical variables to be monitored, i.e., exhaled carbon
dioxide/oxygen (CO2 /O2 ) concentrations, relative humidity and temperature (R.H. & T), were defined.
Exhaled O2 and CO2 concentrations are correlated to alveolar gas exchanges and partial pressures
of O2 and CO2 in the arterial blood (Pa O2 and Pa CO2 ). Alveolar equilibrium values (PA O2 and PA CO2 )
lie between those of the blood vessels and inhaled air and they can be measured by evaluating the
values at the end-tidal of exhalation [37] (Figure 1). By monitoring end tidal O2 and CO2 , it is thus
possible to check continuously the status of hypoxemia and/or hypercapnia; the frequency of invasive
hemogasanalysis could be reduced only to the necessary cases [38]. Exhaled O2 offer complementary
information to blood oxygen saturation level (SpO2 ); SpO2 is expressed as a percentage of the maximum
amount of oxygen that hemoglobin in the blood can carry and it is commonly measured by pulse
oximetry. Unlike SpO2 , exhaled O2 monitors the actual ventilation; exhaled O2 and CO2 are jointly
good indicators of respiratory exchanges [21].
Whereas the respiratory cycle of CO2 and O2 gases is relatively straightforward and understood,
the presence in exhaled breath of thousands of additional Volatile Organic Compounds (VOCs) is a
powerful source of knowledge that reflects both environmental exposures (exogenous compounds)
and relevant systemic and internal metabolic processes (endogenous compounds). Endogenous VOCs
have been proposed to be useful as preclinical biomarkers of various undiagnosed diseases including
lung cancer, breast cancer, and cardio-pulmonary disease [37,39,40]. Currently, there is a huge growing
interest in Breathomics, the emerging metabolomics study of exhaled air that aims to find patterns of
health-related VOCs. Breath analysis has not yet translated to clinical practice due to some critical
issues not related to concept validity but to the need of more research to achieve fundamental goals as
standardization of breath sampling protocols, validation by longitudinal multi-center clinical trials,
understanding of the pathophysiologic origins of these VOCs by the biochemical pathways involved
in disease development. A lot of efforts are devoted to get technological advances developing novel
analytical and sensing platforms. Despite the difficulties in implementing breath-based diagnostics
in daily clinical practice, scientific community believe that breath analysis will realize its long-held
potential becoming a revolutionary tool in personalized medicine [40–43]. Breathomics studies applied
to COPD showed distinct patterns of exhaled volatiles in COPD patients supporting the potential
use of VOCs in discriminating COPD subjects and healthy controls as well as in identifying clinically
relevant COPD subgroups [44–46]. Results published in literature demonstrated that Breathomics
breath analysis will realize its long-held potential becoming a revolutionary tool in personalized
medicine [40–43]. Breathomics studies applied to COPD showed distinct patterns of exhaled
volatiles in COPD patients supporting the potential use of VOCs in discriminating COPD subjects
andSensors
healthy
2020,controls
20, 653 as well as in identifying clinically relevant COPD subgroups [44–46]. Results 4 of 20
published in literature demonstrated that Breathomics can be exploited in: (a) predicting inception
of asthma or chronic obstructive pulmonary disease, (b) inflammatory phenotyping, (c) exacerbation
can be exploited
prediction, in: (a) predicting
and (d) treatment inception
stratification of asthma or chronic obstructive pulmonary disease, (b)
[46–49].
inflammatory phenotyping, (c) exacerbation
Although the various forms of mass spectrometry, prediction,mainly
and (d) treatment
gas stratification [46–49].
chromatography-MS (GC-MS),
Although the various forms of mass spectrometry, mainly
proton transfer reaction-MS (PTR-MS), selected ion flow tube-MS (SIFT-MS) [50], provide gas chromatography-MS (GC-MS),
proton transfer reaction-MS (PTR-MS), selected ion flow tube-MS (SIFT-MS)
information on exhaled substances with molecular identification and quantification, other more [50], provide information
on exhaled
flexible, cheapsubstances with molecular
and functional identification
sensing platforms are and quantification,
electronic other more
noses (e-noses). flexible,
Such cheap
devices
and functional
fingerprint sensing platforms
the ensemble of exhaledare electronic
VOCs noses
(called human(e-noses). Such in
exhalome) devices
termsfingerprint
of gas/VOC thesensors
ensemble
of exhaled VOCs (called human exhalome) in terms of gas/VOC sensors
response patterns; their challenge is to become a screening non-invasive technique supporting gold response patterns; their
challenge
mass is to become
spectrometric techniques a screening non-invasive technique supporting gold mass spectrometric
[40,41,51–54].
techniques [40,41,51–54].
Here the rationale is that e-noses could detect specific exhalome profiles associated with
Here states
exacerbation the rationale
of COPD, is that
thatseem
e-noses
to becould detectcaused
commonly specificbyexhalome
respiratoryprofiles associated
infections of viral orwith
exacerbation
bacterial origin; states
the riskof COPD,
is higher that
in seem to be commonly
mechanical ventilated caused
patientsbysorespiratory infections of viral
that ventilator-associated
or bacterial origin; the risk is higher in mechanical ventilated
pneumonia (VAP) is a known common phenomenon. Since many exhaled Volatile Organic patients so that ventilator-associated
pneumonia(VOCs)
Compounds (VAP) ismay a known
comecommon phenomenon.
from potentially Since many
pathogenic exhaled Volatile
microorganisms Organic Compounds
metabolism [55–58],
e-noses can be used for distinguishing between viral, bacterial, and non-infectious causescan
(VOCs) may come from potentially pathogenic microorganisms metabolism [55–58], e-noses of be
used for distinguishing between viral, bacterial, and non-infectious causes
exacerbations. Numerous literature reports on pilot studies based on e-noses analysis of exhaled of exacerbations. Numerous
literature
breath reports on
to diagnose VAP pilot[59–64].
studies Thisbasedisonimportant
e-noses analysis
in orderof exhaled
to reduce breath
the to diagnose VAP [59–64].
over-prescription of
This is important in order to reduce the
antimicrobials for bacterial respiratory tract infection. over-prescription of antimicrobials for bacterial respiratory
tract infection.

Figure
Figure 1. Respiratory
1. Respiratory gases
gases (CO(CO
2 and2 and
O 2) O
and 2 ) and Volatile
Volatile Organic
Organic Compounds
Compounds (VOCs)
(VOCs) exchange
exchange within
within
CO 2 /O
alveoli. CO2/O2 exchanges are approximated by the gas alveolar formula: PAO2 = (PB − PH2O) × FiO22O)
alveoli. 2 exchanges are approximated by the gas alveolar formula: PA O 2 = (P B − PH − ×
F
(PACOO − (P CO
i 22/R), where
A /R), where P is
2PB is the barometric
B the barometric pressure,
pressure, PAH2O is the water P H O is the water vapor pressure
A 2 vapor pressure (usually 47 mmHg), (usually
FiO47 mmHg), Fi O2 isconcentration
2 is the fractional
the fractionalofconcentration
inspired oxygen, of inspired oxygen,
and R is and R is the
the respiratory respiratory
quotient, quotient,
dependent
on dependent
metabolic on metabolic
activity and activity
diet andand is diet and is considered
considered to be
to be about aboutVOC
0.825). 0.825). VOC exchanges
exchanges dependdepend
on
on blood-air partition coefficients
blood-air partition coefficients (λb:a). (λ b:a) .

Since breath is relatively warm and humid, R.H. & T are also important parameters to be measured
Since breath is relatively warm and humid, R.H. & T are also important parameters to be
in the exhaled air mainly as interference factors for infrared CO2 sensors and gas/VOC sensors based
measured in the exhaled air mainly as interference factors for infrared CO2 sensors and gas/VOC
on semiconducting metal oxides (MOX). Recently, evaluation of the exhaled breath temperature (EBT)
sensors based on semiconducting metal oxides (MOX). Recently, evaluation of the exhaled breath
has been suggested as a new method to monitor pathological processes in asthma, chronic obstructive
temperature (EBT) has been suggested as a new method to monitor pathological processes in
pulmonary disease, and other respiratory diseases [34,65,66]; novel respiratory rate monitor based on
asthma, chronic obstructive pulmonary disease, and other respiratory diseases [34,65,66]; novel
exhaled humidity has been also proposed [67].
respiratory rate monitor based on exhaled humidity has been also proposed [67].
2.2. Design Consideration
2.2. Design Consideration
The Breath Analyzer Module was designed for a continuous breath-by-breath remote acquisition of
signals from a set of sensors exposed to exhaled breath during long-term home-based NIV therapy [35].
The sensor toolbox was expanded including a small electronic nose (e-nose) based on 3-sensors array
based on Metal OXide sensing materials (MOX) sensitive to exhaled Volatile Organic Compounds
Sensors 2020, 20, x FOR PEER REVIEW 5 of 20

The Breath Analyzer Module was designed for a continuous breath-by-breath remote
acquisition of signals from a set of sensors exposed to exhaled breath during long-term home-based
NIV therapy [35]. The sensor toolbox was expanded including a small electronic nose (e-nose) based
Sensors 2020, 20, 653 5 of 20
on 3-sensors array based on Metal OXide sensing materials (MOX) sensitive to exhaled Volatile
Organic Compounds (VOCs) produced by ongoing internal biochemical processes of human
(VOCs) produced
metabolism. by ongoing
All the sensors internal
(i.e., CObiochemical
2, O2, R.H. processes
& T, and of human metabolism.
MOX-based All the
sensors) have sensors
been (i.e.,
selected
CO
from, O
2 the , R.H. & T, and MOX-based sensors) have been selected from the range
2 range of products available on the market based on sensing characteristics, technological of products available
on the market
quality, basedconsumption,
low power on sensing characteristics, technological
price considerations, quality, low power
and compatibility consumption,
with medical price
applications.
considerations, and compatibility
The next challenge was to find withthemedical applications.
right setup of the system made by the mechanical ventilator
and The next challenge
the breathing circuitwas to findtothe
in order right
allow thesetup of the system
connection made by thedevice
of our monitoring mechanical
without ventilator
causing
and
any the breathing
leakage alertcircuit
in theinventilator,
order to allow hencethe ensuring
connectionitsofnormal
our monitoring
operation device without
in safety causing any
conditions for
leakage
patient.alert
The in the ventilator,
Breath AnalyzerhenceModule ensuring its normalsidestream
was connected operation into safety conditions
the expiratory forofpatient.
line The
a standard
Breath
bi-tubeAnalyzer Module was
patient breathing connected
circuit upstream sidestream to the expiratory
of the expiratory valve of line
theofventilator;
a standardabi-tube
minor patient
part of
breathing
the exhaled circuit upstream
air deviates from of the
the mainstream
expiratory valve into aof the ventilator;
gastight cell insidea minor part of
the device, thenthereentering
exhaled air in
deviates from the mainstream
the mainstream. Such flowinto a gastightconfiguration
deviation cell inside the device, then reentering
was implemented byin two
the mainstream.
disposable
Such flow deviation
tee-connectors, that configuration
are standard was implemented
accessories by two disposable
of breathing tee-connectors,
circuits, making the device thatfully
are
standard
compatible accessories of breathing
with all mechanical circuits, making
ventilators the device
set for bi-tube fully compatible
breathing with
circuit. Figure all mechanical
2 schematizes the
ventilators set for bi-tube breathing circuit. Figure 2 schematizes the adopted
adopted connection of the breath analyzer module to the expiratory line of a bi-tube breathing connection of the breath
analyzer
circuit. module to the expiratory line of a bi-tube breathing circuit.

Figure 2.
Figure 2. Scheme
Scheme of the connection
connection of
of the
the device
device to
to the expiratory
expiratory line
line of
of the
the bi-tube
bi-tube breathing
breathing circuit.
circuit.

2.3.
2.3. Hardware
Hardware and
and Firmware
Firmware Design
Design
After
After aa market
market inquiry,
inquiry,the
thefollowing
followingsensors
sensorsaccomplishing
accomplishingthe
thedesignated
designatedtasks
taskswere
wereselected:
selected:
(1)
1) Infrared CO2 sensor: SprintIR™
CO2 sensor: SprintIR™ byby Gas
Gas Sensing
Sensing Solutions
Solutions Ltd.,
Ltd., Cumbernauld,
Cumbernauld, United Kingdom;
2)
(2) Electrochemical O2
O2 sensor:
sensor: KE-25
KE-25by
byFigaro
Figaro Engineering
Engineering Inc.,
Inc., Osaka,
Osaka, Japan
Japan;;
3)
(3) Relative humidity and temperature: SHT75 by Sensirion AG, Staefa ZH, Switzerland;
4)
(4) A dual (NOX-CO)
A dual (NOX-CO) sensor
sensor built with MOX
built with MOX technology:
technology: MiCS-4514
MiCS-4514 byby SGX SensorTech,
SGX SensorTech,
Corcelles-Cormondrèche, Switzerland ;
Corcelles-Cormondrèche, Switzerland;
5) A VOC sensor built with
(5) A VOC sensor built with MOX MOX technology:
technology: AS-MLV-P2
AS-MLV-P2 by amsbyAG,ams AG, Unterpremstaetten,
Unterpremstaetten, Austria;
Austria;
The choice of such commercial sensors was motivated by multiple considerations based on
The choice of such commercial sensors was motivated by multiple considerations based on a
a compromise between sensing characteristics suitable for the specific medical application and
compromise between sensing characteristics suitable for the specific medical application and
mandatory requirements for a proof-of-concept of pre-commercial product (as miniaturization, low
mandatory requirements for a proof-of-concept of pre-commercial product (as miniaturization, low
power consumption, and low cost). Table 1 summarizes the sensors main characteristic together with
power consumption, and low cost). Table 1 summarizes the sensors main characteristic together
the main features addressing sensor selection for the Breath Analyzer Module.
with the main features addressing sensor selection for the Breath Analyzer Module.
Sensors 2020, 20, 653 6 of 20

Table 1. Sensors characteristics

Sensor Main Features Addressing Sensor Selection for the Breath

Sensor Technology Accuracy Sensing Range Power Consumption Comm.
Analyser Module

• Sensing range compatible with hypercapnia levels

NDIR with flow ±70 ppm +/− 5% of • Flow adapter cape with 1 inlet and 1 outlet compatible with
SprintIR 0–20% 35 mW UART
through adapter reading sidestream connection to system
• Application Note AN-128 for operating with Arduino

• Suitable for medical applications

• Linear output voltage signal relative to percent oxygen
KE-25 Galvanic cell ±1% full scale 0–100% N/A Analog (voltage) • No external power supply required for sensor operation
• Virtually no influence from CO2
• Threaded top suitable for connection to sensor chamber
• Low cost

• High accuracy
Proprietary • Attractive price-performance ratio
SHT75 (T) ±0.3 ◦ C −40 ◦ C–123.8 ◦ C
CMOSens® 90 µW (average) I2C • Easy replaceability (pin-type version)
• Fully calibrated digital output
Proprietary • Low power consumption
SHT75 (RH) ±3.0% 0–100%
CMOSens® • High-end version

• Miniaturized MEMS (micro electromechanical system) devices

30 ppm–500 ppm (taken
34 mW (heating • High sensitivity to VOCs (AS-MLV-P2 and MICS-4514 (RED))
AS-MLV-P2 Metal-Oxide N/A from CO sensitivity curve, Analog (Resistance)
element at 320 ◦ C) • High sensitivity to NO2 (MICS-4514 (OX) to catch those exhaled
T and RH not mentioned)
NO molecules, known inflammatory marker, converted in NO2
• Very low power consumption
1 ppm to 1000 ppm (taken • Surface Mounting Device (SMD) package compatible with
88 mW (heating
MiCS-4514 (RED) Metal-Oxide N/A from CO sensitivity Analog (Resistance) Printed Circuit Board Assembly (PCBA)
element)
curve, 25 ◦ C, 50% RH) • Compact and simple front-end (conditioning circuit based on
0.05 ppm to 10 ppm buffered voltage divider)
(taken from NO2 50 mW (heating • Low cost (10–20 €)
MiCS-4514 (OX) Metal-Oxide N/A Analog (Resistance)
sensitivity curve, 25 ◦ C, element) • Scarce selectivity compensated by sensor array with
50% RH) cross-sensitivities
 sensitivity
sensitivity (conditioning
(conditioning circuit
circuit
curve,
curve, based
based on
on buffered
buffered
25°C,
25°C, 50%
50% voltage
voltage divider)
divider)
RH)
RH) •• Low
Low cost
cost (10-20
(10-20 €)
€)
•• Scarce selectivity
Scarce selectivity
Sensors 2020, 20, 653 compensated
compensated by by sensor
sensor
7 of 20
array with
array with
cross-sensitivities
cross-sensitivities
The CO2 sensor was connected by its flow adapter cape to the deviating sidestream tube and to
The
the inlet
TheofCO
CO sensor
sensor waswas connected
a22home-designed by
by its
its flow
cell realized
connected in
flow adapter
adapter cape
cape to
Polyoxymethylene to the deviating
(POM);
the the Osidestream
deviating tube
2 sensor was
sidestream and
and to
inserted
tube to
the inlet
through of
the inlet its a home-designed
of athreads cell
into the screw
home-designed realized in
hole oninthe
cell realized Polyoxymethylene
cell top. Regarding
Polyoxymethylene (POM); the
to the
(POM); O
theother
2 sensor was
sensors,
O2 sensor inserted
was they are
inserted
through
through its
available only
its threads into
in Surface
threads the
the screw
into Mounting hole
hole on
screw Devices the
the cell
on (SMDs) top.
celland Regarding
top.Pin Throughto
Regarding the
Hole
to other
the(PTH) sensors,
sensors, they
other packages, are
so that
they are
available
they only
required a in Surface
custom Mounting
designed Devices
electronic (SMDs)
board, and
labelled Pin Through
MultiSense, Hole
that (PTH)
actuated
available only in Surface Mounting Devices (SMDs) and Pin Through Hole (PTH) packages, so that packages,
also the so that
necessary
they
they required
signal conditioning
required aa custom designed
circuitry.
custom electronic
The sensor
designed cell was
electronic board,
designed
board, labelled
to be MultiSense,
labelled surface-mounted
MultiSense, that
that actuated
actuated also
also the
on the MultiSensethe
necessary
Printed signal
Circuit conditioning
Board (PCB) circuitry.
and gas-tightThe
by sensor
O-ring cell was
(Figure designed
3). to be surface-mounted
necessary signal conditioning circuitry. The sensor cell was designed to be surface-mounted on the on the
MultiSense
MultiSense Printed
Printed Circuit
Circuit Board
Board (PCB)
(PCB) and
and gas-tight
gas-tight by
by O-ring
O-ring (Figure
(Figure 3).
3).

(a)
(a) (b)
(b)
Figure 3. (a)
Figure 3. (a) 3D
3D rendered
rendered model
model of
of the
the gas
gas tight
tight cell;
cell; (b)
(b) front
front and
and back
back views
views of MultiSense
of MultiSense board.
MultiSense board.
board.

Since
Since the target was to to design a low-cost and easy easy
to use tele-monitoring device, ArduinoArduino
MEGA
Since the
the target
target was
was to design
design aa low-cost
low-cost and
and easy toto use
use tele-monitoring
tele-monitoring device,
device, Arduino
2560
MEGA (Ivrea, Italy), equipped with Ethernet Shield v2 board for Arduino, was chosen as microcontroller
MEGA 2560 2560 (Ivrea,
(Ivrea, Italy),
Italy), equipped
equipped withwith Ethernet
Ethernet Shield
Shield v2
v2 board
board forfor Arduino,
Arduino, was was chosen
chosen as
as
due to its low price,
microcontroller low power consumption, and small size features; it also benefits ofitaalso
simple and
microcontroller due to its low price, low power consumption, and small size features; it also benefits
due to its low price, low power consumption, and small size features; benefits
open source and
Integrated Development Environment (IDE) and a huge (IDE)
community
of
of aa simple
simple and open
open source
source Integrated
Integrated Development
Development Environment
Environment and aa support.
(IDE) and huge In order
huge community
community
to properly
support. connect the MultiSense board with the Arduino platform, an additional electronic board,
support. InIn order
order toto properly
properly connect
connect the
the MultiSense
MultiSense board
board with
with the
the Arduino
Arduino platform,
platform, an an additional
additional
labeled
electronicSenseShield,
electronic board, was designed.
board, labeled
labeled Figures
SenseShield,
SenseShield, was 4 and 5 show,
was designed.
designed. respectively,
Figures
Figures 44 and the device
and 55 show,
show, architecture
respectively,
respectively, the and a
the device
device
picture of
architecture the
architecture and realized prototype.
and aa picture
picture of of the
the realized
realized prototype.
prototype.

Figure 4.
Figure 4. Device
4. Device architecture.
Device architecture.
architecture.
Figure
Sensors 2020,
Sensors 2020, 20,
20, 653
x FOR PEER REVIEW 88 of
of 20
20
Sensors 2020, 20, x FOR PEER REVIEW 8 of 20

Figure 5. Realized unboxed prototype.

Figure 5. Realized
Figure 5. Realized unboxed prototype.
unboxed prototype.
Regarding the firmware, it was developed in two distinct modules: the first one implements
sensor Regarding
Regarding
controls thethefirmware,
and firmware, it was
it was
signal acquisition, developed
developed
whereas in second
in two
the two distinct
distinct modules:
modules:
one implements the
the first
the first
one one implements
implements
communication sensor
and
sensor
sendingcontrols
controls and to and
datasignal signal
theacquisition,
ICT acquisition,
platform whereas
(Figurewhereas
the Thethe
6).second second
one
first one part
implements
firmware implements
the the communication
communication
is responsible and sending
for sensors and
setup,
sending
data
signal dataICTto platform
to acquisition
the the from
ICT platform
(Figure
digital 6).(Figure 6).analog-to-digital
The first
sensors, The first firmware
firmware part is part is responsible
responsible
conversion and for sensors
for itsensors
also setup,
setup, signal
performs the
signal acquisition
acquisition
sub-ranging from fromfor
digital
algorithm digital
sensors, sensors,
MOXanalog-to-digital
all of analog-to-digital
the to cover conversion
sensorsconversion and large
their and
it alsooutput it resistance.
performs alsotheperforms
sub-ranging the
A circuit
sub-ranging
algorithm
schematic for of algorithm
all of
the for allsensors
the MOX
sub-ranging of the to
technique MOXcover sensors to
their large
is depicted in cover
output
Figure their large output
7.resistance.
Briefly, A circuit
since the resistance.
schematic
read-out A circuit
of the
circuit of
schematic
sub-ranging of the sub-ranging
technique is technique
depicted in is
Figure depicted
7. Briefly,in Figure
since the7. Briefly,
read-out
the MOX sensor is essentially a voltage divider, the firmware selects, through a proper driving of the since
circuit the
of read-out
the MOX circuit
sensor of
is
the MOX sensor
essentially
MOSFET a voltage
switches, is essentially
divider,
the a voltage
the
load resistorfirmware divider,
closer to thethe
selects, firmware
through
sensor selects,
a proper
resistance through
driving
thus of athe
determining proper
MOSFET driving
a voltage of the
switches,
ratio at
MOSFET
the load switches,
resistor the
closer load
to resistor
the sensor closer to
resistance the sensor
thus resistance
determining thus
a determining
voltage
the output of the voltage divider closer to VDD/2 (VDD system supply voltage). This is due to the ratio at a
thevoltage
output ratio
of at
the
the
fact output
voltage theofcloser
thatdivider the voltage
closer
they divider
to are
VDD/2
two (VDD closersystem
consecutiveto VDD/2 supply(VDD
resistors system
voltage).
of the supply
This
voltage voltage).
isdivider,
due to the fact Thisthat
more is due to the
the closer
sensitive
fact
they that the
are two
resistive closer is.they are
consecutive
reading two consecutive
resistors of the voltage resistors
divider, ofthe
themore
voltage divider,
sensitive thethe more sensitive
resistive reading is.the
resistive reading is.

Figure 6.
Figure 6. Device firmware overview.
Device firmware overview.
Figure 6. Device firmware overview.
Sensors 2020, 20, 653 9 of 20
Sensors 2020, 20, x FOR PEER REVIEW 9 of 20

Sensors 2020, 20, x FOR PEER REVIEW 9 of 20

Auto-ranging circuit
Figure 7. Auto-ranging circuit schematic.
Figure 7. Auto-ranging circuit schematic.
The second
The second firmware
firmware part part implements
implements the the TCP/IP
TCP/IP communication
communication through through Message
Message Queue Queue
Telemetry
TelemetryTheTransport
Transport
second firmware (MQTT),
(MQTT),part aa lightweight
implements communication
lightweight communication
the TCP/IP communicationprotocol suitable
protocol suitable
through forMessage
for embedded
embedded Queue and
and
constrained
constrained systems.
Telemetrysystems.
Transport Since hardware
(MQTT),
Since hardware resources
a lightweight are not
resources communication capable
are not capableprotocol of running
of running secure
suitable
secure standards
forstandards
embedded like
and
like the
the
X.509
X.509 certificates
constrained
certificates used in
systems.
used inSince
many
many secure protocols
hardware
secure protocols
resourceslike like TLS/SSL,
are TLS/SSL,
not capable data
data exchange
of running
exchange fromstandards
secure
from the device
the devicelikeandthe
and the
the
cloud server
X.509 are
certificatesnot secured.
used in However,
many secure this is
protocolsnot a remarkable
like TLS/SSL,
cloud server are not secured. However, this is not a remarkable problem because here MQTT problem
data because
exchange from here
the MQTT
device messages
and the
do not
messagescontain
cloud do notsensitive
server are not data
contain but only
secured.
sensitive data numerical
However,but only isvariables
this numerical without any
not a remarkable
variables reference
problem
without any to patient
because
reference identity
heretoMQTT
patient
messages
(pseudonymization
identity do not
(pseudonymization contain sensitive
of sensorofrawsensor data
signals). but only
raw signals). numerical variables without any reference to patient
identity
Figure(pseudonymization
Figure 88 illustrates
illustrates the of sensor
the system
system raw signals).
network
network consisting of
consisting of aa certain
certain number
number of of devices,
devices, eacheach ofof them
them
connectedFigureto 8
the illustrates
ventilators the system
of network
volunteer consisting
patients of
suffering a certain
from
connected to the ventilators of volunteer patients suffering from chronic respiratory failures and number
chronic of devices,
respiratory each of
failures themand
connected
home-assisted by to the ventilators of volunteer patients suffering from chronic respiratory failures and
home-assisted by the
thehealth
healthdistricts
districtsofofBrindisi
Brindisi and andLecce
Leccein Italy. Thanks
in Italy. Thanks to this architecture
to this architectureand withand
the home-assisted
help of a control by chart
the health
baseddistricts of Brindisi
server-side and Lecce
application, the in Italy.orThanks
doctor the to this architecture
healthcare staff can and
control
with the help of a control chart based server-side application, the doctor or the healthcare staff can
the with
control
the help
monitored
the monitored
of a control
parameters tochart
checkbased
parameters
server-side application,
thetoeffectiveness
check the of the therapy
effectiveness
the ordoctor state
of any
or theofhealthcare
the therapy exacerbation staffof
or any state
canthe
of
control the monitored parameters to check the effectiveness of the therapy or any state of
disease. At present, 3 different prototypes have been produced in
exacerbation of the disease. At present, 3 different prototypes have been produced in order to be order to be used in the configured
exacerbation of the disease. At present, 3 different prototypes have been produced in order to be
telemedicine
used in the system. telemedicine system.
configured
used in the configured telemedicineTM system.
The ICT
The ICTICTplatform
platform (OMNIACARE
(OMNIACARE eResults srl,srl, Cesena, Italy)Italy) [36] that
[36]allocates the cloud thestorage
(OMNIACARETMeResults eResults srl, Cesena, that allocates
allocates cloud
TM
The platform Cesena, Italy) [36] that the cloud
integrates
storage all
integrates the received
all all
thethe aggregate
received data
aggregate into a patient’s electronic medical record (EMR); in such
storage integrates received aggregatedata dataintointoaapatient’s
patient’s electronic medicalrecord
electronic medical record(EMR);
(EMR); inin
EMRs
such other
EMRs clinical
other parameters
clinical related
parameters to COPD
related to patients
COPD were stored
patients in
were digital
stored format,
in allowing
digital format, an
such EMRs other clinical parameters related to COPD patients were stored in digital format,
integrated
allowing anoverview
allowing integrated
an of overview
integrated theoverview
patientoftherapeutic
ofthe patientpath
thepatient and its outcome.
therapeutic
therapeutic path
path andand its outcome.
its outcome.

Figure
Figure 8. 8.Network
Networkarchitecture
architecture(example
(example with
with 4
4 devices).
devices).
Figure 8. Network architecture (example with 4 devices).
3. Results and
3. Results Discussion
and Discussion
3. Results and Discussion
A preliminary
A preliminary characterizationtest
characterization testofofthe
theSmart
SmartBreath
Breath Analyzer
Analyzer device
devicewas
wascarried
carriedout
outininGas
Gas
SensorA preliminary
Sensor Lab
Lab of of characterization
CNR-IMM
CNR-IMM ininLecce test the
Lecce and of
thethe
aimSmart
aim wastoBreath
was toverifyAnalyzer
thethe
verify device
correct was of
operation
correct carried
operationthe 2out
ofOtheandOin2CO
Gas
and
2

Sensor Lab of
sensors, CNR-IMM
simulating in gas
real Lecce and the aimranges
concentration was to of
verify
end the correct
tidal valuesoperation of the
for exhaled O2Oand
2 and CO
CO2 2

sensors, simulating real gas concentration ranges of end tidal values for exhaled O2 and CO2
Sensors 2020, 20, 653 10 of 20

CO2 sensors, simulating real gas concentration ranges of end tidal values for exhaled O2 and CO2
Sensors 2020, 20, x FOR PEER REVIEW 10 of 20
corresponding to various levels (severe/moderate/mild) of hypoxemia and hypercapnia as well as basal
conditions
corresponding (normoxemia/normocapnia) [14,18] (Table 2). Exhaled
to various levels (severe/moderate/mild) air contains
of hypoxemia less oxygen as
and hypercapnia andwell
moreas
carbon dioxide, it is also saturated with water vapor. Water vapor at body temperature
basal conditions (normoxemia/normocapnia) [14,18] (Table 2). Exhaled air contains less oxygen and exerts a partial
pressure
more carbonof 47dioxide,
mmHg. itSince thesaturated
is also total pressure
with is always
water 760 Water
vapor. mmHgvapor and the relative
at body percentagesexerts
temperature of thea
other
partialgases do notof
pressure vary,
47 their
mmHg.partial pressure
Since decreases.
the total /CO2 concentrations
TheisO2always
pressure 760 mmHg and in % the
wererelative
hence
converted considering the following formula:
percentages of the other gases do not vary, their partial pressure decreases. The O2/CO2
concentrations in % were hence converted considering
 the following
 formula:
P gas = %gas· Patm − PH2 O (1)
𝑃 %𝑔𝑎𝑠 ∙ 𝑃 𝑃 (1)
where Patm = 760 mmHg and PH2 O = 47 mmHg.
where 𝑃 760 mmHg and 𝑃 47 mmHg.
Table 2. Alveolar partial pressure levels (PO2 and PCO2 in mmHg) and alveolar concentrations (O2 %
Table 2. Alveolar level of P and P (correspondingly the O2 and CO2 concentration in in basal
and CO2 % in percentage by volume) of oxygen and carbon dioxide in basal normoxemia/normocapnia
condition (normoxemia/normocapnia) and (severe/moderate/mild) of hypoxemia and hypercapnia.
and severe/moderate/mild conditions of hypoxemia/hypercapnia.
𝑷𝑶𝟐 (mmHg) O2 (%)
PO2 (mmHg) O2 (%)
Normoxemia 100 14.0
Normoxemia 100 14.0
Mild Hypoxemia
Mild Hypoxemia 60–80
60–80 8.41–11.22
8.41–11.22
Moderate
ModerateHypoxemia
Hypoxemia 40–60 40–60 5.61–8.41
5.61–8.41
Severe
SevereHypoxemia
Hypoxemia <40 <40 <5.61 <5.61
𝑷𝑪𝑶𝟐 (mmHg)
PCO2 (mmHg) CO2 (%)CO2 (%)
Normocapnia
Normocapnia 40 40 5.61 5.61
Mild
MildHypercapnia
Hypercapnia 45–60 45–60 6.31–8.416.31–8.41
Moderate
ModerateHyperCapnia
HyperCapnia 60–75 60–75 8.41–10.51
8.41–10.51
SevereHyperCapnia
Severe HyperCapnia >75 >75 >10.51 >10.51

The tests
The testswere
were carried
carried out out
withwith a gas-mixing
a gas-mixing station station
connectedconnected to mass
to different different
flow mass flow
controllers
(MFCs) and a MFCs multichannel unit to set the total gas flow and control the O2 /CO2 concentrations in2
controllers (MFCs) and a MFCs multichannel unit to set the total gas flow and control the O2 /CO
concentrations
nitrogen throughinthe
nitrogen
dynamicthrough
dilutionthe dynamic
method. The dilution
total flowmethod. The
was set to 100total flowinwas
mL/min dry set to 100
condition.
mL/min
In Figure in drytwo
9, the condition.
sensor signals O2 /CO
In Figure 9, the two sensor signals O2/CO2 (in %) vs. time during the
2 (in %) vs. time during the related gas-sensing tests were
related gas-sensing tests were reported
reported as acquired by a developed device. as acquired by a developed device.

24
End tidal O2 End tidal CO2
Severe Hypercapnia
Moderate Hypercapnia

20
Moderate Hypoxemia

Mild Hypoxemia
Severe Hypoxemia

Normal

Mild Hypercapnia

16
O2/CO2 (%)

12
Normal

0 10 20 30 40 50 60 70 80 90

Time (min)

Figure9.9. Calibration
Figure Calibration runs
runsfor
forO
O22 and
and CO sensor.
CO22 sensor.

Further preliminary functional tests were carried out in laboratory by a healthy volunteer
disconnected from the ventilator for safety reasons; without the use of facial respiratory mask the
volunteer was asked to inhale through the nose and exhale through the mouth into the respiratory
Sensors 2020, 20, 653 11 of 20

Further preliminary functional tests were carried out in laboratory by a healthy volunteer
disconnected from the ventilator for safety reasons; without the use of facial respiratory mask the
Sensors 2020, 20, x FOR PEER REVIEW 11 of 20
volunteer was asked to inhale through the nose and exhale through the mouth into the respiratory
tube.
tube. Such
Such tests
tests(reported
(reportedelsewhere
elsewhere[35])
[35])proved
provedthe correct
the acquisition
correct acquisition of all thethe
of all sensor signals
sensor by the
signals by
Breath Analyzer Module via PC serial
the Breath Analyzer Module via PC serial port. port.
Next,
Next, after
afterapproval
approvalbyby thethe
hospital Ethics
hospital Committee,
Ethics experimentation
Committee, on patients
experimentation in a hospital
on patients in a
setting was started. In particular, the device was tested in real conditions on a first volunteer
hospital setting was started. In particular, the device was tested in real conditions on a first volunteer patient
during
patienthis NIV sessions
during his NIVwith supplemental
sessions oxygen therapy
with supplemental at thetherapy
oxygen pneumology at theunit of Brindisi hospital,
pneumology unit of
Italy. Prior to participation in the study, the subject provided written, signed, informed
Brindisi hospital, Italy. Prior to participation in the study, the subject provided written, signed, consent. The
Breath Analyzer Module was inserted, as configured in Figure 2, side-stream
informed consent. The Breath Analyzer Module was inserted, as configured in Figure 2, side-streamto the expiratory flow
of
to athe
bi-tube breathing
expiratory flow circuit connected
of a bi-tube to a mechanical
breathing ventilator
circuit connected (Figure 10);ventilator
to a mechanical two water(Figure
traps (not
10);
shown in photo) were also inserted in the breathing circuit with tube extensions
two water traps (not shown in photo) were also inserted in the breathing circuit with tube extensionsthus increasing the
length of a standard bi-tube configuration.
thus increasing the length of a standard bi-tube configuration.

Figure 10.
Figure 10. Breath
Breath Analyzer
Analyzer Module
Module connected
connected toto bi-tube
bi-tube breathing
breathing circuit
circuit in
in real
real operating
operating condition
condition
clinical experimentation
during clinical experimentation in
in hospital
hospital setting.
setting.

The main aim of of this

this first
first clinical
clinical experimentation
experimentation was limited to verify verify the
the functioning
functioning of the the
implemented firmware
firmware for sensor acquisition in real operating condition during NIV. NIV. For this reason
such initial tests were carried
carried out in locallocal without
without sending the data to to developed
developed remote server server
architecture,
architecture, in
in order
order to
to differentiate
differentiate thethe control
control of
of aa correct
correct data
data acquisition
acquisition to
to the possible problems
that
that may
mayoccur
occurinin
data transmission;
data transmission; the data were were
the data transmitted to the serial
transmitted to theport of a port
serial notebook
of a computer
notebook
via device via
computer USBdevice
port. USB port.
Figure 11 reports the temporal registration
registration of
of all
all the
the sensors
sensors tracings
tracings during a NIV session with
supplemental
supplementaloxygen
oxygentherapy
therapy on on
a first volunteer
a first COPDCOPD
volunteer patient.patient.
The acquired raw signals
The acquired rawin signals
resistance in
of MOX-based
resistance sensors (RS1sensors
of MOX-based from AS-MLV-P2
(RS1 from VOC sensor by
AS-MLV-P2 AMS
VOC AG; Rby
sensor S2 and
AMSRS3 AG;from
RS2dual
and NO -CO
RS3 Xfrom
dual NO
sensor X-CO sensor
MiCS-4514 by MiCS-4514
SGX SensorTech)by SGX SensorTech)
were normalized were normalized
to [0,1] to [0,1]
to compare theto compare
sensor the sensor
responses:
responses:
R−R
R0 = 𝑅 𝑅min (2)
𝑅′ R max − Rmin (2)
𝑅 𝑅
As it can be observed, the sampling protocol, according to a firmware version where all the
sensors are sampled simultaneously in parallel with a sampling rate of 1 measurement at 500 ms,
works correctly. All the gas sensors (CO2/O2 & VOCs sensors), each with its own response time,
showed signal modulation enveloping one or more respiratory acts, but of course due to the device
connection configuration not close to the respiratory face mask, it was not possible to deduce the end
tidal part of an exhalation.
As expected, before NIV starting O2 and CO2 concentrations were at normal levels of inhaled air
(20.89% for O2 and about 400 ppm for CO2); during NIV CO2 levels increases from inspiratory values
to higher values of exhaled CO2. However, due to the position of the device at the end of the
expiratory line of the breathing circuit, whose configuration can change according to specific
therapeutic requirements, the CO2 end tidal values of the expired CO2 dilute not only due to
physiologic dead volume but also to the dead volume of breathing circuit. Moreover, the expiratory
reserve volume (ERV) is reduced in a COPD patient (typically about 500 mL), so that the measured
CO2 is the result of more diluting exhalations in the overall dead volume. Although such limitations,
the CO2 track is full of significant related-to-capnia physiologic information that can be easily
extracted after a calibration with an additional standard capnograph sidestream connected to
Sensors 2020, 20, x FOR PEER REVIEW 12 of 20

respiratory line (between the face mask and the Y-adapter of the bitube). This will be the next work
activity.
Sensors 2020, 20, 653 12 of 20

Start mask End

NIV mismatching NIV

RS1 (Ω)
RS1 (Ω)

1.0 1.0
0.8
0.5 0.6
0.4
0.0 0.2

0 240 480 720 960 1200 1440 1680 1920 2160 2400 1560 1580 1600 1620 1640 1660 1680

RS2 (Ω)
RS2 (Ω)

1.0 1.0
0.8
0.5 0.6
0.4
0.0 0.2
0 240 480 720 960 1200 1440 1680 1920 2160 2400 1560 1580 1600 1620 1640 1660 1680

RS3 (Ω)
RS3 (Ω)

1.0 1.0
0.8
0.5 0.6
0.4
0.0 0.2
0 240 480 720 960 1200 1440 1680 1920 2160 2400 1560 1580 1600 1620 1640 1660 1680
22.0
O2 (%)

40

O2 (%)
21.5 O2 (%) 36
21.0
32 20.5 34
20.0
24 32
30
0 240 480 720 960 1200 1440 1680 1920 2160 2400 1560 1580 1600 1620 1640 1660 1680

CO2 (%)
600 CO2 (ppm)
CO2 (%)

3 500 3
2 400
300
2
1 200 1
0
0
0 240 480 720 960 1200 1440 1680 1920 2160 2400 1560 1580 1600 1620 1640 1660 1680

31.5 31.0
T (°C)

T (°C)
31.0 30.5
30.5
30.0
0 240 480 720 960 1200 1440 1680 1920 2160 2400 1560 1580 1600 1620 1640 1660 1680
R.H. (%)

R.H. (%)

34 34
32 32
30 30
28 28
26 26
0 240 480 720 960 1200 1440 1680 1920 2160 2400 1560 1580 1600 1620 1640 1660 1680

Time (s) Time (s)

Figure 11. (left) Traces of all the sensor during a noninvasive ventilation (NIV) session with
supplemental oxygen
Figure 11. (left) therapy;
Traces (right)
of all magnification
the sensor duringofaa noninvasive
temporal segment during(NIV)
ventilation the trace recording.
session with
The vertical dotted green lines indicate the start and the end of the NIV session. The
supplemental oxygen therapy; (right) magnification of a temporal segment during the trace measurements
refer to the first
recording. The day of hospitalization
vertical dotted green of a Chronic
lines indicateObstructive Pulmonary
the start and the end Disease (COPD)
of the NIV patient
session. The
due to an exacerbation event.
measurements refer to the first day of hospitalization of a Chronic Obstructive Pulmonary Disease
(COPD) patient due to an exacerbation event.
As it can be observed, the sampling protocol, according to a firmware version where all the
sensors are sampled simultaneously in parallel with a sampling rate of 1 measurement at 500 ms, works
In the particular case of this experimentation, after NIV start, the O2 concentration increases
correctly. All the gas sensors (CO2 /O2 & VOCs sensors), each with its own response time, showed
from inhaled O2 value to higher levels compatible with supplemental oxygen therapy. However, it
signal modulation enveloping one or more respiratory acts, but of course due to the device connection
can be observed according to respiration physiology that O2 decreases as CO2 increases in
configuration not close to the respiratory face mask, it was not possible to deduce the end tidal part of
correspondence of exhalation. The O2 track is again full of significant related-to-hypoxemia
an exhalation.
physiologic information especially in NIV without supplemental oxygen therapy, just to support the
As expected, before NIV starting O2 and CO2 concentrations were at normal levels of inhaled
eventual clinical decision for a supplemental O2 and its duration and administration modality. The
air (20.89% for O2 and about 400 ppm for CO2 ); during NIV CO2 levels increases from inspiratory
correlation of exhaled O2 by the device with SpO2 values measured continuously by a pulse oximeter
values to higher values of exhaled CO2 . However, due to the position of the device at the end of the
during NIV will be anyway a necessary step to validate the method.
expiratory line of the breathing circuit, whose configuration can change according to specific therapeutic
The signals from MOX-based sensors also vary during NIV accordingly both to O2 variation
requirements, the CO2 end tidal values of the expired CO2 dilute not only due to physiologic dead
and exhaled VOCs content indicating a promising sensitivity to exhaled VOCs, especially for RS3
volume but also to the dead volume of breathing circuit. Moreover, the expiratory reserve volume
followed by RS1 and RS2 sensors. Of course a case-control study of COPD patients with and without
(ERV) is reduced in a COPD patient (typically about 500 mL), so that the measured CO2 is the result of
pneumonia has to be planned and carried out in order to test if a statistical analysis of 3-sensors
more diluting exhalations in the overall dead volume. Although such limitations, the CO2 track is full
array data may be a tool to predict ventilator-associated pneumonia or an exacerbation condition.
of significant
Relativerelated-to-capnia physiologic
humidity (R.H.) content information
in exhaled that can be
air is typically easily
high extracted
(≈90%) and an after a calibration
increase of R.H.
with
was indeed registered during the NIV session compared to the value before the start. However,face
an additional standard capnograph sidestream connected to respiratory line (between the due
mask
to theand the Y-adapter
specific extended of the bitube).
version This will
of the used be the circuit
breathing next work
and activity.
to the use of water traps, the signal
In the
of the particular
R.H. sensor case
did of
notthis experimentation,
saturate. after NIV
Flow increases start, the
during NIVO2cause
concentration increases
temperature from
decreases
inhaled
measured O2 value
by T to higherAll
sensor. levels
thecompatible with supplemental
sensors registered an event oxygen therapy. mask
of respiratory However, it can be
mismatching
observed according to respiration physiology
corresponding to patient’s state of agitation. that O 2 decreases as CO 2 increases in correspondence
of exhalation. The O2 track is again full of significant related-to-hypoxemia physiologic information
especially in NIV without supplemental oxygen therapy, just to support the eventual clinical decision
Sensors 2020, 20, 653 13 of 20

for a supplemental O2 and its duration and administration modality. The correlation of exhaled O2 by
the device with SpO2 values measured continuously by a pulse oximeter during NIV will be anyway a
necessary step to validate the method.
The signals from MOX-based sensors also vary during NIV accordingly both to O2 variation and
exhaled VOCs content indicating a promising sensitivity to exhaled VOCs, especially for RS3 followed
by RS1 and RS2 sensors. Of course a case-control study of COPD patients with and without pneumonia
has to be planned and carried out in order to test if a statistical analysis of 3-sensors array data may be
a tool to predict ventilator-associated pneumonia or an exacerbation condition.
Relative humidity (R.H.) content in exhaled air is typically high (≈90%) and an increase of R.H.
was indeed registered during the NIV session compared to the value before the start. However, due to
the specific extended version of the used breathing circuit and to the use of water traps, the signal of
the R.H. sensor did not saturate. Flow increases during NIV cause temperature decreases measured
by T sensor. All the sensors registered an event of respiratory mask mismatching corresponding to
patient’s state of agitation.
Analogous results were obtained monitoring over time the same patient during his period of
hospitalization. Figure 12 reports the signals acquired from all the sensors during a ventilo-therapy
session with supplemental oxygen corresponding to a hospitalization day following the first day of
admission to hospital.
As preliminary note, we can comment that all the 3-array MOX-based sensors showed a lower
signal variation compared to the signals registered in first day. The characteristic VOC profile
(breathprint) recorded during the initial phase of exacerbation at the time of hospitalization may be
reduced in concentration or composition in the subsequent days of hospitalization. This may be a
consequence of the pharmacological treatment to which the patient was subjected in the hospital to
treat the exacerbation phase. The sensitivity of the sensors to such breathprint variations, probably
linked to the presence of pathogens in the respiratory tract, is hence significant and promising for using
e-nose in detecting the presence of bacterial infections in patients suspected of VAP. E-nose technology
may become a rapid and non-invasive point-of-care tool for excluding the presence of pneumonia and,
thus, withholding certain patients from receiving unnecessary antibiotic treatment.
Moreover, the comparison between the measured exhaled CO2 temporal tracks during the two
NIV sessions of the same patient, i.e., in the admission day at the hospital and in a next day, led
us to make further considerations. By considering the volume of respiratory circuit for the peculiar
configuration of used in the NIV sessions of this COPD patient under treatment, as well as the typical
exhaled volume in a respiratory act, a multiplicative factor for the measured CO2 that corrects the
volumetric dilution of the exhaled CO2 due to the dead space of the used breathing circuit plus that of
the water trap was calculated in first approximation. The estimated exhaled CO2 tracks reveal that,
during the NIV sessions, mild/moderate hypercapnia levels, up to severe hypercapnia level in the first
hospitalization day (Figure 13a), have been reached. The condition improves over time; indeed, in the
following hospitalization day, lower CO2 estimated values within normocapnia with only some spikes
up to mild hypercapnia (Figure 13b) were registered.
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Start End
1.0 NIV NIV

(Ω)
S1
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R
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R.H. (%)

40
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Time (s)

Figure 12. Traces of all the sensors during a NIV session with supplemental oxygen therapy; the
Figure 12. Traces of all the sensors during a NIV session with supplemental oxygen therapy; the
vertical dotted green lines indicates the start and the end of the NIV session. The measurements refer
vertical dotted green lines indicates the start and the end of the NIV session. The measurements refer
to a hospitalization dayday
to a hospitalization following thethe
following first day
first dayofofhospitalization (followingthat
hospitalization (following thatreported
reportedinin Figure
Figure 11).11).

(a) (b)
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(c) (d)
 Sensors
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(a)
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for monitoring
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pre-oxygenation ventilation and
and
treatment is
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hemogasanalysis isis invasive
invasive [21,68–70].
[21,68–70]. AA low-cost
low-cost portable
portable exhaled
exhaled OO2/CO 2/CO 2 2 analyzer
analyzer isis hence
hence aa
known, since SpO2 alone is not adequate for monitoring alveolar ventilation and hemogasanalysis is
valid
validcandidate
candidateto tosatisfy
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suchmonitoring
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patientbedside.
bedside.
invasive [21,68–70]. A low-cost portable exhaled O2 /CO2 analyzer is hence a valid candidate to satisfy
such4.4.monitoring
Conclusions
Conclusions at patient bedside.

4. Conclusions
A novel low-cost Breath Analyzer Module device for remote COPD patient monitoring during
domiciliary non-invasive mechanical ventilation, was designed, realized, and tested. At present, 3
different Breath Analyzer Modules have been produced ready to be used as terminals of the configured
telemedicine system. The device is multi-sensors based. It enhances the monitoring features of basic
Sensors 2020, 20, 653 16 of 20

mechanical ventilators used in home NIV, providing sensors for O2 /CO2 concentration, temperature
and relative humidity in the exhaled air of COPD patients.
The developed Breath Analyzer Module is also:

• Universal: it can be used as external module for any ventilator with bi-tube breathing circuit;
• Plug & Play: it requires only basic connections without configuration;
• Low-cost and highly customizable: it is based on low-cost hardware (Arduino);
• IoT-oriented: the device can communicate data over TCP/IP communication (wired).
• Flexible to further implementations: the system may be configured for advanced data processing
in OMNIACARE hardware/software platform to support local healthcare staff to check the
effectiveness of therapy.

Furthermore, the device including a small array of three chemoresistive sensors (electronic nose
concept) based on MOX technology provides a fingerprint of the Volatile Organic Compounds (VOCs)
pattern in the exhaled air. The integration of electronic nose (e-nose) technology in non-invasive
ventilo-therapy and/or routine spirometry, is a strategic plan to bring this technology to ‘point-of-care’
for respiratory diseases, enabling the detection of ventilator-associated pneumonia. Breath analysis
offers indeed a unique opportunity to retrieve relevant information on ongoing internal biochemical
processes noninvasively, since a lot of volatile components are exchanged at cells/blood and blood/alveoli
interface from alveoli are subsequently exhaled. Moreover, by considering that the results from the
e-nose integrated in our Breath Analyzer Module could be also combined with those from consolidated
analytical methods (as GC/MS), we believe that the realized point-of-care devices could be a useful tool
providing new opportunities for monitoring the patient actual health status and discovering breath
VOC markers characteristic of pulmonary and systemic conditions.
From first evidence of initial clinical experiments, all the acquired sensor traces are valid for a
next data analysis and correlation with routine clinical examinations and clinical data. In particular,
in relation to the 3-array chemoresistive sensors, suitable signals processing and statistical pattern
recognition techniques have to be applied. Of course, an appropriate suitable interpretation of all the
monitored parameters by a physiological point of view is required. At this aim a device positioning a
closer to the respirator mask can certainly help in providing sensor profile outputs more similar to
those of standard sidestream configuration. Further efforts will be devoted to check the reliability and
robustness of the telemedicine system in relation to the communication protocol and data transmission.
An extensive clinical experimentation is also necessary to validate the Breath Analyzer Module as well
as train it on a sample population of patients in different COPD conditions. This stage is fundamental
to build an intelligent software that, based on data analysis algorithms, provides indication about
restoration of a correct respiratory function during NIV therapy.
The developed system looks forward to an advanced evolution in which the Breath Analyzer
Module is integrated into the ventilator or constitutes an optional additional external component; in
this new scenario for patient monitoring system, it is the ventilator itself which becomes a terminal
of the telemedicine system and transmits all the parameters recorded and displayed during home
ventilation to an IoT platform. Manufacturers of mechanical fans may be interested in developing a
ventilator model designed for inclusion into a remote monitoring system.

Author Contributions: Conceptualization, A.V.R., P.A.S., S.S., E.S., and S.C.; funding acquisition, P.A.S. and S.S.;
investigation, A.V.R. and S.C.; project administration, S.S.; software, A.V.R.; supervision, S.C.; visualization, A.V.R.
and S.C.; writing—original draft, A.V.R. and S.C.; writing—review and editing, S.C. All authors have read and
agreed to the published version of the manuscript.
Funding: This research was funded by project ReSPIRO (Rete dei Servizi Pneumologici: Integration, Research &
Open-innovation-Cluster Tecnologici Regionali, Apulia Region, project cod. F29R1T8).
Acknowledgments: We thank the physicians E. Sabato and F. Satriano for hosting the clinical trial in their hospital
wards. We thank G. A. Di Lauro and N. Fiore-Dedalo Solutions s.r.l. for contributing in firmware development.
We also thank eResults s.r.l. for providing the Omniacare platform. We thank SAD s.r.l. for providing ventilators
Sensors 2020, 20, 653 17 of 20

and the necessary technical assistance and support in experimental set up. We thank L. De Paolis and V. De
Luca—University of Salento, for IoT algorithms.
Conflicts of Interest: The authors declare no competing interests.

Abbreviations
The following abbreviations are used in this manuscript:

VOC Volatile Organic Compound

COPD Chronic Obstructive Pulmonary Disease
ECOPD exacerbation of COPD
NIV Noninvasive ventilation
NHS National Health Service
TCP/IP Transmission Control Protocol/Internet Protocol
R.H. & T Relative Humidity & Temperature
MFC Mass Flow Controller
GC/MS Gas Chromatography/Mass Spectroscopy
IoT Internet of Things
MQTT Message Queue Telemetry Transport
TLS/SSL Transport Layer Security/Secure Sockets Layer
PCB Printed Circuit Board
SMD Surface Mounting Devices
PTH Pin Through Hole
IDE Integrated Development Environment
PC Personal Computer
ICT Information and Communication Technology
MOSFET Metal Oxide Semiconductor Field Effect Transistor

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