Biomedical Signal Processing and Control 28 (2016) 9–18

Contents lists available at ScienceDirect

Biomedical Signal Processing and Control

journal homepage: www.elsevier.com/locate/bspc

Review

Automated control of inspired oxygen for preterm infants:

What we have and what we need
Omid Sadeghi Fathabadi a,∗ , Timothy J. Gale a , J.C. Olivier a , Peter A. Dargaville b
a
School of Engineering and ICT, University of Tasmania, Hobart, TAS 7001, Australia
b
Department of Paediatrics, Royal Hobart Hospital and Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia

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

Article history: This review provides the first comprehensive technically focused image of algorithms developed for
Received 13 November 2015 automation of inspired oxygen control in preterm infants. The paper has three main parts; the first
Received in revised form 14 March 2016 provides an overview of the existing algorithms, the second presents the major design challenges
Accepted 15 March 2016
of automation and the third proposes directions for future research and development of improved
Available online 19 April 2016
controllers. In the first section, the algorithms are classified in four categories, namely rule-based,
proportional-integral-derivative, adaptive, and robust. The second section discusses variability in oxy-
Keywords:
genation, technologic shortcomings of infant monitoring and safety considerations as the three major
Oxygen saturation
Hypoxia
challenges for designing automated controllers. The paper finally proceeds to suggest some future direc-
Apnoea tions for improving automated oxygen control in the preterm infant. It suggests that based on the nature
Automated control of the physiological system, an optimal algorithm must be capable of making continuous adjustments
Preterm infants and it should be adaptive, including to alterations in severity of lung dysfunction and position on the
oxygen saturation curve. It is also suggested that future controllers must utilise additional inputs for
tasks such as oximeter signal validation and real-time prediction of hypoxic events.
© 2016 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2. Existing algorithms for automated control of FiO2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.1. Rule-based controllers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.1.1. Non-fuzzy algorithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.1.2. Fuzzy algorithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.2. PID controllers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.3. Adaptive controllers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.4. Robust controllers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.5. Target range achievement and automated control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3. Design challenges for automated controllers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.1. Variability in oxygenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.1.1. Unpredictable variability of the oxygenation response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.1.2. Fluctuating oxygenation in preterm infants on respiratory support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.2. Technologic shortcomings of automated control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.2.1. Oxygenation monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.2.2. Respiratory monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

∗ Corresponding author.
E-mail address: omid.sadeghi@utas.edu.au (O.S. Fathabadi).

http://dx.doi.org/10.1016/j.bspc.2016.03.002
1746-8094/© 2016 Elsevier Ltd. All rights reserved.
10 O.S. Fathabadi et al. / Biomedical Signal Processing and Control 28 (2016) 9–18

3.3. Safety considerations and target range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

3.3.1. Safety considerations in the existing controllers and role of caregivers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.3.2. Target range limits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

1. Introduction feedback of oxygenation. The control loop includes the control algo-
rithm programmed in a computer or an embedded processing unit.
Newborn infants, particularly those born prematurely, often This algorithm receives the oxygenation feedback and provides the
need respiratory support in a period following their birth. This fre- suggested FiO2 . The other part of the loop is composed of the infant
quently includes supply of a warmed and humidified mixture of air to whom the air-oxygen mixture with the desired FiO2 is delivered
and oxygen, delivered either via a stand-alone gas blender as part of and from whom the oxygenation measurement is obtained. The
non-invasive respiratory support, or by a blender incorporated into control loop is closed by the electrical and mechanical actuators
a mechanical ventilator. Regardless of the mode of respiratory sup- which receive the proposed FiO2 from the algorithm and deliver
port, adjustment of the fraction of inspired oxygen (FiO2 ) is critical, the blended air-oxygen mixture.
with the aim of keeping partial pressure of oxygen in the arterial Published reports reveal four major approaches to algorithm
blood (PaO2 ) in an optimal range. In the neonate, PaO2 levels that design for inspired oxygen control in the neonate: (a) rule-based,
are too low (hypoxia) or too high (hyperoxia) are dangerous, being (b) proportional-integral-derivative (PID), (c) adaptive and (d)
associated with an increased risk of mortality, retinopathy, brain robust approaches. These are defined and examined in detail below.
injury and chronic lung disease [1]. A compelling argument thus
exists for avoiding extremes of oxygenation in the newborn infant, 2.1. Rule-based controllers
especially for prolonged periods. Putting this into practice is chal-
lenging enough, but the difficulty is compounded by the lack of a Rule-based controllers make adjustments to FiO2 based on a set
direct, continuous and precise measure of PaO2 in the neonate. For of rules which stem from expert knowledge. A rule-based controller
this reason a proxy measure of oxygenation is used, that of oxygen may be in the form of a simple if-then loop or can engage fuzzy logic
saturation (SpO2 ) measured via a skin probe by a pulse oximeter, [15].
rather than PaO2 itself. Given that the SpO2 –PaO2 relationship is
far from linear, reliance on measurement of SpO2 to guide titration 2.1.1. Non-fuzzy algorithms
of oxygen therapy imposes an additional layer of complexity to the Automation of oxygen control for preterm infants began with
problem of optimising oxygenation in the newborn. a simple rule-based controller proposed by Beddis et al. [7] and
The current approach to titration of oxygen therapy in the technically described in more detail by Collins et al. [8]. This servo-
preterm newborn is that of manual adjustment of FiO2 by bedside controller adjusted FiO2 in 5% single step increments or decrements
caregivers in an effort to maintain SpO2 in the target range. It is at 1-min intervals if the measured partial pressure of arterial oxy-
well-established, however, that this method is not very effective gen (PaO2 ) was out of the desired range, or took no action if the PaO2
[2,3]. Recent reports indicate that the average proportion of time was acceptable. Later rule-based algorithms [16–18] were simi-
spent within the target range during manual control, can be as low lar in terms of making step adjustments in FiO2 with a period of
as 30–40% [4,5]. Accordingly, there have been efforts to automate inaction thereafter, but were significantly more elaborate in their
this process [6]. While early efforts towards automation of FiO2 con- decision-making. The algorithm of Morozoff et al. [16] used three
trol for preterm infants date back to 1970s [7,8], manual control is error-based indices as inputs to a state machine controller.
still the common practice. The controller inputs were the signs of the magnitude, velocity
Previous reviews of automated control of FiO2 have discussed and acceleration of the error based on which the state machine
the rationale and potential benefits and risks of automated con- determined a qualitative parameter called trend of the error. The
trol for preterm infants [6,9–13] as well as reviewing the available value of the trend defined the next state of the machine, an FiO2
evidence from clinical trials [12–14]. These papers point to the adjustment and a delay to give time for reaction to the adjustment.
potential for automated control to more effectively maintain oxy- Although the authors defined the states and trends in a table, they
genation in a target range and reduce the workload of bedside did not present detailed information about transitions between the
caregivers. The need to perform large-scale clinical trials of auto- states, how the delay and adjustments were determined and what
mated control has also been highlighted, including a study of longer were the actual values of these outputs [16]. The state machine was
term outcomes in preterm infants receiving this form of support. updated every second.
The published reviews appear not to reflect the importance of Along similar lines, the more recent controller of Urschitz et al.
the technical characteristics of automated oxygen control systems. [17] utilised the concept of trend in its decision-making but defined
The existing algorithms have not been comprehensively described, it a totally different way. The algorithm made a decision based
critically appraised and compared. Accordingly, the first aim of the on “state analysis” (180 s) and “trend analysis” (60 s) followed by
current paper is to summarise and classify algorithms for auto- “no action” episodes (180 s). There were five possible adjustments
mated control, and identify directions for future improvement. The (−2%, −1%, 0, +2%, +5%) according to the state, which could be
second objective is to identify the main obstacles in developing postponed according to the extracted trend. Qualitative descrip-
automated FiO2 control devices, and suggest some potential solu- tions (state and trend) were extracted from moving windows of
tions. the recorded oxygen saturation and allowed for accommodation
of the variability in SpO2 for decision-making. There were five
2. Existing algorithms for automated control of FiO2 possible states (substantially above, above, normal range, below,
substantially below), and three possible trends (increasing, sta-
During automated or closed loop FiO2 control, regular adjust- ble, decreasing). The abstraction method was presented by Miksch
ments to the fraction of inspired oxygen are made based on a et al. [19] and included linear regression steps; the basis of control
 O.S. Fathabadi et al. / Biomedical Signal Processing and Control 28 (2016) 9–18
Fig. 1. Sample membership functions for a four-subset fuzzy set, a value of 1 denotes
full membership to a subset while a value between 0 and 1 indicates to the extent
of partial membership.
algorithm was introduced by Seyfang et al. [20]. The authors stated
that this controller was not designed to respond to acute severe
hypoxic episodes [17]. The algorithm also called CLAC (Closed
Loop Automated oxygen Control) has been clinically evaluated on
preterm infants [21] and is commercially available in the Leoni Plus
Ventilator (Heinen & Löwenstein GmbH, Bad Ems, Germany) which
supports mechanical and non-invasive ventilation.
The most recently developed rule-based algorithm [18] called
PRICO (PRedictive Intelligent Closed loop control of Oxygenation)
is similar to its predecessors [16,17] in making step adjustments fol-
lowed by no-action episodes (at least 30 s) and using the concept
of trend along with the SpO2 readings in decision-making. How-
ever, PRICO uses the trend for identifying abrupt changes in SpO2
and fine-tuning the size of FiO2 adjustments to prevent possible
under/overshoots. PRICO will be commercially available in Fabian
ventilators (Acutronic Medical Systems AG, Hirzel, Switzerland) for
mechanical and non-invasive ventilation including a device called
fabian Therapy evolution dedicated to CPAP/O2 therapy [Elroy Zon-
neveld, Acutronic Medical Systems AG, Personal communications,
January 2016].
2.1.2. Fuzzy algorithms
The application of a fuzzy logic controller to neonatal inspired
oxygen control was first reported by Sun et al. [22], paralleling the
efforts of Morozoff [23]. Fuzzy logic controllers are similar to sim-
ple rule-based controllers in using if-then pairs but they make it
possible for a given set of inputs to correspond to more than one
rule with variable extents. This work is performed using member-
ship functions (Fig. 1) which define the extent of membership of a
variable to subsets of a fuzzy set. The final control decision is then
made in a procedure using the outputs of the relevant rules as well
as the obtained memberships.
Putative advantages of fuzzy control over classical control the-
ory are (a) the applicability to systems which are hard to model
mathematically and are nonlinear, (b) the capacity to incorporate
expert knowledge in the algorithm, (c) the possibility to facilitate
linguistic description of continuous variables associated with fuzzy
subsets, (d) less noise sensitivity and more robustness, and finally
(e) less complexity of the design and faster computations in real-
time [22].
In the first use of fuzzy logic for this purpose, Sun et al. [22] used
SpO2 and SpO2 slope (pulse oximetry) as inputs which were then
fuzzified into 7 and 5 regions, respectively, using triangular mem-
bership functions. The error was defined as the difference between
average SpO2 and the target SpO2 while SpO2 slope was obtained
from a regression line; both were updated every 10 seconds. The
fuzzification process created 35 combined regions which corre-
sponded to 35 if-then fuzzy inference rules. The logic of the fuzzy
inference rules was defined based on neonatologists’ knowledge.
An example of these rules was the application of a very large FiO2
increment when both SpO2 and SpO2 slope had negative values
of high magnitude.
11
Along similar lines, a more recent fuzzy logic controller incor-
porated within a medical device (Auto-mixer, Centro Médico
Imbanaco, Cali, Colombia) [24] created a fuzzy inference system
including 35 rules with the error and derivative of the SpO2 as
its inputs. Unlike Sun et al. [22] however, the error was divided
into five and the derivative into seven regions. In the following
defuzzification stage, where Sun et al. [22] used a weighted-mean
method to combine the outputs of the rules and to create a control
action, by contrast Lopez et al. [24] prescribed 11 possible values for
an adjustment ranging from −5% to +5% based on the pre-defined
rules. Implementation of both controllers was performed using a
look-up table to expedite the computation process in real time.
The test conditions of rule-based controllers have been widely
disparate, which must be taken into account in assessing their per-
formance. Beddis et al. [7] tested their controller on 12 infants
receiving supplemental oxygen via headbox, continuous positive
airway pressure (CPAP) or intermittent positive pressure ventila-
tion (IPPV). Morozoff et al. [16] on the other hand studied only
neonates that were intubated and requiring assisted ventilation.
In many cases the tests were performed in two stages. As an exam-
ple, Urschitz et al. [17] initially tested their algorithm on preterm
infants supported with nasal continuous positive airway pressure
but later [21] on patients receiving mechanical ventilation and
CPAP. Similarly, Sun et al. [22] reported some preliminary clinical
results, before testing the algorithm in open loop on 16 mechan-
ically ventilated infants [25]. Lopez et al. [24] used a first-order
model of FiO2 –SpO2 relationship for their preliminary tests on their
controller and later reported the results of a randomised controlled
trial [26]. The patients in this trial received supplemental oxygen
using nasal cannulae without mechanical ventilation. Finally, Hüt-
ten et al. [18] tested their controller on mechanically ventilated
preterm lambs.
One major issue with the performance of rule-based controllers
is that step adjustments are followed by a lockout period with no
action. It is thus possible that the response to a sudden change in
oxygenation will be inappropriately postponed. Additionally, the
different sets of rules based on clinical knowledge appear to be
incompletely validated. A clinical comparison of the effectiveness
of these algorithms would be the only way to assess their relative
performance.
2.2. PID controllers
PID control, the most popular form of control algorithm in indus-
try, defines an error (e) which is the deviation of the process signal
from the set-point. The value of the manipulated signal output (u)
at each moment is proportional to the value of error, its integral and
derivative (Eq. (1)), with a different multiplying coefficient (Kp , Ki ,
Kd ) in each case. The integral term considers accumulated past error
and can eliminate steady state error, whereas the derivative term
is in essence a prediction of the future error [27].

de(t)
u(t) = Kp e(t) + Ki e()d + Kd (1)
dt
A conventional PID algorithm was first applied to automated
oxygen control by Tehrani and Bazar [28], and updated in 2001
[29]. These controllers were designed for infants given oxygen via
an oxyhood or incubator, and were tested in simulation studies
using a mathematical model of the neonatal respiratory system.
For both algorithms, although oxygen saturation was measured, the
PID algorithm used partial pressure of arterial oxygen derived from
SpO2 as the input. One of the features of the earlier algorithm [28]
was frequent adjustment of the setpoint of PaO2 within the range
of 80–90 mmHg while in the later version [29] a stepwise algorithm
12 O.S. Fathabadi et al. / Biomedical Signal Processing and Control 28 (2016) 9–18
was incorporated to respond to abrupt desaturations, followed by
a switch back to the PID algorithm for fine regulation.
Beyond those mentioned above, Morozoff and Evans [30]
described a “differential” feedback-control algorithm, which was
studied in ventilated infants. The algorithm used the sign of the
error as well as the velocity and acceleration of the filtered SpO2
to make FiO2 adjustments, followed by a delay in which no further
adjustment was made. Based on the described inputs and function
of the controller, and with a lack of further detail about the manner
of reaching control decisions, this algorithm can hardly be consid-
ered a subset of PID family. The controller was too slow to properly
respond to rapid desaturations and manual interventions were reg-
ularly necessary. The authors suggested that incorporation of an
algorithm to identify and respond to rapid desaturations would
improve performance. In the most-recently published and the only
experimentally tested example of a non-adaptive PID algorithm for
automated FiO2 control [31] the performance of three different con-
trollers was compared. The results indicated that besides its need
for manual tuning, the tuned PID algorithm performed compara-
bly to a state-machine controller in terms of SpO2 targetting and
manual interventions but not as well as an adaptive one.
One major challenge in utilising a PID algorithm for control of
FiO2 in preterm infants is tuning of its coefficients so that it remains
stable and provides adequate oxygen to the patients despite the
variability of the system that it controls within infants and over
time.
2.3. Adaptive controllers
Adaptive control is an approach to control in which the
behaviour of the algorithm is adjusted based on varying charac-
teristics of the process and its signals [32]. This approach has been
used in a number of the automated oxygen control devices for new-
born infants described in the past 3 decades. One of the earliest
and most significant contributions was made by Sano and Kikucki
[33]. Their adaptive feedback controller was intended for newborn
infants receiving supplemental oxygen in an incubator.
In their study, the relationship between FiO2 and oxygen pres-
sure inside the incubator (PiO2 ) was described by a first order
differential equation, and the association between PiO2 and PaO2
was estimated by another first order equation. The second equa-
tion was then estimated as a linear equation (Eq. (2)) neglecting
the time constant of the body compared to the incubator. The slope
and intercept of the line described in Eq. (2) namely K1 and K2
were considered the changing variables during adaptive control.
The two equations were then combined to create a discrete mathe-
matical model of the PaO2 in response to FiO2 . This combined model
with average K1 and K2 for infants with lung disease was called the
nominal model.
PaO2 = K1 × PiO2 + K2
A model reference adaptive control approach was then used,
consisting of two parts, an adaptive compensator and an optimum
digital controller (Fig. 2). The optimum controller was designed to
make FiO2 adjustments to control the nominal model. The adaptive
compensator on the other hand, was in charge of compensating
the dynamics of the subject’s respiratory system so that the com-
bination of the compensator and the subject remained equal to the
nominal model from the controller’s point of view. In other words,
the optimum controller assumed a constant nominal model of the
system while the adaptive compensator adaptively updated itself
so that the overall input-output model assumed by the optimum
controller was realised. The controller was tested using an analyt-
ical model of the respiratory system, and in experimental animals.
Despite sophistication of the approach and an apparent depth of
physiological understanding on the part of the authors, this work
Fig. 2. Adaptive controller of [33].
Reproduced by permission of the Institution of Engineering & Technology.
is lacking for supporting clinical data and has shortcomings such as
the restricted focus on delivery of ambient oxygen, and the reliance
on transcutaneous partial pressure of oxygen measurement.
In work inspired by Sano and Kikucki [33], Bhutani et al. [34]
examined the performance of a PID algorithm developed within
their group [35,36]. The sole adaptively tuned parameter was the
slope of the PaO2 –FiO2 relationship. This slope was iteratively cal-
culated using SpO2 measurement, with the new value of slope
being a weighted summation of the previous value and the cur-
rent ratio of PaO2 (derived from SpO2 ) to FiO2 . Again the focus
was on infants receiving supplemental oxygen by hood. Studies
on fourteen infants showed superior performance of the adaptive
algorithm compared to both standard protocol-based and bedside
manual control in terms of the time spent in the target range, SpO2
stability and reduced overshoots introducing adaptive approach as
an efficient solution.
A further adaptive oxygen controller for neonates was proposed
by Morozoff et al. [37], operating on the basis of changes to the
FiO2 –SpO2 relationship. This method described the relationship by
a curve which consisted of three lines with various slopes and cov-
ering various ranges of FiO2 and SpO2 . The algorithm adjusted the
lines periodically by evaluating the proportion of time that was
spent within, over or under the target range. The controller made
its periodic adjustments to FiO2 on the basis of the updated model
(curve) at each time.
Shortcomings of this work were the limited justification for the
method of updating the lines, and for the determination of the mag-
nitude of FiO2 adjustments based on the model. The algorithm was
compared with manual control, a state machine controller and a
PID controller in several infants and appeared overall to achieve
the highest proportion of time in the target SpO2 range, with lit-
tle need for manual intervention. However the study conditions
including the target range were variable and the results were not
presented in detail. Morozoff and Smyth [31] later included these
(2)
algorithms in clinical experiments with similar findings.
The most clinically tested algorithm thus far developed for auto-
mated oxygen control is also adaptive. Claure et al. [38], devised a
hybrid algorithm which is a combination of differential feedback
and rule-based control to maintain SpO2 in a target range. Both tim-
ing and magnitude of the FiO2 adjustments are calculated based on
parameters such as current SpO2 , direction and rate of variations
in SpO2 , severity and duration of the hypxoic/hyperoxic episode,
current FiO2 and basal FiO2 during normoxia. Adjustments dur-
ing hyperoxia are of lesser magnitude and speed than during acute
hypoxia episodes.
The algorithm is adaptive in the sense that FiO2 adjustments
are directly proportional to the severity of lung dysfunction, as
measured by the current baseline oxygen requirement. After the
initial clinical study in mechanically ventilated preterm infants
[38], several clinical trials have compared the performance of this
 O.S. Fathabadi et al. / Biomedical Signal Processing and Control 28 (2016) 9–18
algorithm with manual control in preterm infants [39–42]. Auto-
mated control was associated with a greater proportion of time in
the target SpO2 range compared with manual control in all stud-
ies. Time spent in the hyperoxic range was reduced. In the early
studies this appeared to be at the cost of more time spent in mild
hypoxia [39,40], although in the two most recent studies time in
mild hypoxia has been on par with or less than during manual con-
trol [41,42]. This algorithm is incorporated as an option (CliOTM 2
) in
a mechanical ventilator (Avea, Carefusion, Seven Hills, Australia),
and is approved for use in numerous countries. The (CliOTM 2
) option
has not been approved by the US Food and Drug Administration
and is thus not currently available in the United States.
Finally, the most recent adaptive controller is called SPOC (SpO2
Controller) which will be commercially available in the Sophie Ven-
tilator (Fritz Stephan GmbH, Gackenbach, Germany) for invasive
and non-invasive ventilation [43]. SPOC employs the PID concept as
the operating principle and makes several adaptive modifications.
Firstly, the PID coefficients are scheduled depending on the range
of the measured SpO2 and are adjusted according to the direction
of its change, secondly the proportional coefficient of the controller
is weighted exponentially depending on the baseline FiO2 require-
ment of the infant and thirdly a second PID loop can update the
baseline FiO2 requirement of the patient every 5 min. The controller
makes moderate adjustments to FiO2 while saturation is in the tar-
get range but remains sensitive to the large changes in SpO2 by an
increased proportional coefficient. A randomised controlled trial
with cross-over design has been performed on this controller at the
University of Ulm [Wolfgang Braun, Fritz Stephan GmbH, Personal
communications, February 2016].
Review of existing adaptive control algorithms reveals a
gradual improvement. However in many cases particularly in
older algorithms, the designs are based on numerous underlying
assumptions. The first assumption is possibility of modelling the
oxygenation system a certain way for instance by a single or three
lines. The next assumption is that the variables which are used for
the purpose of adaptation are predictive of the variations of the sys-
tem e.g. proportion of time that was spent within the target range
or severity and duration of hypxoic/hyperoxic episodes. Finally, it
is assumed that the association of these input variables and the
oxygenation dynamics is well known and accommodated by the
algorithm. In the absence of independent studies on the extent of
reliability of these assumptions, results of clinical trials are the only
indirect references for assessing their appropriateness.
2.4. Robust controllers
A robust controller is a constant controller which is designed
to remain stable and perform within a particular range of control
performance despite an inexact process model and large parameter
changes [32]. Two algorithms designed for automated oxygen con-
trol can be classified in this category. The first, by Dugdale et al. [44]
was designed to respond to PaO2 measured using an in-dwelling
oxygen sensor in neonates with respiratory distress syndrome. The
algorithm was developed to account for dynamic characteristics
of the system under study, and the potential differences between
infants. A monotonic response in PaO2 was assumed (Fig. 3), and
preliminary studies in 5 infants became a basis for calculation of
system characteristics. The PaO2 response was represented by a
delayed (T) and scaled (b) step function (Fig. 3). Variables ‘b’ and ‘T’
became the design parameters chosen to achieve stability criteria.
The stability criteria were defined based on b and T.
The control rule was very simple; the sampling interval was cho-
sen equal to ‘T’ and the value of input to the system was equal to the
summation of the previous input and ratio of the current error to ‘b’.
Once the algorithm had been established, function of the controller
was evaluated in seven premature infants receiving supplemental
13
Fig. 3. An assumed monotonic PaO2 response to a step change in FiO2 and its step
function model used by [44].
Reproduced by permission of IOP publishing.
oxygen via a headbox and improved targeting compared to man-
ual control was observed. The authors suggested that enhancing
the safety aspects of their controller could make it appropriate
for routine use. A further robust controller was described by Keim
et al. [45]. Clinical data from premature infants was collected dur-
ing recovery from hypoxia. A first-order transfer function was fitted
to the observed FiO2 –SpO2 relationships, and the parameters of the
first-order model were estimated. An error model based on the esti-
mated parameter ranges was created, and consequently developed
into a -synthesis robust controller [46].
A detailed description of this method is beyond the scope of this
article but as a general statement, this design approach results in
the controller in a mathematical optimisation process considering
the stability and performance requirements. This work did not take
the time delay of the response into account and the controller was
not tested in clinical studies. Moreover, both the assumption of a
first order model and the way the parameter estimation was per-
formed had limitations which will be mentioned when discussing
the oxygenation variability inherent in the premature infant.
2.5. Target range achievement and automated control
Performance of automated control algorithms can be measured
in several ways, including proportion of time in the target range,
time spent in varying degrees of hypoxia and hyperoxia when
receiving oxygen, number of episodes of prolonged hypoxia and
hyperoxia, as well as the number of manual FiO2 adjustments
required. The analysis should examine the performance in the
group of infants overall, but also focus on the most challenging
cases (outliers) within the group. A comprehensive clinical study is
required to compare the effectiveness of various algorithms. Until
such a study would be carried out, investigating the relative per-
formance of automated controllers to manual control based on the
existing reports is a logical initial step. However, different levels
of success in manual control among various clinical centres should
be considered in assessing the relative effectiveness of the con-
trollers. Results of clinical trials since 2000 are presented in brief
in Table 1. The manual control outcomes are consistent with the
results of independent investigations on target range achievement
during manual control [2–4], and in part reflect the span of the
target range.
In addition to the published results, outcomes of the clinical
evaluation of SPOC [43] on preterm infants are submitted as an
abstract to the Pediatric Academic Societies Meeting 2016. The
study performed on very low birth weight infants receiving nasal
CPAP has indicated superior performance of SPOC over manual
control [Wolfgang Braun, Fritz Stephan GmbH, Personal commu-
nications, February 2016].
The recent clinical trials have all found automated control to
improve time in the target SpO2 range compared with standard
manual control, although in some cases the benefit has been mod-
est. Furthermore, recent studies on automated controllers [41,42]
14 O.S. Fathabadi et al. / Biomedical Signal Processing and Control 28 (2016) 9–18

Table 1
Clinical studies of automated oxygen control in preterm infants.

Author, year Control algorithm Target range Time in range (manual) Time in range Other findingsa
(automated)

Claure et al. [38] Claure et al. [38] 88–96% 66% (dedicated) 75%
Urschitz et al. Urschitz et al. [17] 87–96% 82% (routine), 91% 91% Fewer hyperoxic episodes with automated
[17] (dedicated) control.
Morozoff and Morozoff et al. [16], m. (90–96%), a. 57% 73% (adaptive), 71%
Smyth [31] Morozoff et al. [37] (target ± 3%) (others)
Claure et al. [39] Claure et al. [38] 88–95% 42% 58% More time in (SpO2 <88%) with automated
control, less time in severe hyperoxia.
Claure et al. [40] Claure et al. [38] 87–93% 32% 40% More time in (SpO2 80–86%) with
automation, severe hypoxia not different
between groups, less time and fewer
episodes of severe hyperoxia.
Hallenberger Urschitz et al. [17] Centre-specific 61% 72%b Less time below target range with
et al. [21] automated control.
Zapata et al. [26] Lopez et al. [24] 85–93% 34% 58% More time in moderate hypoxic range
(SpO2 <85%) with automated control, less
time with SpO2 >94%.
Waitz et al. [42] Claure et al. [38] 88–96% 69% 76% Severe hypoxia reduced during automated
control, and fewer episodes with SpO2
<80% for >60 s.
Van Kaam et al. Claure et al. [38] 89–93%, 91–95% 54%, 58% 62%, 62% Severe hypoxia reduced with automation
[41] for both ranges and severe hyperoxia
reduced for lower range, in both cases with
fewer 60 sec episodes.
a
Definitions: severe hypoxia – SpO2 <80%; hyperoxia – SpO2 >96% when in supplemental oxygen; severe hyperoxia – SpO2 >98% when in oxygen.
b
In this case the automated control mode of the trial is called routine manual control supported with closed-loop automated control.

have reported reduced duration of episodes of severe hypoxia as
well as fewer occurrences of persistent and severe hypoxia. The
variable extent of improvement in different trials may stem from
factors such as the chosen target range and the approach to man-
ual control, but also reflect the effectiveness of the algorithm itself.
Further information about these trials can be found in a systematic
review by Hummler et al. [14] and elsewhere [12,13].
3. Design challenges for automated controllers
Analysis of the existing approaches reveals challenges which
need to be overcome in order to significantly improve the per-
formance of automated oxygen control in preterm infants. Three
fundamental issues stand out, these being the variability in the
biological system controlling oxygenation, technological short-
comings of both physiological monitoring and oxygen delivery and
finally safety considerations including the need to choose an appro-
priate SpO2 target range. These challenges are discussed further
below.
3.1. Variability in oxygenation
3.1.1. Unpredictable variability of the oxygenation response
The oxygenation response refers to the way in which SpO2
changes as a result of a change in FiO2 . A variable oxygenation
response means that a given FiO2 adjustment may lead to a different
SpO2 response on different occasions. An automated control algo-
rithm must remain stable and perform reasonably in spite of such
variability. Although many existing rule-based controllers attempt
to deal with this variability based on expert clinical knowledge,
in the field of control engineering, design techniques are heavily
dependent on characterising the system under control in the form
of an input-output model, and quantifying the possible variations
in it as a basis for controller design (as exemplified earlier).
A first-order relationship between FiO2 and oxygen level in the
blood (SpO2 or PaO2 ) has been assumed in algorithms used for
automated control in various studies in the past [24,33,45], but
the applicability and characteristics of a first order model have
been insufficiently understood. In a study assessing the validity and
predictability of this model in preterm infants receiving CPAP [47]
we found that the first order model for the FiO2 –SpO2 relation-
ship was valid in 37% of 2369 FiO2 adjustments. We also found that
first-order responses were more frequent among FiO2 increments
than decrements, due largely to the non-linearity of the PaO2 -SpO2
relationship [48,49] (Fig. 4).
The shape of the PaO2 –SpO2 relationship results in poor resolu-
tion of SpO2 for estimation of PaO2 at high levels of saturation; with
wide variation in PaO2 for a single SpO2 reading (Fig. 4). Use of SpO2
may thus fail to detect a wide departure in PaO2 from an acceptable
range and distort the first order behaviour. This non-linearity also
affects the characteristics of the oxygenation response even when
it can be represented by a first-order model. Additionally, parame-
ters that influence the SpO2 –PaO2 relationship such as temperature
and acidity of the blood [50] can also influence the response.
In a further study, [51] we characterised the oxygenation
response by evaluating the parameters of the first order model,
namely delay, time-constant and gain, among 993 adjustments
with first order responses. We found that, notwithstanding signif-
icant intra- and inter-infant variability, for both FiO2 increments
and decrements, more severe lung dysfunction (as evidenced by
higher baseline FiO2 ), was associated with lower value of gain. This
finding along with the effect of SpO2 starting point has important
Fig. 4. The relationship between SpO2 and PaO2 . The curve represents the mean
regression line of 110 data points obtained from 73 infants <1 week postnatal age
(27–38 weeks gestational age) and acute oxygen requirement [48].
 O.S. Fathabadi et al. / Biomedical Signal Processing and Control 28 (2016) 9–18
implications and potential applications for adaptation of an auto-
mated controller. Unlike many possible influencing factors which
cannot be non-invasively measured and input to an automated con-
troller, values of both FiO2 and SpO2 are available in real time. It is
important to note that while our studies [47,51] explained some of
the variability of the SpO2 response to FiO2 adjustments, in large
part the variability remains unexplained, as does the cause of non-
first order responses.
3.1.2. Fluctuating oxygenation in preterm infants on respiratory
support
A major issue with control of FiO2 in preterm infants is fluctu-
ating SpO2 , limiting the proportion of time a given target range can
be achieved. Hyperoxia in preterm infants is related to unneces-
sarily high levels of FiO2 [10] and automated controllers developed
so far are relatively successful in managing this condition. Note
that SpO2 values above target range (≥96%) when in room air are
not considered hyperoxia, and simply reflect intact oxygen trans-
fer. Hypoxia on the other hand has a legion of causes, including
worsening lung dysfunction, transient airway blockage, diaphrag-
matic splinting and apnoea [52–54]. Decrease in lung volume and
development of an intrapulmonary shunt as result of diaphrag-
matic splinting in expiration has been identified as one cause of
hypoxia in mechanically ventilated preterm infants [53], with agi-
tation and hypoventilation more generally being additional factors
[10]. Agitation and hypoventilation are also important in the gen-
esis of hypoxia in non-ventilated infants on non-invasive support,
with apnoea being an important additional cause [55].
Hypoxia imposes two challenges on the design of a controller.
The first is that characteristics of hypoxic events, including their
frequency and severity, should be considered in algorithm design.
For instance controllers which make periodic FiO2 adjustments fol-
lowed by wait episodes may not be optimally effective in treatment
of infants with fast and frequent declines in SpO2 . However, charac-
teristics of each individual algorithm such as the length of the wait
period as well as the sampling rate are influential factors in defin-
ing the reaction speed of the controller. The severity of a hypoxic
event on the other hand defines the position on the oxygen dis-
sociation curve, which as discussed earlier affects the oxygenation
response and ultimately the magnitude of adjustment in FiO2 that
is required.
The second challenge is that the appropriate response to a
hypoxic event should vary according to its cause. Apnoea-induced
hypoxia is an example, with an FiO2 increment before apnoea
cessation being unlikely to immediately increase alveolar partial
pressure of oxygen, given that the infant is not breathing. Repeated
FiO2 increments during apnoea would likely increase the risk of
post-apnoeic hyperoxic overshoot. Identifying the cause of hypoxic
events using additional inputs to the control algorithm may thus
be useful in scheduling FiO2 adjustments. Identification of the
causative mechanism of hypoxia may also be useful in prediction of
the likely oxygenation response, and allow adaptation of the control
algorithm accordingly.
3.2. Technologic shortcomings of automated control
3.2.1. Oxygenation monitoring
Apart from early automation efforts using PaO2 measured via
indwelling umbilical artery electrodes or transcutaneous sensors
as the feedback signal [7,33,44], more recent control devices have
relied on SpO2 derived from pulse oximetry as the primary, indeed
the sole input. This adaptation and the standardisation in general
of pulse oximetry as the common method for prolonged patient
monitoring is due to the ease of measurement of SpO2 together with
the practical limitations of measuring PaO2 . However, pulse oxime-
try has well-known shortcomings [56]. The non-linear SpO2 –PaO2
15
relationship discussed earlier is the major inherent issue. If with
technological advances the possibility emerges to measure PaO2
non-invasively and accurately for extended periods, this might be
the preferred oxygenation input to guide automated oxygen con-
trol.
Other practical shortcomings of monitoring SpO2 , especially
poor accuracy in low perfusion and most notably motion arte-
fact, deserve consideration. Potential spurious readings caused by
these factors may misguide a closed-loop control algorithm and
lead to inappropriate FiO2 adjustments. Therefore, it is necessary
that motion resistant technology is used and also signal validation
considerations are embedded in control algorithms to identify and
exclude such periods [57]. Among other issues with pulse oximetry,
low accuracy even of newer generation devices at low saturation
levels [58] and the problem of signal dropout are most prominent.
These problems are particularly relevant during automated con-
trol when FiO2 adjustments are being made solely based on SpO2 .
In our recent study [59], since a majority of SpO2 dropouts during
hypoxia recovered in relative normoxia, we concluded that blind
FiO2 adjustments when the signal is missing would not be useful
in most circumstances. However, there might be occasions that an
FiO2 increment is required to prevent bradycardia.
3.2.2. Respiratory monitoring
Apart from oxygenation, monitoring of respiratory motion (i.e.
spontaneous breathing movements) is another area where tech-
nological advances can offer a benefit in automated FiO2 control
for preterm infants. For instance alterations in respiratory pattern
may assist in prediction of hypoxic events or differentiating various
types of hypoxia. This information may in turn become a basis for
making FiO2 adjustments e.g. temporary episodes of increased FiO2
to prevent/resolve hypoxia after brief apnoea and fast SpO2 declines
[57]. Furthermore, other informative parameters such as estima-
tions of the lung volume during non-invasive ventilation and phase
shift between the thoracic and abdominal movements are poten-
tial outputs from respiratory monitoring. Continuous measurement
of respiratory motion might thus provide future automated con-
trollers with an unprecedented level of knowledge about the infant
when making control decisions.
The existing respiratory monitoring methods can be divided
into contact and noncontact approaches. Contact devices including
respiratory inductance plethysmography [60] and pressure sensor
plethysmography [61] are capable of relatively reliably monitoring
respiratory patterns but they are difficult to use continuously and
may intervene the routine nursing care of the infant. Noncontact
devices on the other hand are preferable in terms of minimal dis-
turbance to the patient but they have not reached an adequate level
of maturity for becoming a part of routine clinical care [62]. Exam-
ples of noncontact approaches include radar [63], vision-based [64]
and thermal [65] methods. Despite the potential benefits, measure-
ment of respiratory patterns beyond respiration rate is currently
not a part of routine clinical care for preterm infants which might
be due to the increased instrumentation and decision-making com-
plexity caused by a new device.
3.3. Safety considerations and target range
3.3.1. Safety considerations in the existing controllers and role of
caregivers
A high priority should be given to safety in the design of any
medical equipment to be used in preterm infants, and it appears
that attention has been paid to this concern in current auto-
mated oxygen control devices. In-built safety precautions currently
include various alarms to alert bedside caregivers, along with rudi-
mentary SpO2 validation procedures and suspension of algorithm
function and default to a preset FiO2 if the signal is invalid.
16 O.S. Fathabadi et al. / Biomedical Signal Processing and Control 28 (2016) 9–18
These actions have been triggered in response to repeated FiO2
adjustments in a single direction [7,44], sudden or rapid falls in
SpO2 [17,28], low quality SpO2 signal [17,18,21,26,39,43], low SpO2
values [17,66], SpO2 remaining outside the target range for a min-
imum duration [24], and missing signal or device disconnection
[18,30,38,39,43].
The process of automated oxygen control is complicated by the
fact that a change in FiO2 alone may not always be the best action,
and intervention of clinical staff may be necessary particularly
in cases where a hypoxic event stems from impaired ventilation
including apnoea [10,11]. Thus, rather than entirely replacing man-
ual care, automated controllers should be thought of as providing
“on-time care” for preterm infants, decreasing the workload of the
nursing staff [9]. The potential for reduced attentiveness of the
bedside staff, and failure to recognise deterioration of an infant’s
condition, are concerns which have been expressed [10,11]. Design
of alarms to alert staff to persistent increase in oxygen requirement
is thus important [13,43].
3.3.2. Target range limits
Regardless of the type of control algorithm, another difficulty
of oxygen targeting both in manual and automated control is the
selection of the target range boundaries. Five recent large scale
clinical trials involving thousands of preterm infants [67–69] have
compared a lower oxygen saturation range (85–89%) with a higher
range (91–95%). These studies individually [67,68], as well as a sys-
tematic review and meta-analysis of all five [70], suggested that the
lower range resulted in a reduction in retinopathy of prematurity
but an increase in mortality. Recommendations to avoid saturations
below 90% have followed [70–73], but some uncertainty about the
most appropriate target range remains [74]. Saugstad and Aune [70]
also highlighted other unanswered questions, such as whether the
target range should be altered for different gestational ages, or over
time, or based on patient conditions.
Apart from the longer term safety considerations, selection of
the SpO2 target range may have more immediate consequences
during FiO2 control, including on the incidence of hypoxia. Di Fiore
et al. [75] found an association between lower target range and
higher rate of intermittent hypoxia at certain postnatal ages. In
another study of the effect of target range on outcome of auto-
mated control in 21 infants, a narrower and higher target range
(90–93% vs. 87–93%) did not increase the time spent in the range of
87–93% but it made the SpO2 distribution tighter [76]. The optimal
span of the SpO2 target range for automated control remains to be
determined, and should be a topic for further research. A further
related question for study in this context is where within the tar-
get range to locate the “set point”, and whether to attenuate error
where SpO2 readings fall within the desired range.
4. Future directions
In light of the aforementioned challenges, a number of direc-
tions for future research can be identified. The largely unexplained
variability of the oxygenation system is an area where further
research is necessary. Using large datasets to develop a simula-
tion of oxygenation in the preterm infant will potentially help to
understand the relationship of predictor variables with response
characteristics. A simulation of the oxygenation response would
also allow the validity of the assumptions underlying existing
adaptive controllers to be tested, and the performance of algo-
rithms to be directly compared. The role of measurable predictors
of hypoxic events as inputs to future adaptive control algorithms
clearly deserves attention.
As far as technological challenges are concerned, developments
in pulse oximetry allowing for more reliable measurements in spite
of motion, would directly improve the quality of automated control.
Novel approaches such as multi-wavelength, wireless, reflective
and in-ear pulse oximetry [77–81] could be investigated in this
regard. Identifying a practical respiratory monitoring technique for
preterm infants during automated oxygen control should be stud-
ied. The validity and precision of respiratory motion measurement,
as well as the feasibility and tolerance of long-term monitoring
need to be investigated.
Based on our review, we propose that future automated con-
trol algorithms should accommodate the following features. Firstly,
the base algorithm must be capable of responding to fast and fre-
quent hypoxic events. Algorithms which can make instant and
continuous adjustments to FiO2 are thus preferred to controllers
making frequent but delayed stepwise adjustments. These algo-
rithms may then be modified or tuned intuitively to match the
requirements of infants. Secondly, the controller must be adaptive,
so as to overcome the variability in the oxygenation system that
might otherwise de-stabilise or at least degrade the performance
of the controller. Parameters such as position on the oxygen satura-
tion curve and severity of lung dysfunction should be incorporated
in the algorithm.
Thirdly, a controller should ideally utilise additional inputs to
assist the algorithm in identifying the cause of hypoxic events, the
prediction of response variability as well as validation of oximeter
readings. An additional input for identification of apnoea will be an
important advance. A sophisticated suite of alarms and/or actions
are required, triggered by prolonged apnoea, equipment failure and
respiratory deterioration, to name but three. The device must com-
plement but not supplant the clinical acumen and attentiveness of
the bedside staff, with the recognition that interventions other than
adjustment of FiO2 may be required.
5. Conclusion
Although four decades have passed since the first attempts to
automate oxygenation control for preterm infants, the number of
algorithms developed for this purpose is limited, and much remains
to be done. The conclusions of our review are as follows:
1. Increased interdisciplinary collaboration, data-sharing, and fur-
ther experimental and clinical research will be needed in the
effort to improve automated oxygen control devices.
2. The oxygenation system is highly variable within and between
preterm infants, manifested in both the variations of the SpO2
response to an FiO2 adjustment, as well as in the rapid and
repeated fluctuations in SpO2 that occur. Incorporation of pre-
dictors of the SpO2 response (position on the dissociation curve,
severity of lung dysfunction) and of sudden hypoxia (apnoea
and hypoventilation) may enhance automated oxygen control
algorithms.
3. Given the variability of the oxygenation system, adaptive and
intuitive modifications to a rapidly responsive algorithm are
likely to afford more effective control of oxygenation than using
slow and non-adaptive algorithms.
4. Automated control of inspired oxygen is currently limited by the
technological shortcomings of infant monitoring. Pulse oximetry
readings are an imprecise measure of oxygenation, particularly
at high and low values of SpO2 , or in the presence of low
perfusion and motion artefact. Current respiratory monitoring
devices are not designed for continuous and accurate use dur-
ing automated control. Future automated controllers will benefit
from refined and additional inputs of physiological data.
5. Safety considerations remain essential in the design and appli-
cation of automated controllers, including appropriate alarms
together with signal validity and device functionality checks.
 O.S. Fathabadi et al. / Biomedical Signal Processing and Control 28 (2016) 9–18
Control devices must be viewed as enhancing rather than replac-
ing the skills of the bedside caregiver. Careful selection of the
SpO2 target range also remains crucial.
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