1. Gas Control System for Neonates
Alvaro Hermida1, Antonio Martínez-Millana2, Marta Aguar Carrascosa3, Max Vento3, Vicente Traver Salcedo2
1
Department of Information Systems and Computation (DSIC), Polytechnic University of Valencia, Spain
ahermida@dsic.upv.es
2
Research Group of Technologies for Health and Wellbeing (TSB), ITACA Institute, Polytechnic University of Valencia, Spain
anmarmil, vtraver@itaca.upv.es
3
Hospital La Fe, Valencia, Spain
maraca@alumni.uv.es, Maximo.Vento@uv.es
Abstract— Preterm infants pose a significant challenge for the
neonatologist: They have an immature antioxidant defense B. Kidney and Heart Damage.
system, but they often need resuscitation at birth, including Vento and colleagues have shown the existence of an
forced ventilation and supplemental oxygen supply. The exponential relationship between a marker of oxidative stress
neonatologist should keep a careful balance to accelerate the (GSSG - oxidized glutathione) and biochemical markers of
establishment of a physiological breathing pattern while
damage at renal tubular level (N-acetyl-glucosaminidase) and
minimizing the amount of oxygen delivered. The REOX
multicenter clinical study is generating the knowledge needed to myocardial (cardiac troponins), 48 hours after birth in infants
optimize the amount of oxygen supplied from the precise resuscitated with higher concentrations of oxygen [5].
moment of birth, when the sensors do not provide yet the reliable
information required to titrate the amount of oxygen using the C. Lung Damage Induced by Unnecessary Lengthening of
resuscitation algorithms. Forced Ventilation.
Although forced ventilation by continuous positive pressure
saves lives, it can also induce lung injury [6], so minimization
I. INTRODUCTION of its duration will improve the prognosis.
At rest, in physiological conditions, human arterial blood is Both experimental models and clinical studies show that a
saturated of oxygen. Most of this oxygen is bound to lower initial oxygen concentration accelerates the
hemoglobin, although a small quantity is just dissolved on the establishment of an effective spontaneous breathing pattern,
blood. The normal percentage of oxygenated hemoglobin as significantly reducing the time of resuscitation [7]. Some
detected by the pulse oximeter (SpO2) ranges between 95% markers of oxidative stress remain high even 28 days after
and 99%. A value under 95% may compromise cellular resuscitation, when 100% oxygen is used.
perfusion, and an SpO2 lower than 90% is defined as acute
respiratory failure.
III. BENEFICIAL ASPECTS OF SUPPLEMENTAL OXYGEN DURING
But before birth, when placental gas exchange in a liquid-
RESUSCITATION.
filled intrauterine environment is the only source of oxygen,
this percentage is as low as 43% [1] [2], rising rapidly after Despite its side effects, the use of a certain amount of
labor, with the onset of spontaneous ventilation after birth, supplemental oxygen may be necessary to successfully
reaching 80-90% in a few minutes [3]. resuscitate an asphyxiated newborn. As Wang and colleagues
The term infants already have a physiological antioxidant demonstrated in their study [8], there is a highly significant
system (developed during the third trimester of pregnancy) probability of failing in the attempt to reach the desired
that allows them to withstand the potentially pro-oxidant state, saturation levels when the resuscitation is started with an
but preterm infants do not yet have these defenses. The oxygen concentration of 21%. Meanwhile, Dawson has
situation worsens when you need to apply resuscitation after published [9] that in her hospital, 92% of the infants under 30
birth, including forced ventilation and supplemental oxygen. weeks of gestation whose resuscitation begun with an oxygen
concentration of 21% required an increase of this
concentration.
II. SIDE EFFECTS OF SUPPLEMENTAL OXYGEN DURING Relatively low oxygen concentrations are sufficient to
RESUSCITATION. ensure a safe resuscitation. Escrig team has shown that the
resuscitation of extremely premature infants (less than 28
A. Decreased Brain Mass. weeks of gestation) can be started safely with an oxygen
In a study with rats, Yis and colleagues have recently concentration of 30%, reaching saturation and heart rates
shown that oxygen concentrations of 80% in the developing similar to those obtained with higher concentrations, while
brain trigger an apoptotic neurodegenerative reaction causing reducing the burden of total oxygen delivered to the patient,
cell death and decreased brain mass [4], with a significant minimizing hyperoxemia and its consequences [10].
reduction of neuronal density.

2. IV. THE ALGORITHM FOR RESUSCITATION FROM THE SPANISH C. Ventilatory support:
SOCIETY OF NEONATOLOGY Continuous positive airway pressure (CPAP) will be
The question about the ideal percentage of supplemental applied from start to all infants ≤ 28 weeks according to the
oxygen affects especially the beginning of resuscitation, when rules of the SEN.
it is necessary to decide the initial amount of added oxygen For prematures of 29 weeks, the ventilatory support will be
(FiO2, Oxygen Inspired Fraction) without having objective individualized according to the FC, respiratory effort, SpO2
information on which to rely. Once the sensors are beginning and color.
to provide quantitative information on the patient's condition, Once initial stabilization is achieved by maintaining a heart
as the degree of blood oxygenation (SpO2) and heart rate rate > 100 bpm, SpO2 > 75% or progressive rise in respiratory
(HR), and the neonatologist observes the patient's response to effort present, CPAP will be delivered using a face mask
resuscitation and stabilization, it is time to apply the connected to the "T" piece at H 5cmH2O.
resuscitation algorithm established by the Spanish Society of If at any time appear bradycardia, maintained apnea,
Neonatology [11] [12] [13]. gasping or SpO2 does not rise gradually, positive pressure
ventilatory support will be applied.
A. Stimulation:
Endotracheal intubation will be considered individually if
The gentle handling of the premature infant in the first assessment is negative after check that the positive pressure
seconds of life is usually enough to start the spontaneous ventilatory support is being correctly applied.
breathing. If not, evaluate the gentle stimulation of the skin in
caudo-cranial direction. D. Oxygen administration:
Changes in the Inspired Oxygen Fraction (FiO2) will
B. Assess the situation:
always be performed in combination with changes in
1) Breathing: - Spontaneous respiration is normally set ventilatory support, after checking the effectiveness of the
between the first and third minute of life. The breathing ventilatory support.
pattern more or less regular basis will maintain a heart rate > If the SpO2 has to be modified (increased or decreased) the
100 bpm, a progressive increase in SpO2 and progressive changes will be in steps of 10% at intervals of 10-30 seconds.
improvement of the color. In extreme situations it is possible to initiate the
- The presence of prolonged apnea, gasping type breathing, administration of oxygen at 100% for any of the groups when
or bradycardia are indications of initiation of ventilatory cardiac massage or administration of medication in the
support. delivery room is needed (HR < 60 bpm for 30 seconds which
does not respond to proper positive pressure ventilation), or
2) Heart: - Assessed by direct auscultation, palpation of when HR < 100 bpm for more than 2 minutes.
central or brachial pulses, pulses at the base of the umbilical
cord or by pulse oximetry. E. Circulatory support:
- An HR > 100 bpm is considered a leading indicator of the Heart rate will be monitored in all patients initially by
effectiveness of the stabilization-resuscitation maneuvers. auscultation or palpation of pulses and then by pulse oximetry.
- In extremely preterm (≤ 26 weeks) consider that the An HR < 100 bpm will be considered bradycardia and
establishment of a HR ≥ 100 bpm physiologically may take 2 extreme bradycardia when HR < 60 bpm.
to 3 minutes. Positive pressure ventilatory support during 30 seconds will
be applied to bradycardia newborns and the situation will then
3) Color and SpO2: - The color is an unreliable indicator be re-evaluated, regardless of the initial FiO2.
for being difficult to assess during the fetal-neonatal transition If the heart rate does not increase over 60 bpm, cardiac
and not be a marker of tissue oxygenation status. massage will be started with a sequence of 3:1 for 30 seconds.
- The saturation by pulse oximetry provides accurate Assess endotracheal intubation at this time. If there is no
information of the oxygenation status in real time and proper response to ventilatory support and cardiac massage,
subsequent changes in response to resuscitation. adrenaline will be administered.
- In non-asphyxiated premature infants, the first
measurements of SpO2 at birth typically range from 40-45%.
Subsequently, these figures rise slowly to 80-85% at 10 V. THE STANDARD SATURATION CURVE OF THE HEALTHY
NEWBORN AS A GUIDE TO DRIVE RESUSCITATION EFFORTS.
minutes after birth.
- When required supplemental oxygen during resuscitation, To achieve a balance between minimizing oxygen load and
the safety range of SpO2 to avoid both hypo as hyperoxemia accelerating the establishment of a "normal" physiological
had been established between 85-93%. breathing pattern, it is necessary to establish a benchmark to
- In preterm infants who require resuscitation at birth, there define the normal pace and "natural" evolution during the first
are no reference ranges, therefore, the assessment of the minutes of life. To this end, studies such as Dawson and
effectiveness of stabilization-resuscitation maneuvers should colleagues [9] have analyzed the evolution of pulse oximetry
be based on the combination of FC, response to stimuli and saturation measured by optical SpO2 during the first 10
rise of the SpO2.

3. minutes of life of hundreds of infants who did not need concentration of 100% can be dangerous, especially in
resuscitation at birth. situations of ischemia followed by reperfusion, where the
accumulation of purine derivatives during ischemia causes the
appearance of large amounts of free radicals in the lung at the
sudden combination with pure oxygen [16].
It is also proven [8] that the natural concentration of 21% is
in most cases insufficient to achieve the target saturations in
an acceptable time.
Once the extremes are discarded, it is still necessary to
reduce the range of initial concentrations where the best
balance can be found. This is the purpouse of our study.
B. Working Hypothesis
"The use of low concentrations of oxygen as the initial
gas mixture during resuscitation of preterm infants of
extremely low birth weight can help reduce the toxicity
due to excess oxygen."
C. Main Objective
Fig. 1 Third, 10th, 25th, 50th, 75th, 90th, and 97th SpO2 percentiles for term
infants at ≥ 37 weeks of gestation with no medical intervention after birth.
The REOX trial (EUDRACT: 2008-005047-42) whose
promoter and principal investigator is Dr. Maximo Vento
Torres (Hospital La Fe, Consellería de Sanitat de la
Generalitat Valenciana), aims to reduce the cited range by
comparing the results of two intermediate concentrations: 30%
and 60%.
Initial O2 O2 relative Group
concentration concentration
21% 100% Insufficient
30% 150% REOX-LOX
60% 300% REOX-HOX
100% 500% Excessive
To do this, a multicenter randomized double-blind study
was designed, with a cohort of 325 patients selected from
infants who required any ventilatory support maneuver during
Fig. 2 Third, 10th, 25th, 50th, 75th, 90th, and 97th SpO2 percentiles for resuscitation, during the first 10 minutes after birth, and
preterm infants at < 32 weeks of gestation with no medical intervention after whose gestational age were less than 30 weeks but greater
birth.
than or equal to 24 weeks.
Randomization was balanced in blocks of 10 patients,
From these data, the standard target saturations are defined: stratified into two gestational age groups: ≤ 26 weeks (24, 25
and 26) and > 26 weeks (27, 28 and 29).
Time from birth Target SpO2 Range Formally, the main objective of the study is "to reduce the
3 minutes 55-80% rate of intubation in the delivery room derived from the quick
5 minutes 75-90% establishment of normal diaphragmatic movement and
10 minutes 90-97% physiological breathing pattern using low concentrations of
supplemental oxygen following the same pattern as in
experimental models." [17]
VI. THE REOX CLINICAL TRIAL
VII. BRIEF DESCRIPTION OF THE PHASES OF CLINICAL
TRIAL PROTOCOL.
A. Context
A. Phases 1 and 2: Validation of the Comprehensive
A decade after the heated debate [14] about the safety and Monitoring System.
necessity of using pure oxygen for resuscitation of
asphyxiated newborns [15], it can be assumed as proven that a "A comprehensive monitoring system will be implemented
to register at all times the performed resuscitation maneuvers

4. and the patient's response to them. This system will consist of REFERENCES
a central computer with special software that collects real-time [1] Stiller, R., et al. - How well does reflectance pulse oximetry reflect
biomedical signals sent from various monitors and peripherals intrapartum fetal acidosis? - Am J Obstet Gynecol, 2002. 186(6).
connected to the patient from ventilatory support system. [2] Merrill, J. and R. Ballard - Avery's diseases of the newborn. 8 ed. 2005,
New York: Elsevier.
Among the peripheral monitoring systems is included a pulse [3] Kamlin, O., et al. - Oxygen saturation in healthy infants immediately
oximetry to monitor both SpO2 and HR, an oximeter that after birth. - J Pediatr, 2006. 148(5).
monitors the amount of supplemental oxygen administered at [4] Yis, U., et al. - Hyperoxic exposure leads to cell death in the
any time and a pressure transducer to measure the pressure developing brain. - Brain and development, 2008. 30.
[5] Vento, M., et al. - Room-air resuscitation causes less damage to heart
applied to the airway. The system also includes a digital and kidney than 100% oxygen. - Am J Resp Care, 2005. 172.
camcorder that will record the entire resuscitation process [6] Hilman, N., et al. - Brief, Large Tidal Volume Ventilation Initiates
allowing to check that everything in the system worked Lung Injury and a Systemic Response in Fetal Sheep. - Am J Respir
properly. During this phase preterm infants < 30 weeks Crit Care Med, 2007. 176.
[7] Vento, M., et al. - Resuscitation With Room Air Instead of 100%
gestation who follow the usual algorithm of CPR will be Oxygen Prevents Oxidative Stress in Moderately Asphyxiated Term
monitored throughout the process, so we can validate the Neonates. - Pediatrics, 2001. 107(4).
system and the different resuscitation teams will acquire [8] Wang, C., et al. - Resuscitation of preterm infants using room air or
specific skills in its management." 100% oxygen. - Pediatrics, 2008. 121.
[9] Dawson JA, Kamlin CO, Vento M, Wong C, Cole TJ, Donath SM,
Davis PG, Morley CJ. - Defining the reference range for oxygen
B. Phase 3 Clinical Trial.
saturation for infants after birth. - Pediatrics. 2010 Jun;125(6):e1340-7.
... "Once the ventilatory support system is started with the Epub 2010 May 3.
initial parameters, the FiO2 will be adjusted according to the http://pediatrics.aappublications.org/content/125/6/e1340.long
[10] Escrig, R., et al. - Achievement of targeted saturation values in
measurements, to achieve an SpO2 target of 75% at 5 minutes extremely low gestational age neonates resuscitated with low or high
after birth and 85% at 10 minutes." ... oxygen concentration: a prospective, randomized trial. - Pediatrics,
2008. 121.
C. Phase 4: Patient Monitoring and Data Analysis. [11] ILCOR, A.i.c.w. - Guidelines 2000 for Cardiopulmonary Resuscitation
"All patients included in the study will be monitored until and Emergency Cardiovascular Care: international consensus of
science. - Circulation, 2000. 102: p. 343-58.
the age of 24 months of corrected age. In addition to the [12] Buron, E. and J. Aguayo - Neonatal resuscitation. Neonatal RCP
routine monitoring of such patients, at 40 weeks group of Neonatology Spanish Society. - An Pediatr, 2006. 65: p. 470-7.
postconceptional age will be held a structured neurological [13] M. Iriondo, E. Szyld, M. Vento, E. Burón, E. Salguero, J. Aguayo, C.
examination and brain MRI. In addition, the Ruiz, D. Elorza y M. Thió, Grupo de reanimación neonatal de la
Sociedad Española de Neonatología. - Adaptación de las
neurodevelopment will be evaluated using the Bayley scale at recomendaciones internacionales sobre reanimación neonatal 2010:
24 months corrected age. During this phase of the study the comentarios. - An Pediatr (Barc). 2011;75(3):203.e1—203.e14
data collected from the recruited patients will be processed [14] Modesto V, Pantoja J. - Reanimación neonatal con oxígeno al 100%. -
and the necessary analysis of the result variables whose An Esp Pediatr 2000; 53: 279.
[15] Vento M. - ¿Cuánto oxígeno es suficiente para reanimar a un recién
process is complete will be carried out . An interim analysis of nacido asfíctico? - An Esp Pediatr 2000; 53: 210-212
the data will be made once collected at least half of the sample [16] Kondo M, Itoh S, Isobe K, Kondo M, Kunikata T, Imai T et al. -
to determine if there are clear results that can change the Chemiluminiscence because of the production of reactive oxygen
course of study." species in the lungs of born piglets during resuscitation periods after
asphyxiation load. - Ped Res 2000; 47: 524-527.
[17] Bookatz, B., et al. - Effect of suplemental oxygen on reinitation of
breathing after neonatal resucitation in rat pups. - Pediatr Res, 2007.
61(6).