Oxygen in neonatal anesthesia: friend or foe?
Augusto Solaa,b
a
Mid Atlantic Neonatology Associates and Atlantic
Neonatal Research Institute, Morristown, Atlantic
Health System and bUniversity of Medicine and
Dentistry New Jersey, New Jersey, USA
Correspondence to Dr Augusto Sola, MD, Director of
Neonatal Research and Academic Affairs, Division of
Neonatology, Mid Atlantic Neonatology Associates and
Atlantic Neonatal Research Institute, 100 Madison
Ave, Morristown, NJ 07960, USA
Tel: +1 973 971 8985; fax: +1 973 290 7175;
e-mail: [email protected]
Current Opinion in Anaesthesiology 2008,
21:332–339
Purpose of review
Clinical practices in oxygen administration are in need of change based on the
increasing understanding of oxygen toxicity. Hypoxemia is due to many
pathophysiological causes; avoiding hypoxemia is an important objective during
neonatal anesthesia. Nevertheless, the only known cause for hyperoxemia is the excess
and unnecessary administration of oxygen by healthcare providers. To avoid
hyperoxemia is an important objective during neonatal anesthesia.
Recent findings
Neonatal exposure to 100% oxygen is almost never necessary. Much lower
concentrations of inspired supplemental oxygen during the neonatal period can also lead
to oxygen toxicity if oxygen is used when it is not necessary. Excess oxygen is associated
with serious morbidities such as retinopathy of prematurity, bronchopulmonary dysplasia,
injury to the developing brain, and childhood cancer. When providing supplemental
oxygen, monitoring with modern SpO2 technology and avoidance of SpO2 values of 95–
100% are less frequently associated with hyperoxemia.
Summary
Even brief neonatal exposures to pure oxygen must be avoided during neonatal
anesthesia. When any dose of supplemental oxygen is given, a reliable pulse oximeter
aiming to avoid hyperoxemia is necessary. Even though further research is essential,
administration of oxygen by healthcare providers when it is not necessary is a foe and a
neonatal health hazard.
Keywords
alveolar ventilation, injury to the developing brain, long-term outcomes, oxygenation,
pulse oximetry saturation, retinopathy of prematurity
Curr Opin Anaesthesiol 21:332–339
ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
0952-7907
Introduction
Oxygen during neonatal anesthesia can really be a great
‘pal’, a ‘true friend’. Conversely, if used in excess or when
not necessary, it can be one of the worst foes or antagonists
for health, a true neonatal health hazard.
Ventilation with more than 21% oxygen (hyperoxic ventilation) is widely used in neonatal practice for resuscitation, acute interventions, and chronic supplementation,
but it can accentuate problems, worse if there is increased
alveolar ventilation.
The potential risks of unnecessary exposure to inspired
oxygen are described in recent publications [1 –4,5–8,
9,10,11,12]. We have stressed that avoiding hypoxemia,
as essential as it is, should not be equated with causing
hyperoxemia [1,7,8,9].
Efforts aimed at avoiding unnecessary oxygen use lead
to significant decreases in neonatal morbidities [13,14,15,
16–19,20] and have not been associated with increases in
mortality, short-term morbidity or long-term morbidity
[3,14,18]. Furthermore, 100% oxygen during neonatal
resuscitation is almost always unnecessary and potentially
harmful [6,11,19,20,21], stressing the need to ‘dose’ the
oxygen as needed [22].
The use of oxygen during neonatal anesthesia has not
been well studied [5]. The percentage of all newborns that
require surgery is very small, but they are usually tiny,
immature, or critically ill infants.
The scope of this review is to evaluate physiologic concepts of neonatal oxygenation and recent information on
morbidities associated with the use of excess oxygen and
oxidant stress. Among the many systemic changes associated with hyperoxemia, which will not be discussed in this
review, are increased plasma insulin and glucagon levels,
and reduced myocardial contractility and relaxation.
My objective is to provide educational tools for clinical
practice in neonatal anesthesia. Although it is essential to
continue to zealously avoid hypoxemia and tissue
hypoxia, we must avoid causing hyperoxemia, oxidant
damage, and reperfusion injury.
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Oxygen in neonatal anesthesia Sola 333
Table 1 Potential benefits and harms of excess oxygen during
the neonatal period
Oxygen and oxidant stress
Supplemental oxygen allies with us as a friend in the
struggle and cause to fight hypoxemia. A great friend
who supports infants in bad times.
Tissue hypoxia is bad and should be avoided. There are
more than 100 causes of hypoxemia and hypoxia and
never a practice guideline has been designed to cause, or
induce, hypoxemia.
On the contrary, there is absolutely no known pathophysiological cause of hyperoxemia in a living organism. The
only known reason of neonatal hyperoxemia (and I do not
mean oxidant stress) is us, the healthcare providers.
Excess oxygen has no benefit in neonatal medicine
and it is potentially harmful (Fig. 1, Table 1).
Oxygen causes tissue injury through formation of reactive
oxygen intermediates that cause lipid peroxidation,
directly damage DNA and cause protein sulfhydryl oxidation. No one knows how short an exposure to unnecessary oxygen can trigger this complex metabolic cascade in
neonates, who have decreased antioxidant defenses and
are highly susceptible to oxidative stress.
The evidence available over the past 15 years clearly
suggests that oxygen toxicity is intimately involved
in the damage that has been attributed to hypoxia [23,
24–28]. Organ damage can occur when there is insufficient
blood flow or oxygen. Many physicians assume that organ
damage is causedby lactic acidosis. Thereare, however, few
Figure 1 Conditions associated with unnecessary use of oxygen
Bronchopulmonary
dysplasia
Retinopathy
of
prematurity
Damage to
the
developing
brain-CP
DNA
damage
Cancer
Reduced
myocardial
contractility
Oxygen
as
foe
Endocrine
(insulin,
glucagon)
Prolonged
hospital
stay
Infection
Renal
effects
Alveolar
collapse
Atelectasis
Potential
benefit
Oxidation
Oxidative stress
Reperfusion
Cell proliferation
Brain
Lungs
Atelectasis
None
None
None
None
None
Lung compliance
Apnea
Eyes
Long-term development
Survival
None
None
None
None
None
Potential harm
Serious and multisystemic:
radicals damage proteins,
membranes and DNA
Cancer
Neuronal death,
BPD, edema, atelectasis
Worse (and much worse
with 100% oxygen)
Worsens with 100% oxygen
Worse apnea, oxygen toxicity
Retinopathy of prematurity
Impaired
With 100% oxygen: worse
mortality rates, death if
prolonged use
BPD, bronchopulmonary dysplasia.
data to support this concept. Moreover, acidosis is protective, even during reperfusion when cellular damage may
occur. Reperfusion is accompanied by generation of free
radicals and other reactive species that damage proteins,
membranes, and nucleic acids [26]. Cellular proteins modified during reperfusion, in part by metal-catalyzed oxidation in which iron plays a key role, are involved in the
pathogenesis of many severe disorders (Fig. 1, Table 1).
The problem is not just 100% oxygen but any amount of
oxygen that is not necessary. For example, resuscitation
of piglets for only 15 min with ‘just’ 40 or 60% oxygen
causes increased oxidative stress and dose-dependent
oxidation of DNA and phenylalanine. The increase in
the hydroxyl attack may lead to a pro-oxidative status and
risk of genetic instability [28]. Interestingly, it has
been shown that insects breathe discontinuously to avoid
oxygen toxicity and death [29]. Perhaps there is a lesson
to be learned from all this that will lead to improved
outcomes.
The present body of knowledge is important for routine
clinical practice, so that we do not induce, initiate, or
aggravate oxidant stress and the pathogenesis of many
disorders, including cancer [30,31].
Anesthesia, oxygen, the developing brain, and
long-term outcomes
The question arises whether modern anesthesia practices
can harm the uniquely vulnerable developing brain
[32,33,34]. Their potential toxicity and risks/benefits
have been reviewed [32,35–41].
Aging
CP, cerebral palsy.
Why administer drugs that have never been well studied
in neonates? Why give babies drugs that all available
evidence suggests are a serious risk and potential danger
for the developing brain?
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334 Pediatric anesthesia
One classic example is midazolam, a potent short-acting
agent that has never been carefully studied in newborns,
with high osmolality, benzyl alcohol, decreased clearance,
and prolonged elimination half-life in neonates. Midazolam affects the developing brain and adds risk for poor
outcomes. Poor neurological outcomes (neonatal death,
severe intraventricular hemorrhage grade III or IV, or
periventricular leukomalacia) were nine times more
frequent with midazolam than with morphine in one
randomized trial [42]. In another study, cerebral oxygenation, BP, and cerebral blood flow velocity decreased
within 15 min after the loading dose in some ventilated
premature infants [43]. Compared with placebo, midazolam has significant adverse effects and no apparent clinical
benefit [44]. Animal studies showed that midazolam can
trigger widespread apoptotic neurodegeneration in the
developing brain and learning deficits for life [45,46].
Authors have asked whether ‘pediatric drugs cause developing neurons to commit suicide’ [47]? The answer seems
to be ‘yes’ for midazolam. Finally, the Cochrane collaboration states that further research on the effectiveness and
safety of midazolam in neonates is needed before it is used
clinically [48]. If we give midazolam to neonates, we must
know what motivates us to do so and be responsible for
unnecessary and avoidable acute or long-term serious
adverse effects.
Oxygen by itself also causes cell death in the developing
brain [27,49–51]; no study has addressed the combined
effects of hyperoxemia and midazolam. It is likely that
both combined are worse than each of them individually.
Oxidative stress and reperfusion damage are implicated as
two of the leading causes for delayed neuronal cell death
and proteome changes in the developing brain. In animals,
the greatest vulnerability to oxygen neurotoxicity is around
the first 2 weeks of life, which in humans expands from 6
months of pregnancy to the third year of life. Damage by
radical oxygen species and reperfusion is a potential
serious problem for the developing brain [27,28,49–51].
Clinical studies are consistent with laboratory studies.
Hyperoxemia is ‘a foe’. Oxygen toxicity has been identified as a contributing factor to the pathogenesis of cerebral
palsy. In a large study of 1105 preterm infants [52], the risk
of disabling cerebral palsy was double in those exposed to
hyperoxia and eight-fold in the highest quintiles of oxygen
exposure. Practicing to avoid hyperoxia does not produce
poor outcomes [3], actually the outcomes improved [14].
In a two-center prospective study, infants cared for with
the aim of avoiding SpO2 values likely to cause hyperoxemia (i.e. SpO2 > 94–95% when breathing supplemental
oxygen) had better long-term mental developmental index
according to the Bayley scale [14].
The impact of clinical practices during the neonatal
period on the developing brain cannot be ignored [53].
It has been over 45 years since Van Den Brenk and
Jamieson [54] showed that, in mammals, there is potentiation by anesthetics of brain damage due to breathing
high-pressure oxygen.
Anesthesia, lung physiology, and oxygen
Fourteen healthy children aged 8–15 had brain functional
magnetic resonance imaging (fMRI) while breathing pure
oxygen. In 2 min (!), there were pronounced responses in
brain areas that modify hypothalamus-mediated autonomic (sympathetic) and hormonal outflow, including
the insula and hippocampus [55]. Breathing 100% oxygen unleashes a cascade of ‘dastardly chemicals’ and
quickly has potentially detrimental effects in humans.
During anesthesia or any neonatal ventilatory practice,
alveolar pressures of carbon dioxide and oxygen can
change in just a few seconds after ‘minimal’ modifications
in care due to the simple but important alveolar gas
equation. Therefore, PaO2 can change significantly and
rapidly and lead to altered circulation and oxygenation,
key processes in oxidative and reperfusion injury. Table 2
Table 2 Alveolar gas equation: minimal increases in alveolar ventilation and oxygenation can rapidly change PACO2 and PAO2 and,
therefore, neonatal blood oxygenation (PaO2)
(1) Neonate in room air (warm humid gas)
(2) Modify ventilation (manual or respirator)
increasing AV 10%
(3) Modify ventilation (manual or respirator)
increasing AV 10% þ FiO2 from 0.21 to
0.30 (increased by about 0.1)
(4) Baseline on ventilation and FiO2 of 0.40
(5) Modify ventilation (manual or respirator)
increasing AV 10% þ an increase of
‘resting’ FiO2 (0.40) to 0.5
(6) 100% oxygen
PACO2, kPa (mmHg)
PAO2, kPa (mmHg)
PaO2, kPa (mmHg)
5.3 (40)
4.8 (35)a
14.6 (110)
15.2 (115)a
9.3 (70)
9.7 (74)a
4.8 (35)
24 (180)
14.6 (110)
6.3 (47)
4.8 (35)
32.3 (242)
42.8 (321)
8 (60)
>13.3 (100)
8 (60)
80 (600)
As high as 60 (450) depending
on V/Q and shunt
AV, alveolar ventilation.
a
The lower the PACO2 the higher will be the PAO2 and the PaO2. Numbers 2–3 and 5–6 (with rounded numbers) show what happens when
modifications are made. As can be easily understood, this must be avoided when not necessary.
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Oxygen in neonatal anesthesia Sola 335
shows how ‘minimal’ changes can affect alveolar gases
and PaO2. Hypocarbia and hyperoxemia are detrimental
for the developing brain. This can occur only if we do not
pay careful attention to details, and we ventilate and
oxygenate the alveoli more than is needed (Table 2).
Infants have a small functional residual capacity (FRC),
high closing volume, and unstable architecture of the
lungs [56]. Compression atelectasis (air effectively
squeezed out) and absorption atelectasis (airway closure
and absorption of the gases distal to the closure) do occur.
With extremely narrow, but not closed airways (always
present, more so in premature infants), atelectasis occurs
when the rate at which alveolar gas is absorbed into the
blood exceeds the rate at which gas can flow through
the narrow airway to replace it. The gas mixture we give
infants influences atelectasis in these cases.
Known physiological principles very accurately predict
the rate at which absorption atelectasis occurs during
anesthesia. High FiO2 worsens compliance and pure
oxygen results in reabsorption atelectasis shortly after
its application [57,58,59] (Table 3). The alveolar to
venous pressure gradient must be countered by the
respiratory elastic recoil to keep alveoli open, but this
gradient is too high with 100% oxygen (Table 3). With
just 3 min of ‘preoxygenation’, the higher the FiO2, the
greater the areas of atelectasis [4,60] and the shorter
the time required for collapse to occur, irrespective of the
FiO2 used after induction. Interestingly, nitrous oxide,
which is discussed in detail in this same issue, behaves at
an early stage in a similar fashion to oxygen, increasing
the risk of atelectasis.
Alveolar recruitment maneuvers are useful [56,57,58–62],
more so if done with low FiO2. When an FiO2 of 1.0 is used,
there is rapid recurrence of the atelectasis [61], and
decreased FRC and ventilation homogeneity. One recruitment technique, effective to maintain FRC and ventilation distribution, is positive end-expiratory pressure
(PEEP) of 6 cmH2O [56]; the other may be a vital capacity
maneuver with a sustained inspiratory pressure. When
they are used with high FiO2, this is detrimental because
of atelectasis and because the PaO2 will increase to very
high levels immediately upon recruitment (Table 2), with
potentially serious toxicity. This same occurs with an FiO2
of 1.0 before extubation, which also increases the risk for
postoperative atelectasis (Table 4). Therefore, FiO2 should
be titrated with an oxygen : air blender to try to avoid
hypoxemia and hyperoxemia (i.e. SpO2 not less than
85–88% and not above 94–95%).
More oxygen than necessary in the postoperative period
can, paradoxically, aggravate central hypoventilation and
apnea (Tables 1 and 4). Adequate monitoring is mandatory but pure oxygen should not be used in the recovery
room. If saturation is normal in room air (95–100%), the
FiO2 used should be 0.21; otherwise, it should be dosed to
maintain the SpO2 within the ranges mentioned above.
The treatment of apnea, including postoperative apnea,
is to ventilate the alveoli, to breathe, and not to give
supplemental oxygen.
In an editorial a question was posed: ‘Is it always a good
idea to get ‘‘just a little oxygen’’ to breathe as you go off to
sleep’ [4]? My answer is definitely not. It is never a good
idea to get ‘just a little oxygen’ to breathe, unless there are
clear clinical indications. More than 57 years ago Comroe
et al. [63] described mental changes during oxygen therapy,
and, in 1975, it was clearly described that lung units with
low VA/Q ratios become more unstable with oxygen
breathing [64]. Comroe, in his elegant book, discusses
‘how to delay progress without even trying’ [65]. Another
editorial [66], arguing that routine preoxygenation could
be recommended, fits well into that category. The body of
knowledge showing potential adverse effects of providing
unnecessary oxygen has expanded exponentially. To
decrease the gap between knowledge and practice clinicians should not turn their back on it.
Oxygen and retinopathy of prematurity
A 32-week-gestation infant without cardiopulmonary disease and severe retinopathy of prematurity (ROP) was
described in 1977 [67]. Oxygen was given only on the
fourth day for 4 h, during and after general anesthesia.
FiO2 varied between 1.0 and 0.5; no PaO2 was measured.
Prior to extubation, with FiO2 1.0, the PaO2 was 325 torr
(41.4 kPa) and, 30 min post extubation with FiO2 0.28, the
PaO2 was 104 torr (13.8 kPa). After 30 min and 6 h in room
Table 3 Absorption atelectasis is greatly influenced by the gas mixture present in the alveolus
Alveolar pressure of gases (minus water vapor pressure)
Alveolar pressure of nitrogen
Blood nitrogen pressure
Total mixed venous blood gases pressure
Alveolar to venous pressure gradient
Rapid alveolar–capillary transfer of O2
Absorption atelectasis
If airway narrowing is present
Room air
100% oxygen
About 95 kPa (713 mmHg)
Normal 69.8 kPa (523 mmHg)
Normal
About 87 kPa (652 mmHg)
8 kPa (60 mmHg)
No
No
The same
About 95 kPa (713 mmHg)
Falls quickly to 0 kPa
Negligible
About 12.5 kPa (93 mmHg)
82.5 kPa (620 mmHg)
Yes
Yes
Much worse
Inhaled gas should always be warm and humid.
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336 Pediatric anesthesia
Table 4 Several practices that increase potential for risk before, during, and after neonatal anesthesia
Problems
Impact
Midazolam
Manual ventilation
Developing brain
Hypocarbia
Manual ventilation – no humidified
warm gas
Lack of air : oxygen blender
100% oxygen
Inadequate gas conditioning
Apoptosis, neurological outcome (see text)
Hyperoxemia, blood flow modifications,
altered oxygen delivery
Airway and alveolar damage
Excess oxygen, any FiO2
‘Preoxygenation’ (even 2–3 min)
Insufficient PEEP
Alveolar recruitment maneuvers
FiO2 of 1.0 before extubation
Apnea
Wide rapid fluctuations in oxygenation
SpO2 >95% when breathing
supplemental O2
Inability to dose FiO2
‘We see no problems’; ‘Cannot allow hypoxia’;
‘We have always done this’; ‘Baby looks good
(or pink)’; ‘SpO2 is great’; (other)
‘We see no problems’; ‘Cannot allow hypoxia’;
‘We have always done this’; ‘Baby looks good
(or pink)’; ‘SpO2 is great’; (other)
‘We see no problems’; ‘Cannot allow hypoxia’;
‘We have always done this’; ‘Baby looks good
(or pink)’; ‘SpO2 is great’; (other)
Decrease FRC
Risk if too high pressures
High PaO2 and systemic damage
Giving unnecessary oxygen; hyperventilating
Care providers still do not quite understand
how bad this is
High risk for high PaO2
Administration of 100% oxygen
Even brief periods of 100% oxygen (<2 min)
can be harmful, more so if repeated.
Many serious consequences are
described in the text
Many risks (described in text)
Many risks (described in text)
Atelectasis and ateletrauma
Prevents/recovers atelectasis
Risk for postoperative atelectasis (text)
See text and alveolar gas equation (Table 2)
Higher rates of worse ROP, risk for other
oxidative damages
Oxidant stress
FRC, functional residual capacity; PEEP, positive end-expiratory pressure; ROP, retinopathy of prematurity.
air the PaO2 as 70 and 64 torr, respectively. Phibbs [68]
warned clinicians that this case was not unique and that
susceptible infants can be blinded by brief exposure to
high PaO2. He recommended, 30 years ago, that FiO2
always be adjusted to maintain normal neonatal
PaO2 using an oxygen : air blender that reliably delivers
FiO2 between 0.21 and 1.0.
Excess oxygen is risky for newborns [1,2]. More
oxygen than necessary, even for a short time, serves to
oppose or impede health objectives and is associated with
injury, fitting perfectly the definition of ‘foe’, being
hostile to the purposes or interests of healthcare providers
(Fig. 1).
The risk of ROP persists until the retinal vasculature has
matured. In general terms, the retina of a 2–3-month-old
infant who was 24 weeks, gestation at birth or of a 5–8week-old infant born at 26–30 weeks, gestation may still
be highly susceptible to hyperoxemia.
Monitoring of oxygenation during anesthesia
Interestingly, wide, rapid fluctuations in oxygenation
may cause more derangement of vascular responses than
persistent hyperoxia, and must be avoided [7,8,9,13].
A practice aiming to avoid hyperoxemia and fluctuations
is associated with lower rates of severe ROP and laser
surgery [13,14,15,16–18]. Only one small retrospective
study [69], from the University of North Carolina, shows
no significant improvement in ROP rates. In an editorial,
the same author [70] states that he will continue to
inform that data suggest that lowering oxygen saturation reduces severe ROP but the risk to overall development is not yet known. As shown here, however,
knowledge and evidence of practices that aim to
avoid hyperoxemia demonstrate benefits for ROP and
for prevention of potential harm to the developing
brain, long-term development and other morbidities
(Table 1, Fig. 1).
Owing to space limitations I cannot cover this in detail.
More than 90 publications have addressed SpO2 monitors.
Table 5 summarizes a few [7,8,9,71,72–78].
Cellular oxygenation is complex [9]; one day we may be
able to monitor this clinically. With the aim of avoiding
hypoxemia and hyperoxemia and oxidant stress, we have
shown [71] that when the SpO2 is more than 94%, in
neonates who are receiving supplemental O2, there is
hyperoxemia in 60% of the samples.
Fortunately, for the well being of many newborns, the
history of neonatal O2 monitoring is ‘coming of age’ after
the past 10–12 years of extensive research and education.
Summary
Oxygen should never be denied when necessary. An
adequate state-of-the-art SpO2 monitor serves as a guide
to increase FiO2 and by how much. Pure oxygen is almost
never necessary.
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Oxygen in neonatal anesthesia Sola 337
Table 5 Practical concepts on saturation monitoring, based on peer-reviewed publications and reports
Statement
Comments
Clinical significance
SpO2 monitors are valuable to detect
hypoxemia
SpO2 is not a measurement of tissue
oxygenation
Six type of noise can ‘confuse’ the monitor,
when it is most needed
Monitors vary in the ability to accurately
detect hypoxemia
A low SpO2 does not necessarily mean that
there is tissue hypoxia
Medications, shock, venous desaturation and
stasis, anesthesia, surgery, motion, cold
extremities, light and others
See below
SpO2 monitors are different according to the
manufacturer
Signal extraction technology is extremely useful
‘One monitor is not the same as another monitor’
Sensors are also different according to the
manufacturer
Normal SpO2 in room air
SpO2 cannot detect hyperoxemia
During resuscitation time to stable SpO2
reading is very different between monitors
Relative risk reduction of severe ROP is
associated with the technology utilized
No one knows what the ‘best’ or ‘ideal’
saturation range is at all times
SpO2 >95% when breathing supplemental O2
Extraction of the arterial signal from all other noises
and motion prevents SpO2 ‘confusion’
Low noise optical probes (LNOP) act as a
‘shock absorber’
Not an adequate SpO2 target when neonates
receive supplemental O2
SpO2 96–100% when giving supplemental O2
is frequently associated with hyperoxemia
Mean of 22 s for Masimo SET and 64 to 74 s
for two other monitors
Two-center study; 40% reduction with Masimo
SET; P ¼ 0.02
Eradicating some bad practices is not the same as
implementing routinely unproven practices in
a rigid way
Is of high risk for high PaO2
Oxidant stress is a ‘part of life’, but the only neonatal cause
for PaO2 greater than normal are treatments administered
by healthcare providers. To avoid hyperoxemia, without
permitting hypoxemia, is neither easy nor simple. Understanding oxygen toxicity leads to new ways of interrupting
pathologic sequences. We can neither simplify complex
matters nor take one good friend for granted. The dual
nature of oxygen is clear: therapeutically beneficial and
potentially toxic, a great friend or the worst foe.
Inducing brief, prolonged and/or widely fluctuating
hyperoxemia is a potentially bad and high-risk practice
for newborn babies, despite lack of a randomized trial.
Absence of evidence is not evidence of absence [79], and
this well applies to the risks of hyperoxemia and oxidant
stress in neonates.
On the basis of evidence and knowledge and on more
than 10 years of studying this topic and observing practices and resistance to change, my opinion is that oxygen
is not really the foe. Just as for art (‘Art hath an enemy called
Ignorance’, Ben Johnson), some infants have an enemy
in ignorance and/or guidelines, strict rules, or practices
that may induce hyperoxemia. Therefore, without even
trying, we are the real foes, not oxygen, putting the well
being of some infants at high risk, by not refining the use
and indications of oxygen. Maybe, the coming of age for
neonatal oxygen therapy will be reached when we diminish or eliminate the gap between knowledge and practice,
We do not have a tool to measure
tissue oxygenation
‘Confusion’ leads to falsely low SpO2
readings, data drop out, false
bradycardia, holding periods and
false alarms
Those with greatest accuracy are more
valuable in caring for sick patients
Provides more accuracy in readings
Minimize noise interference by ambient
light, electro-surgical noise and the
noise produced by the movement
of the infant
See below
Avoiding ‘normal’ SpO2 when breathing
O2 decreases risk of oxidant damage
Better guided administration of the
needed dose of oxygen
Education, alarm limits, targets,
implementation of practice guidelines
and adequacy of technology are all
necessary
Paying attention to ‘details’ we can
accomplish a clinical difference and
improve outcomes
Risk of inducing oxidant stress
and we implement the aim of never administering
unnecessary oxygen and of trying to avoid SpO2 more
than 95%, to decrease episodes or periods of hyperoxemia
and its associated risks.
You can now move on to something else, relax and ‘take a
(deep) breath, but do not add oxygen if it is not needed’,
as Ola Saugstad wrote [2].
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 417).
1 Sola A, Rogido MR, Deulofeut R. Oxygen as a neonatal health hazard: Call for
détente in clinical practice. Acta Paediatr 2007; 96:801–812.
Thorough review with important concepts and detailed descriptions for clinicians.
2 Saugstad OD. Take a breath–but do not add oxygen (if not needed). Acta
Paediatr 2007; 96:798–800.
Elegant, brief, complete and fun editorial by the person who has investigated the
most in neonatal oxygen toxicity. A must.
3 Tin W, Gupta S. Optimum oxygen therapy in preterm babies. Arch Dis Child
Fetal Neonatal Ed 2007; 92:F143–F147.
Pros and cons, known and unknown, and uncertainties on trying to define
‘optimum’ in clinical care today.
4 Lumb AB. Just a little oxygen to breathe as you go off to sleep. . .is it always a
good idea? Br J Anaesth 2007; 99:769–771.
Wonderful editorial for all anesthesiologists. Oxygen is also a foe for adults!
5
van der Walt J. Oxygen – elixir of life or Trojan horse? Part 2. Oxygen and
neonatal anesthesia. Paediatr Anaesth 2006; 16:1205–1212.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
338 Pediatric anesthesia
6
Vento M, Sastre J, Asensi MA, Viña J. Room-air resuscitation causes less
damage to heart and kidney than 100% oxygen. Am J Respir Crit Care Med
2005; 172:1393–1398.
32 Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates
and young children. Anesth Analg 2007; 104:509–520.
Excellent description of the current situation and the need for further research.
7
Sola A, Chow L, Rogido M. Retinopathy of prematurity and oxygen therapy: a
changing relationship. An Pediatr (Barc) 2005; 62:48–63.
33 Doherty D, Splinter W. Can modern anesthesia practice harm the developing
brain? Paediatr Drugs 2007; 9:213–214.
8
Sola A, Chow L, Rogido M. Pulse oximetry in neonatal care in 2005. A
comprehensive state of the art review. An Pediatr (Barc) 2005; 62:266–281.
34 Davidson A, McCann ME, Morton N. Anesthesia neurotoxicity in neonates: the
need for clinical research. Anesth Analg 2007; 105:881–882.
9 Sola A, Pérez Saldeño Y, Favareto V. Clinical practices in neonatal oxygena tion: Where have we failed? What can we do? J Perinatol (in press).
Description of tissue oxygenation, limitations in practice, and clinical recommendations for how to try to avoid hyperoxemia.
35 Kinouchi K. Anaesthetic considerations for the management of very low and
extremely low birth weight infants. Best Pract Res Clin Anaesthesiol 2004;
18:273–290.
10 Saugstad OD. Optimal oxygenation at birth and in the neonatal period.
Neonatology 2007; 91:319–322.
Excellent description of current and salient aspects on oxygenation.
11 Saugstad OD, Ramji S, Vento M. Oxygen for newborn resuscitation: how
much is enough? Pediatrics 2006; 118:789–792.
12 Silverman WA. A cautionary tale about supplemental oxygen: the albatross of
neonatal medicine. Pediatrics 2004; 113:394–396.
13 Chow LC, Wright KW, Sola A. Can changes in clinical practice decrease the
incidence of severe retinopathy of prematurity in very low birth weight infants?
Pediatrics 2003; 111:339–345.
14 Deulofeut R, Critz A, Adams-Chapman I, Sola A. Avoiding hyperoxia in infants
<1250 g is associated with improved short-and long-term outcomes.
J Perinatol 2006; 26:700–705.
15 Deulofeut R, Dudell G, Sola A. Treatment-by-gender effect when aiming to
avoid hyperoxia in preterm infants in the NICU. Acta Paediatr 2007; 96:990–
994.
Oxygen toxicity and effects of practices that aim to prevent hyperoxemia seem to
be different in boys than in girls.
16 Vanderveen DK, Mansfield TA, Eichenwald EC. Lower oxygen saturation
alarm limits decrease the severity of retinopathy of prematurity. J AAPOS
2006; 10:445–448.
17 Wright KW, Sami D, Thompson L, et al. A physiologic reduced oxygen
protocol decreases the incidence of threshold retinopathy of prematurity.
Trans Am Ophthalmol Soc 2006; 104:78–84.
18 Tin W, Milligan DW, Pennefather P, Hey E. Pulse oximetry, severe retinopathy,
and outcome at one year in babies of less than 28 weeks gestation. Arch Dis
Child Fetal Neonatal Ed 2001; 84:F106–F110.
19 Vento M, Asensi M, Sastre J, et al. Six years of experience with the use of room
air for the resuscitation of asphyxiated newly born term infants. Biol Neonate
2001; 79:261–267.
20 Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a
systematic review and meta-analysis. Resuscitation 2007; 72:353–363.
Recent thorough and objective review of published evidence, benefits of avoiding
unnecessary oxygen, as well as descriptions of further areas of research based on
the current findings.
21 Paneth N. The evidence mounts against use of pure oxygen in newborn
resuscitation. J Pediatr 2005; 147:4–6.
22 Sola A, Deulofeut R, Rogido M. Oxygen and oxygenation in the delivery room.
J Pediatr 2006; 148:564–565.
23 Brahimi-Horn MC, Pouysségur J. Oxygen, a source of life and stress. FEBS
Lett 2007; 581:3582–3591.
New information and wonderful insight, both for scientists and for clinicians.
24 Oliver CN, Starke-Reed PE, Stadtman ER, et al. Oxidative damage to brain
proteins, loss of glutamine synthetase activity, and production of free radicals
during ischemia/reperfusion-induced injury to gerbil brain. Proc Natl Acad Sci
U S A 1990; 87:5144–5147.
25 Stadtman ER, Oliver CN. Metal-catalyzed oxidation of proteins. Physiological
consequences. J Biol Chem 1991; 266:2005–2008.
26 Levine RL. Ischemia: from acidosis to oxidation. FASEB J 1993; 7:1242–
1246.
27 Felderhoff-Mueser U, Bittigau P, Sifringer M, et al. Oxygen causes cell death in
the developing brain. Neurobiol Dis 2004; 17:273–282.
28 Solberg R, Andresen JH, Escrig R, et al. Resuscitation of hypoxic newborn
piglets with oxygen induces a dose-dependent increase in markers of oxidation. Pediatr Res 2007; 62:559–563.
29 Hetz SK, Bradley TJ. Insects breathe discontinuously to avoid oxygen toxicity.
Nature 2005; 433:516–519.
30 Naumburg E, Bellocco R, Cnattingius S, et al. Supplementary oxygen and
risks of childhood lymphatic leukaemia. Acta Pediatr 2002; 91:1328–1333.
31 Spector LG, Klebanoff MA, Feussner JH, et al. Chilhood cancer following
neonatal oxygen supplementation. J Pediatr 2005; 147:27–31.
36 Sale SM, Read JA, Stoddart PA, Wolf AR. Prospective comparison of
sevoflurane and desflurane in formerly premature infants undergoing inguinal
herniotomy. Br J Anaesth 2006; 96:774–778.
37 Kachko L, Simhi E, Tzeitlin E, et al. Spinal anesthesia in neonates and infants – a
single-center experience of 505 cases. Paediatr Anaesth 2007; 17:647–653.
38 Von Ungern-Sternberg BS, Habre W. Pediatric anesthesia – potential risks
and their assessment: part I. Paediatr Anaesth 2007; 17:206–215.
39 Von Ungern-Sternberg BS, Habre W. Pediatric anesthesia – potential risks
and their assessment: part II. Paediatr Anaesth 2007; 17:311–320.
40 Carmosino MJ, Friesen RH, Doran A, Ivy DD. Perioperative complications in
children with pulmonary hypertension undergoing noncardiac surgery or
cardiac catheterization. Anesth Analg 2007; 104:521–527.
41 Sukhani R, Pappas AL, Black PR, Noles DM. Postoperative oxygen desaturation requiring clinical intervention in premature infants receiving spinal
anesthesia for inguinal herniorrhaphy. J Clin Anesth 1997; 9:520–521.
42 Anand KJ, Barton BA, McIntosh N, et al. Analgesia and sedation in preterm
neonates who require ventilatory support: results from the NOPAIN trial.
Neonatal Outcome and Prolonged Analgesia in Neonates. Arch Pediatr
Adolesc Med 1999; 153:331–338.
43 van Alfen-van der Velden AA, Hopman JC, Klaessens JH, et al. Effects of
midazolam and morphine on cerebral oxygenation and hemodynamics in
ventilated premature infants. Biol Neonate 2006; 90:197–202.
44 Aranda JV, Carlo W, Hummel P, et al. Analgesia and sedation during
mechanical ventilation in neonates. Clin Ther 2005; 27:877–899.
45 Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common
anesthetic agents causes widespread neurodegeneration in the developing
rat brain and persistent learning deficits. J Neurosci 2003; 23:876–882.
46 Young C, Jevtovic-Todorovic V, Qin YQ, et al. Potential of ketamine and
midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol 2005; 146:189.
47 Olney JW, Young C, Wozniak DF, et al. Do pediatric drugs cause developing
neurons to commit suicide? Trends Pharmacol Sci 2004; 25:135–139.
48 Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of
infants in the neonatal intensive care unit. Cochrane Database Syst Rev 2003;
1:CD002052.
49 Kaindl AM, Sifringer M, Zabel C, et al. Acute and long-term proteome changes
induced by oxidative stress in the developing brain. Cell Death Differ 2006;
13:1097–1109.
50 Gerstner B, Bührer C, Rheinländer C, et al. Maturation-dependent oligodendrocyte apoptosis caused by hyperoxia. J Neurosci Res 2006; 84:306–315.
51 Gerstner B, Sifringer M, Dzietko M, et al. Estradiol attenuates hyperoxia-induced
cell death in the developing white matter. Ann Neurol 2007; 61:562–573.
52 Collins MP, Lorentz JM, Jelton R, Paneth N. Hypocapnia and other ventilation
related risk factors for cerebral palsy in low birth weight infants. Pediatr Res
2001; 50:712–719.
53 Gressens P, Rogido M, Paindaveine B, Sola A. The impact of neonatal
intensive care practices on the developing brain. J Pediatr 2002;
140:646–653.
54 Van Den Brenk HA, Jamieson D. Potentiation by anaesthetics of brain damage
due to breathing high-pressure oxygen in mammals. Nature 1962; 194:777–
778.
55 Macey PM, Woo MA, Harper RM. Hyperoxic brain effects are normalized by
addition of CO2. PLoS Med 2007; 4:e173.
Very original study in 14 children showing rapid adverse effects of pure oxygen on
the brain and how carbon dioxide affects the response.
56 Gregory GA. Pediatric anesthesia. 4th ed. New York: Churchill Livingstone;
2002.
57 von Ungern-Sternberg BS, Regli A, Schibler A, et al. The impact of positive
end-expiratory pressure on functional residual capacity and ventilation homogeneity impairment in anesthetized children exposed to high levels of inspired
oxygen. Anesth Analg 2007; 104:1364–1368.
Important findings for clinical practice.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Oxygen in neonatal anesthesia Sola 339
58 Marcus RJ, van der Walt JH, Pettifer RJA. Pulmonary volume recruitment
restores pulmonary compliance and resistance in anesthetized young children. Paediatr Anaesth 2002; 12:570–584.
59 Tusman G, Bohm SH, Tempra A, et al. Effects of recruitment maneuver on
atelectasis in anesthetized children. Anesthesiology 2003; 98:14–22.
60 Edmark L, Kostova-Aherdan K, Enlund M, Hedenstierna G. Optimal oxygen
concentration during induction of general anesthesia. Anesthesiology 2003;
98:28–33.
61 Rothen HU, Sporre B, Engberg G, et al. Influence of gas composition on
recurrence of atelectasis after a reexpansion maneuver during general anesthesia. Anesthesiology 1995; 82:832–842.
62 Halbertsma FJJ, van der Hioeven JG. Lung recruitment during mechanical
positive pressure ventilation in the PICU: what can be learned from the
literature? Anaesthesia 2005; 60:779–790.
63 Comroe JH Jr, Bahnson ER, Coates EO Jr. Mental changes occurring in
chronically anoxemic patients during oxygen therapy. J Am Med Assoc
1950; 143:1044–1048.
64 Dantzker DR, Wagner PD, West JB. Instability of lung units with low VA/Q
ratios during O2 breathing. J Appl Physiol 1975; 38:886–895.
65 Comroe JH Jr. Retrospectroscope. Insights into medical discovery. Mento
Park, CA: Von Gehr Press; 1977 [How to delay progress without even trying,
pp. 114–119].
66 Bell MD. Routine preoxygenation – a new ‘minimum standard’ of care?
Anaesthesia 2004; 59:943–945.
67 Betts EK, Downes JJ, Scaffer DB, Johns R. Retrolental fibroplasia and oxygen
administration during general anethesia. Anesthesiology 1977; 47:518–
520.
68 Phibbs RH. Oxygen therapy: a continuing hazard to the premature infant.
Anesthesiology 1977; 47:486–487.
69 Wallace DK, Veness-Meehan KA, Miller WC. Incidence of severe retinopathy
of prematurity before and after a modest reduction in target oxygen saturation
levels. J AAPOS 2007; 11:170–174.
70 Wallace DK. Oxygen saturation levels and retinopathy of prematurity – are we
on target? J AAPOS 2006; 10:382–383.
71 Castillo A, Sola A, Baquero H, et al. Pulse oximetry saturation levels and
arterial oxygen tension values in newborns receiving oxygen therapy in the
neonatal intensive care unit: is 85% to 93% an acceptable range? Pediatrics
(in press).
When neonates are receiving supplemental oxygen and the SpO2 is more than
94%, there is hyperoxemia in 60% of the samples. We also describe salient clinical
issues regarding SpO2 monitoring.
72 Bohnhorst B, Peter CS, Poets CF. Detection of hyperoxaemia in neonates:
data from three new pulse oximeters. Arch Dis Child Fetal Neonatal Ed 2002;
87:F217–F219.
73 Workie FA, Rais-Bahrami K, Short BL. Clinical use of new-generation pulse
oximeters in the neonatal intensive care unit. Am J Perinatol 2005; 22:357–
360.
74 Robertson FA, Hoffman GM. Clinical evaluation of the effects of signal integrity
and saturation on data availability and accuracy of Masimo SE and Nellcor
N-395 oximeters in children. Anesth Analg 2004; 98:617–622.
75 Hay WW Jr, Rodden DJ, Collins SM, et al. Reliability of conventional and new
pulse oximetry in neonatal patients. J Perinatol 2002; 22:360–366.
76 Deulofeut R, Sola A. Risk for late bacterial sepsis in infants <1000 g: another
beneficial effect of avoiding hyperoxia? E-PAS 2006; 59:2851.14830.
77 Baquero H, Alviz R, Sola A. Avoiding hyperoxemia during neonatal resuscitation: time to response to different SpO2 monitors. Presented at Pediatric
Academic Societies Annual Meeting; 5–8 May 2007; Toronto, Canada.
78 Castillo A, Deulofeut R, Sola A. Clinical practice and SpO2 technology in the
prevention of ROP in ELBW infants. Presented at Pediatric Academic
Societies Annual Meeting; 5–8 May 2007; Toronto, Canada.
79 Sola A, Dominguez Dieppa F, Rogido MR. An evident view of evidence-based
practice in perinatal medicine: absence of evidence is not evidence of
absence. J Pediatr (Rio J) 2007; 83:395–414.
A comprehensive and simple analysis of what is really ‘evidence’ and what is not.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.