Oxygen Supplementation,
Delivery, and Physiologic Effects
Stacey Peterson-Carmichael, Ira Cheifetz,
and Laurent Storme
Educational Aims
• Review the various oxygen delivery
­systems available to the pediatric and
neonatal patient population.
• Describe the numerous central and
peripheral ventilatory control centers.
• Discuss various therapies to treat pul-
monary vasoconstriction and their
mechanisms of action.
• Describe the appropriate physiologic
response to oxygen supply.
• Describe the hemodynamic effects of
oxygen supply and delivery.
S. Peterson-Carmichael (*) • I. Cheifetz
Division of Pediatric Critical Care Medicine,
Duke Children’s Hospital,
3046, Durham, NC 27710, USA
e-mail: stacey.peterson-carmichael@duke.edu;
cheif002@mc.duke.edu
L. Storme
Pôle Femme Mère Nouveau-né / EA4489,
Hôpital Jeanne de Flandre,
CHRU de Lille / Université Lille 2,
1 rue Eugène Avinée,
Lille, JE 2490, France
e-mail: laurent.storme@chru-lille.fr
P.C. Rimensberger (ed.), Pediatric and Neonatal Mechanical Ventilation,
DOI 10.1007/978-3-642-01219-8_6, © Springer-Verlag Berlin Heidelberg 2015
6
6.1 Introduction
The delivery of oxygen is a vital component of
patient care within pediatric and neonatal inten-
sive care units. Clinicians are constantly altering
the support provided to each patient in an attempt
to optimize global oxygen delivery as defined by
the following equation:
DO 2 = CO × arterial O 2 content
 SaO 2 saturation 
arterial O 2 content =  
 ×1.39 ( mL/g ) × Hb 
+ ( 0.003 × PaO 2 )
where DO2 represents oxygen delivery; CO, car-
diac output; SaO2, arterial oxygen saturation;
Hb, hemoglobin; and PaO2, partial pressure of
oxygen in arterial blood. Thus, decreased oxy-
gen delivery can result from inadequate car-
diac output, low arterial oxygen saturation,
inadequate hemoglobin concentration, or low
PaO2 as a minor contributor (secondary to the
factor of 0.003 in the formula outlined above).
In this chapter, we will review the variety of
mechanisms by which clinicians can improve
the supply of oxygen to the patient to meet the
metabolic demands involved with various patho-
physiologic processes.
123
124
6.2 Oxygen Delivery Systems
The various methods to physically deliver
­oxygen depend on the patient’s respiratory sta-
tus and oxygen demands. In the neonatal and
pediatric populations, the options are patient
specific as body habitus, size, and tolerance for
various oxygen delivery devices vary signifi-
cantly. The most important factor is the gas flow
rate since this determines if the oxygen delivery
system is sufficient to meet a patient’s inspira-
tory demand. If gas flow is inadequate, then in
turn, the FiO2 is likely to be variable and insuf-
ficient as the patient entrains room air. We can
better delineate this concept by dividing the
available delivery systems into low-flow and
high-flow devices.
Low-flow devices tend to provide a less con-
sistent concentration of inspired oxygen and
include traditional nasal cannulae, simple face
masks, and tracheostomy collars.
High-flow devices provide a more reliable
concentration of inspired oxygen to the patient
regardless of respiratory effort. These devices
include partial and non-rebreather face masks,
nebulizers, high-flow nasal cannulae, oxy-
gen hoods, noninvasive ventilation (NIV), and
mechanical ventilation.
6.2.1 Low-Flow Devices
6.2.1.1 Nasal Cannulae
Various sizes of nasal prongs are available for
the neonatal and pediatric populations. Oxygen
can be supplied from a wall or tank source at a
rate of 1–6 liters/minute (L/min) for the pedi-
atric population. This provides an approximate
FiO2 of 0.24–0.50. The actual FiO2 delivered
to the patient depends on the patient effort
and the potential for entrainment of room air.
Humidification is important to minimize drying
of nasal and upper airway secretions. In addi-
tion, a blender with ambient air can be used
to decrease flows to as low as 0.025 L/min,
which can be especially useful in the premature
­neonatal population.
P.C. Rimensberger et al.
6.2.1.2 Simple Face Mask
Such a device fits over the nose and mouth and
provides a gas flow rate of 6–10 L/min and FiO2
of 0.35–0.60.
6.2.1.3 Venturi Face Mask or
Tracheostomy Collar
This is a face mask with a controlled jet of high-­
flow oxygen which entrains a continuous flow of
ambient air. Such a device allows a controlled
provision of FiO2 at 0.24, 0.28, 0.31, 0.35, 0.40,
or 0.50. This approach can be crucial for patients
with chronic carbon dioxide retention. The
­manufacturer lists the predetermined flow rates
required to provide the chosen FiO2. The FiO2
is dependable as long as the flow rate does not
exceed the inspiratory demand of the patient.
6.2.2 High-Flow Devices
6.2.2.1 High-Flow Nasal Cannulae
In the neonatal intensive care unit (NICU), high-­
flow nasal cannula (HFNC) (>1 L/min for the
neonatal population) has been introduced as an
alternative to nasal continuous positive airway
pressure (NCPAP) which has been the traditional
standard of care for infants with respiratory dis-
tress syndrome (RDS) or apnea. Current HFNC
devices deliver gases heated to near body tem-
perature. These gases are saturated with water
vapor and deliver typical gas flow of 1–5 L/min
in the NICU population via a nasal cannula setup
(Kubicka et al. 2008). This 1–5 L/min has a higher
partial pressure than flow from a simple nasal can-
nula secondary to the degree of humidification.
A theoretical concern with the use of HFNC has
been the potential to produce an unknown and
excessive pressure accumulation in the lungs. For
a more in-depth review of this topic, please refer
to Chap. 4 of this text.
6.2.2.2 Non-rebreather Face Masks
This delivery device combines a simple face mask
with a reservoir bag and an inflow system for
fresh gas, thus, allowing the system to theoreti-
cally deliver up to 100 % oxygen to the patient.
Pediatric and Neonatal Mechanical Ventilation
This is made possible by two separate one-way
valves. One valve is located between the mask
and the reservoir, while the other is located at
the exhalation port. This setup ensures fresh gas
delivery with each inspiration while preventing
the exhaled gas from being rebreathed. A safety
backup in the design allows a port to open in case
the flow of oxygen is disrupted, such that the
patient can then entrain room air with inspiratory
effort.
6.2.2.3 Partial Rebreather Face Masks
This mask is essentially the same setup as the
non-rebreather mask except there is no one-
way valve between the mask and the reservoir.
Therefore, exhaled gas can mix with the oxygen
in the reservoir bag, and thus, the delivered frac-
tion of inspired oxygen is less than 1.0.
6.2.2.4 Oxyhood
This device allows for the delivery of high-flow
oxygen to a contained space surrounding the
patient’s head while allowing easy access for
patient care. The FiO2 quickly re-equilibrates
after any movement of the hood, which could
allow for potential entrainment of room air. The
oxygen level must be continuously monitored
near the patient’s face as there is an increasing
gradient in the FiO2 from the top of the hood to
the bottom due to the slight increase in density
of oxygen (1.42 kg/m3) as compared to room air
(1.29 kg/m3).
6.2.2.5 Noninvasive Ventilation (NIV)
This mode of ventilation and oxygen delivery can
be effective in decreasing atelectasis, improving
alveolar ventilation, and decreasing respiratory
muscle fatigue in specific groups of neonatal and
pediatric patients (RDS, neuromuscular disease).
Unfortunately, there are minimal pediatric stud-
ies in the acute care setting and even less so in
direct comparison with intubation and mechani-
cal ventilation. NIV does allow for close control
of FiO2 from 0.21 to essentially 1.0. NIV is gen-
erally the preferred mode of support for patients
with neuromuscular weakness and upper airway
obstruction from poor pharyngeal tone and/or
125
enlarged tonsils and adenoids. Although there are
a variety of nasal and full-face masks for large
pediatric patients and adults, the options for
infants and small children in the USA are limited.
For a more in-depth review of this topic, please
refer to Chap. 4 of this text.
6.2.2.6 Oxygen Delivery via Invasive
Mechanical Ventilation
Invasive mechanical ventilation allows for com-
plete control of the gas mixture being admin-
istered to the patient via an endotracheal tube.
A FiO2 of 1.0 can be delivered consistently regard-
less of patient effort, but this should be minimized
to prevent oxygen toxicity to the lungs.
6.2.2.7 Hyperbaric Oxygen
Hyperbaric oxygen therapy is appropriate for those
clinical conditions involving severely impaired
oxygen delivery and altered hemoglobin-­oxygen
binding, such as carbon monoxide (CO) poison-
ing. Please see the corresponding section later in
this chapter for further detail.
6.3 Physiologic Effects
of Oxygen Breathing
6.3.1 Respiratory Effects
6.3.1.1 Breathing Control
Respiratory control is possible because of three
key components: sensors, central control, and
effectors (the muscles of respiration) (West
2000).
6.3.1.1.1 Sensors
Sensors include (1) central chemoreceptors, (2)
peripheral chemoreceptors, and (3) pulmonary
stretch receptors, each of which responds to
changes in arterial oxygenation and inadequate
ventilation.
1. Central chemoreceptors exist in the milieu
of the brain’s extracellular fluid and are
located between the blood vessels and the
cerebrospinal fluid (CSF). Carbon dioxide
diffuses from the vasculature into the CSF,
126
thus ­decreasing pH. This decrease in CSF
pH stimulates the central chemoreceptors to
increase ventilation.
2. Peripheral chemoreceptors are located in the
carotid bodies above and below the aortic
arch. The carotid bodies are the most cru-
cial element of the receptor system as they
are responsible for an appropriate increase
in ventilation in response to arterial hypox-
emia. The response to changes in PCO2
is a less important role of the peripheral
chemoreceptors.
3. Pulmonary stretch receptors, a type of lung
receptor, occur within airway smooth muscle.
These receptors aid in decreasing respiratory
frequency with lung distention. This is known
as the Hering-Breuer reflex and is thought to
be of greatest importance in newborn infants.
Included within this group of receptors are
the irritant receptors which lie between air-
way epithelial cells and are stimulated by
noxious gases, such as cigarette smoke. This
stimulus causes bronchoconstriction and
hyperpnea. The juxta-capillary or J-receptors
lie in the alveolar wall and are attributed to
causing the rapid, shallow breathing exhib-
ited in heart failure and interstitial lung
disease.
6.3.1.1.2 Central Control
Central control of ventilation involves the brain-
stem as the primary mediator or triage center
for the various types of input from the above-
mentioned sensors. Central control begins in the
cerebral cortex, which supports voluntary (corti-
cospinal) breathing, and incorporates input from
the brainstem which is involved with automatic
(reticulospinal) breathing. These signals are then
conducted to the anterior horn cells of the spinal
cord and on to the motor neurons that supply the
muscles of respiration. The motor neurons (in
the cervicothoracic portion of the spinal cord)
propagate these signals to the peripheral nerves
and finally across the neuromuscular junctions
leading to initiation of the respiratory muscles.
Alterations with any part of this system, from
the brainstem to the musculature, can result in
­respiratory insufficiency or failure.
P.C. Rimensberger et al.
6.3.1.1.3 Effectors (Respiratory Muscles)
Effectors are the muscles involved in ventilation
including the diaphragm. Excess effector activity
does provide negative feedback to the brainstem,
which efficiently allows control of ventilation
and oxygenation such that the PaCO2 and PaO2
levels are usually maintained within the nor-
mal range. The lower motor neurons propagate
the incoming signal to the peripheral (or effer-
ent) nerves supplying the muscles of respiration.
The efferent nerves extend to the diaphragm,
intercostals muscles, and the accessory muscles
of the neck. These nerves divide into branches
that reach the specific muscle fibers and apply
themselves to the muscle membrane at the motor
endplates. At these neuromuscular junctions, the
chemical transmitter acetylcholine is released.
Acetylcholine is responsible for depolarizing the
muscle membrane, which results in the release
of intracellular calcium, thus, initiating the con-
traction of the muscle fiber (Polkey and Moxham
2001). The muscles of respiration are divided
into three main groups: (1) inspiratory muscles,
(2) expiratory muscles, and (3) accessory mus-
cles of respiration.
1. Inspiratory muscles: Inspiratory muscles pro-
vide outward forces and include our main
inspiratory muscle, the diaphragm, which
contributes almost three quarters of the inspi-
ratory workload. Cervical nerves 3–5 supply
the phrenic nerve, which controls the dia-
phragm. The external intercostal muscles pro-
vide additional inspiratory force, thus allowing
elevation of the lower ribs and expansion of
the rib cage during inspiration. They are
innervated via the intercostal nerves, which
derive from the thoracic spinal nerve roots.
2. Expiratory muscles: This group includes the
internal intercostals which aid in expiration by
passive relaxation. In addition, the abdominal
muscles (internal obliques, external obliques,
and transverse abdominus) help to reduce the
thoracic volume by contracting to displace the
diaphragm into the thoracic cavity. An addi-
tional contributor to this group, the rectus
abdominus, helps to raise the pleural pressure
during exhalation thus aiding in airflow out of
the thorax.
Pediatric and Neonatal Mechanical Ventilation
3. Accessory muscles of respiration: This group
includes the sternocleidomastoid, scalene, tra-
pezii, latissimus dorsi, platysma, and pectora-
lis muscle groups. The accessory muscles
contribute most prominently in situations
associated with increased ventilatory demand,
such as exercise, impending respiratory fail-
ure, and neuromuscular weakness. By contrib-
uting to rib cage expansion, these muscles
support inspiration during active spontaneous
breathing, though they may also add support
during quiet breathing (Benditt 2006;
Phillipson and Duffin 2005). The upper air-
ways must maintain their patency throughout
inspiration, and there is a corresponding
increase in neural output to the pharyngeal
wall muscles (genioglossus and arytenoid
muscles) just prior to diaphragmatic contrac-
tion. Thus, the pharyngeal wall muscles are a
crucial adjunct when the accessory muscles
are in use.
6.3.1.1.4 Special Considerations
for Infants
The infant’s compliant chest wall and more cir-
cular thorax make the above respiratory pro-
cesses less efficient. With increased inspiratory
effort and diaphragmatic contraction, the lower
ribs descend rather than elevate secondary to the
compliant nature of the chest wall. The result is
subcostal retractions and deformation of the chest
wall rather than full lung expansion. Compared to
older children and adults, infants are more likely
to exhibit muscle fatigue due to the increased
workload on the diaphragm. In addition, the dia-
phragm of infants has fewer type I muscle fibers
which are slow-twitch, high-­ oxidative fibers
inherently more resistant to fatigue. As children
mature, the rib cage and diaphragm achieve a less
horizontal position, and the quantity of type I
fibers increases. These changes lead to increased
generation of maximal inspiratory pressures and,
hence, a less compliant chest wall.
6.3.1.2 Pulmonary Vasodilatation
Pulmonary vascular resistance (PVR) is pre-
dominantly determined by the diameter, length,
and number of pulmonary vessels. The ability
127
to cause or allow pulmonary vasodilatation is
­dependent on the status and reactivity of the pul-
monary vascular bed of each individual patient
and may change within a given patient over time.
The most important factor is the diameter of the
pulmonary vessels, which is directly related to the
vascular smooth muscle tone. In normal circum-
stances, minimal tone is present in the pulmonary
circulation, and thus, pulmonary vascular resis-
tance is low. Unlike the systemic vascular sys-
tem, the pulmonary vasculature reacts to hypoxia
with vasoconstriction. The exact mechanism is
unknown but occurs when the alveolar PO2 falls
below approximately 50–60 mmHg. It should be
noted that alveolar hypoxia is a more important
factor in influencing PVR than pulmonary arte-
rial hypoxia. This pulmonary v­ asoconstriction is
an adaptive attempt to prevent flow of blood to
hypoxic regions of the lung, thus improving ven-
tilation-perfusion matching. The pulmonary arte-
rial pH also affects the pulmonary vasculature in
a manner opposite to what occurs systemically
with acidosis causing pulmonary vasoconstric-
tion. The prevention and treatment of metabolic
acidosis help to limit any existing pulmonary
hypertension. In addition, elevated levels of car-
bon dioxide in the blood increase PVR indepen-
dent of an acidotic or alkalotic metabolic milieu.
6.3.1.2.1 Specific Therapies
to Decrease PVR
Vasodilators are used to decrease pulmonary
artery pressure (PAP) and to halt or reverse the
vascular changes related to an elevated PVR.
Oxygen: From the perspective of the pulmo-
nary vasculature, the purpose of optimal oxygen
delivery is to reverse hypoxic pulmonary vaso-
constriction. With chronic hypoxemia, supple-
mental oxygen is given to maintain a goal arterial
oxygen saturation level of ≥90 % (Rubin and
Rich 1997).
Nitric oxide (NO): Inhaled nitric oxide (iNO)
is a potent, selective pulmonary vasodilator that
acts to dilate the pulmonary vascular smooth
muscle (endothelium) via cyclic GMP (guanosine
monophosphate). Inhaled NO has a very short
half-life of approximately 4 s and is synthesized
from L-arginine by NO synthase. Nitric oxide
128
Table 6.1 Fraction of inspired oxygen by various
­delivery systems
FiO2 delivery Flow required
Delivery system (%) (L)
Nasal cannula 24–50 <6
Simple face mask <60 6–10
Venturi face mask <60 Variable
or trach collar
Partial rebreather <60 15
face mask
Non-rebreather ~100 15
face mask
Adapted from: Pediatric Critical Care Medicine.
Slonim AD, Pollack MM. 1st ed. Philadelphia, PA:
Lippincott Williams & Wilkins. 2006. Adapted from
Table 42.1. Page 717
is avidly bound to hemoglobin, so the intended
effect is local. Impaired endogenous production
of NO is intrinsic to the pathogenesis of pul-
monary arterial hypertension. Inhaled NO via a
ventilator circuit, face mask, or nasal cannula has
been used clinically since the 1990s in the treat-
ment of pulmonary hypertension. It has also been
used diagnostically in the cardiac catheteriza-
tion lab to determine pulmonary vasoreactivity.
Inhaled NO lowers pulmonary artery pressure
(PAP) in various disease states, including idio-
pathic pulmonary hypertension, congenital heart
disease (CHD), and postoperative pulmonary
hypertension (Atz et al. 2002) (Table 6.1). Rare
side effects include systemic hypotension, methe-
moglobinemia, and excess generation of nitrogen
dioxide (a highly reactive oxidant). The most sig-
nificant risk of iNO is rebound pulmonary hyper-
tension, which can occur when weaning a patient
from iNO. There are data advocating a slow wean
of iNO at doses less than 5 ppm. The addition of a
single dose of sildenafil 1 h prior to discontinuing
iNO therapy has been demonstrated to blunt the
rebound effect (Namachivayam et al. 2006).
Nitroprusside and milrinone: Unfortunately,
there is no intravenous (IV) pharmacologic agent
that acts as a selective pulmonary vasodilator.
The effect of various nonspecific IV vasoactive
medications can have a variable relative effect
on PVR. No IV vasodilator reliably decreases
PVR more than SVR. When the patient requires
left ventricular (LV) afterload reduction due to
P.C. Rimensberger et al.
decreased myocardial function, then a medica-
tion such as nitroprusside may have beneficial
clinical value. Unfortunately, nitroprusside
can cause systemic hypotension, thus lowering
coronary perfusion pressure. Milrinone, a phos-
phodiesterase type-3 inhibitor in cardiac and
smooth muscle, acts as an inotrope and vaso-
dilator via an increase in cytoplasmic cyclic
adenosine monophosphate (cAMP). Milrinone
is used primarily in heart failure associated with
congenital heart disease as well as for patients
with ­cardiomyopathy. It is a nonspecific vaso-
dilator and, thus, affects both PVR and SVR.
Milrinone’s long half-life often prevents its
usage in patients with hypotension.
Intravenous prostacyclin (epoprostenol): An
imbalance in the levels of prostacyclin exists
in adults and children with severe pulmonary
hypertension. Additionally, there is a decreased
expression of prostacyclin synthase in the pul-
monary vasculature. Prostacyclin (prostaglandin
I2) induces vascular smooth muscle relaxation
via the production of cAMP. It is also an inhibi-
tor of platelet a­ggregation. Epoprostenol has
been approved for the treatment of pulmonary
arterial hypertension since the 1990s. Long-term
IV epoprostenol improves quality of life and
survival in adults and children with primary pul-
monary hypertension (Barst et al. 1999; Sitbon
et al. 2002; Yung et al. 2004). Unfortunately, it
must be administered as a continuous IV infu-
sion via a central venous line secondary to its
short half-life of 3 min. Clotting, hemorrhage,
sepsis, and life-threatening cessation of IV infu-
sion are all significant potential complications.
Common and dose-related side effects include
nausea, headache, flushing, diarrhea, musculo-
skeletal pain, and anorexia.
Inhaled prostacyclin (iloprost): Iloprost is a
prostacyclin analogue delivered as aerosolized
particles of 0.5–3 μm to ensure alveolar deposi-
tion and pulmonary selectivity. Inhaled prosta-
cyclin has shown significant improvements in
quality of life and symptoms in adults with pul-
monary hypertension (Olschewski et al. 2002).
Due to its half-life of only 25 min, it must be
administered by inhalation at least 6–9 times
a day for clinical effect. It allows selective
Pediatric and Neonatal Mechanical Ventilation
vasodilatation of the pulmonary vasculature
with avoidance of central line complications.
There are no data on chronic effects of inhaled
prostacyclin in children, although it does appear
to be a tolerable equivalent to IV prostacyclin.
Side effects included headache, cough, dizzi-
ness, and systemic vasodilation. An additional
potential side effect is lower airways obstruc-
tion, which can be potentially reversed with
inhaled corticosteroid and β-agonist therapies
(Ivy et al. 2008).
Phosphodiesterase-5 inhibitor (sildenafil):
Sildenafil is an oral phosphodiesterase-5 inhibi-
tor that prevents cGMP inactivation/breakdown,
thus increasing the activity of endogenous NO at
the level of vascular smooth muscle with resul-
tant pulmonary vasodilatation. It is demonstrated
to be as effective as iNO and may be useful in
preventing rebound pulmonary hypertension
during iNO weaning (Namachivayam et al.
2006; Schulze-Neick et al. 2003), in postopera-
tive pulmonary hypertension (Atz et al. 2002;
Schulze-­Neick et al. 2003), and in pulmonary
hypertension associated with chronic lung dis-
ease (Ghofrani et al. 2002).
Endothelin-receptor antagonist (bosentan):
Endothelin-1 (ET-1) expression is increased
in the pulmonary arteries of patients with pul-
monary hypertension and causes direct vaso-
constriction while stimulating the proliferation
of vascular smooth muscle and contributing to
fibrosis. ET-1 is a pro-inflammatory mediator
produced by vascular endothelial and smooth
muscle cells. Its activity is mediated by ETA and
ETB receptors which are sites of potential mod-
ulation of the effects of ET-1. Bosentan, a dual
ET-receptor antagonist, lowers PAP and PVR in
adults and children with good overall tolerance.
Bosentan may be used as a first-line agent in
advanced pulmonary hypertension or in conjunc-
tion with other therapies, such as epoprostenol.
Potential side effects include elevated hepatic
transaminases, peripheral edema, systemic hypo-
tension, and fatigue (Fig. 6.1).
6.3.1.3 Absorption Atelectasis
Atelectasis or “imperfect expansion” describes
non-aerated but normal lung parenchyma.
129
Atelectasis can be secondary to intrinsic bron-
chial obstruction, mass effect from nearby struc-
tures, increased intrapleural pressure, abnormal
alveolar surface tension, and neuromuscular
disease. Absorption atelectasis describes a phe-
nomenon which can occur with the inspiration
of elevated concentrations of inspired oxygen
(generally FiO2 1.0). Since the increase in venous
PO2 when breathing 100 % oxygen is only about
10–15 mmHg, the sum of the partial pressures
in the alveolar gas mixture exceeds the partial
pressures in the venous blood. Thus, gas can
­diffuse from the alveoli to the blood resulting in
rapid collapse of the alveoli. Alveolar collapse
is most likely to occur at the base of the lung,
where the lung is least well expanded at baseline.
Absorption collapse can also occur in regions
of obstruction even when breathing room air,
but the process is much slower. The rate of col-
lapse is limited by the presence of N2 which has
a low solubility and acts as a “splint” support-
ing the alveoli and delaying collapse. Even small
amounts of N2 can provide this beneficial effect.
6.3.1.4 Pulmonary Oxygen Toxicity
Animal studies have demonstrated that expo-
sure to FiO2 1.0 for even short periods of time
results in damage to the alveolar epithelium
with eventual replacement by type II alveo-
lar cells. In addition, there is the loss of tight
junctions in the alveolar capillary endothelium
leading to increased permeability and hence
pulmonary edema. Over time, interstitial fibro-
sis can develop. In humans, there is evidence of
impaired gas exchange after only 30 h of inha-
lation of 100 % oxygen. Normal adult subjects
who breathe FiO2 1.0 at atmospheric pressure
for 24 h can develop respiratory distress and a
significant decrease in vital capacity (VC) by
500–800 mL, likely due to absorption atelectasis
(West 2000). Although there is no definite FiO2
threshold associated with oxygen toxicity, most
pediatric intensivists use a FiO2 of 0.50–0.60 as
an unacceptable oxygen level during prolonged
mechanical ventilation. There is the additional
danger of oxygen toxicity in premature infants
with resultant retinal disease from local vaso-
constriction of blood vessels behind the lens.
130
Fig. 6.1 Therapies to promote pulmonary vasodilatation: (Humbert et al. 2004)
This significant adverse effect can be avoided by
lowering the acceptable PaO2 levels. Please see
Section 6.3 for further discussion.
6.3.2 Non-respiratory Effects
of Oxygen
6.3.2.1 Hemodynamic Effects
The delivery of oxygen is a vital component of
patient care within pediatric and neonatal inten-
sive care units. Clinicians are constantly altering
the support provided to each patient in an attempt
to optimize global oxygen delivery as defined by
the following equation:
P.C. Rimensberger et al.
DO 2 = CO × arterial O 2 content
 SaO 2 saturation 
arterial O 2 content =  
 × 1.39 ( mL/g ) × Hb 
+ ( 0.003 × PaO 2 )
where DO2 represents oxygen delivery; CO,
c­ ardiac output; SaO2, arterial oxygen saturation;
Hb, hemoglobin; and PaO2, partial pressure of
oxygen in arterial blood. Thus, decreased oxy-
gen delivery can result from inadequate cardiac
output, low arterial oxygen saturation level, inad-
equate hemoglobin concentration, and/or low
PaO2. Oxygen delivery to the tissues and organs
of the body can be optimized by augmenting
Pediatric and Neonatal Mechanical Ventilation
cardiac output (via volume loading and/or vaso-
active agents). Transfusion of packed red blood
cells will augment oxygen delivery by increas-
ing the arterial oxygen content; however, recent
publications have raised increasing concerns
over the use of transfusions in the critical care
environment. Lastly, optimization of the oxygen
delivery devices as discussed earlier in this chap-
ter will lead to an increase in the arterial oxygen
content and, thus, an increase in oxygen delivery
to organs and tissues.
6.3.2.1.1 Response to Oxygen
An increase in PaCO2 and/or a decrease in PaO2
can cause an increase in ventilation. However,
when PaCO2 is within a normal range, the hypoxic
stimulus to drive ventilation is blunted. In this
circumstance, a PaO2 of less than 50 mmHg is
often required to elicit the appropriate ventila-
tory response. However, if the PaCO2 is acutely
elevated, a PaO2 of less than 100 mmHg will be
sufficient to elicit an increase in respiratory drive.
In conditions with chronic CO2 retention, such as
bronchopulmonary dysplasia (BPD) and late-­
stage cystic fibrosis, arterial hypoxemia becomes
the primary stimulus to ventilation. With chronic
elevation of their CO2, these patients lose the
stimulus to ventilate when exposed to increas-
ing CO2 levels. Their initial decrease in blood pH
is buffered by renal compensation (HCO3 reab-
sorption), leaving little pH stimulation for the
peripheral chemoreceptors. In these situations,
arterial hypoxemia becomes the main stimulus to
increase ventilation. Thus, delivering increased
FiO2 to such patients can result in significant
hypoventilation and respiratory depression.
6.3.2.2 Oxygen Consumption
Traditional methods for measuring oxygen con-
sumption, such as spirometry, preclude routine
measurement in the neonatal and pediatric inten-
sive care units. Advanced techniques with porta-
ble metabolic monitors and mass spectrometry are
available. The metabolic monitors or “metabolic
carts” use a gas-dilution principle to measure
flow, a differential oxygen sensor for measuring
change in oxygen concentration, and an infrared
131
carbon dioxide sensor. If we know the flow and
differential concentrations, oxygen content can
be calculated (Nichols 2008). Oxygen content in
arterial and mixed venous blood is measured with
co-oximetry techniques and a blood gas analyzer
(PaO2) using the following formula:
O 2 content ( mL O 2 /L blood )
= 1.34 × Hg ( g/L ) × %saturation/100 
+  PaO 2 ( mm Hg ) × 0.003
where Hb represents hemoglobin.
6.3.2.3 Retinopathy of the Prematurely
Born Infant (ROP)
ROP is characterized by the proliferative vas-
cularization of the retina in preterm newborn
infants. This disease is a major cause of visual
­impairment and sequelae in USA and Europe,
including ametropias, strabismus and impaired
color discrimination, or retinal detachment,
resulting in decreased visual acuity (Phelps
1992). Prevention, actual screening recom-
mendations, and novel treatment strategies
decreased the incidence and improved the prog-
nosis of ROP.
6.3.2.3.1 Pathophysiology
The retinal vessels develop between 16 weeks and
40 weeks of gestation. Vasculature of the retina is
therefore incomplete and vulnerable in the pre-
mature newborn infant. An initial phase of ROP
consists in microvascular obliteration causing a
delay in the progression of the retina vessels from
the center of optic disc towards the retinal periph-
ery. The relative hyperoxia after birth mediates a
decrease in the production of vascular endothelial
growth factor (VEGF) and a vasoconstriction of
the retinal capillaries. Ischemia of the retina trig-
gers a compensatory neovascularization through
upregulation of VEGF and IGF-1 expressions
(Penn et al. 1994).
Neovascularization begins by 32–34 weeks
postconceptional age. This proliferative reti-
nopathy occurs at the junction between the
vascularized and the avascular zone of the ret-
ina. Neovascularization leads to a fibrous scar
132
extending from the retina to the vitreous gel.
Retraction of this scar tissue can cause retinal
detachment.
6.3.2.3.2 Risk Factors
The main risk factors are prematurity, intra-
uterine growth restriction, and exposure to
supplemental oxygen (Darlow et al. 2005).
Better monitoring of supplemental oxygen and
decrease in baseline oxygen saturation have
reduced the incidence of ROP (Sears et al. 2009).
Recently, a large randomized study showed that
a lower target range of oxygenation (85–89 %),
as compared with a higher range (91–95 %),
resulted in a significant decrease in severe reti-
nopathy among survivors despite no change in
the composite outcome of severe retinopathy or
death (SUPPORT Study Group of the Eunice
Kennedy Shriver NICHD Neonatal Research
Network 2010). An increased magnitude and
variability of fluctuations in oxygenation have
been implicated in the development of ROP
(Cunningham et al. 1995). Hypoxemic episodes
during the first 8 weeks of life in preterm infants
have been associated with severe ROP requir-
ing laser therapy (Di Fiore et al. 2010). ROP has
also been associated with prolonged mechani-
cal ventilation, apnea, male sex, Caucasian
race, sepsis, anemia, red blood cells transfusion,
multiple gestations, and intraventricular hemor-
rhage (Darlow et al. 2005).
Furthermore, human and animal studies indi-
cate that 70 % of the variance in susceptibility
to ROP may be the result of genetic influences
in the pathogenesis of ROP (Holmstrom et al.
2007).
6.3.2.3.3 Screening Guidelines
Systematic screening for ROP is recommended
in infants less than 1,500 g or 30 weeks gesta-
tional age and selected infants with a birth weight
between 1,500 and 2,000 g or a gestational age
greater than 30 weeks at high risk for ROP
(Section on Ophthalmology et al. 2006). The cur-
rent benchmark is regular screening by indirect
ophthalmoscopy until the retina is nearly or fully
vascularized. Newborn infants less than 28 weeks
gestation should be screened at 31 weeks post-
P.C. Rimensberger et al.
conceptional age. Newborn infants at or above
28 weeks gestation should be screened at 4 weeks
after birth.
ROP is classified according to location, sever-
ity, and extent of the lesions. Five stages of ROP
exist, ranging from stage 1 characterized by a
demarcation line between vascularized and avas-
cularized retina to stage 5 marked by a total reti-
nal detachment. Plus disease is defined as venous
dilation and arteriolar tortuosity in at least two
quadrants of the posterior pole. Plus disease is
the primary feature to indicate the necessity of
treatment in high-risk ROP.
Digital imaging of the retina is currently used
for sequential ROP screening (RetCam 120,
Massie Research Laboratories, CA). Ocular
imaging can be transmitted to distant specialized
centers for analysis.
6.3.2.3.4 Current Treatments
Treatment of current ROP is based on peripheral
retinal ablation by cryotherapy or laser photoco-
agulation (Good 2004; Hubbard 2008). Advances
in treatments are being investigated with better
knowledge on the pathogenesis of ROP, includ-
ing factors regulating VEGF and IGF-1 pro-
duction. Hence, monoclonal antibody directed
against VEGF has been used in combination
or not to laser photocoagulation in severe ROP.
Injection of VEGF antibody has been associated
with regression of retinal proliferation within
days (Kong et al. 2008). The role of omega-3-­
polyunsaturated fatty acids in the prevention of
ROP is being currently studied. Experimental
studies in mouse showed that elevation of omega-
3-­PUFA content was protective against neovas-
cularization (Connor et al. 2007). Additional
omega-3-polyunsaturated fatty acids intake may
be of benefit in preventing retinopathy.
6.3.3 Hyperbaric Oxygen
Therapy (HBO)
During hyperbaric oxygen therapy, a patient
is placed in a treatment chamber where he or
she breathes 100 % oxygen as the pressure of
the chamber is increased to greater than 1 atm.
Pediatric and Neonatal Mechanical Ventilation
When the inspired oxygen is increased to 3 atm
in a hyperbaric chamber, the amount of dissolved
O2 in arterial blood increases from 1.5 mL/dL to
6 mL/dL, and O2 tension in tissues is increased to
nearly 400 mmHg. In this altered environment,
O2 has various biochemical, cellular, and physio-
logic benefits as described below. HBO therapy is
indicated for use in carbon monoxide (CO) poi-
soning, myonecrosis, necrotizing fasciitis (gas
gangrene of soft tissues), arterial air emboli, and
decompression sickness.
6.3.3.1 CO Poisoning
Hemoglobin has 240 times the affinity for CO
than oxygen. Once bound, carboxyhemoglo-
bin (COHb) shifts the oxyhemoglobin curve to
the left leading to decreased oxygen-carrying
capacity. CO also binds to cytochrome oxi-
dase, interfering with electron transport and
­adenosine triphosphate (ATP) production with
resultant cellular dysfunction. In CO poison-
ing, the patient’s arterial oxygen content (PaO2)
is often normal or elevated, and routine pulse
oximetry measurements can be falsely normal
since most technologies do not differentiate
between oxyhemoglobin and carboxyhemoglo-
bin. In general, co-oximetry is required to quan-
tify COHb concentration. The most important
therapeutic intervention is administration of
100 % oxygen after removing the patient from
the carbon monoxide source. Only very high
PaO2 levels can compete with CO for Hb bind-
ing, thus driving CO out of the blood. At 3 atm
of pressure in an HBO chamber, the half-­life
of COHb is reduced from 5.3 h to just 23 min.
However, the COHb level is not reflective of
the severity of illness, and patients should be
treated based on presence of symptoms, espe-
cially neurologic abnormalities. Referral to a
facility with hyperbaric oxygen (HBO) capa-
bilities is recommended for concerning clinical
signs such as seizures, altered mental status,
syncope, chest pain, severe acidosis, preg-
nancy. The risk of fatality is high with levels
over 70 %. However, it must be noted that no
consistent dose response relationship has been
demonstrated between carboxyhemoglobin
level and clinical effect.
133
6.3.3.2 Wound Healing
Since HBO increases the capillary-tissue oxy-
gen gradient, this likely explains potential ben-
efits that have been seen in wound healing. HBO
helps to promote angiogenesis and can help
restore neutrophil-mediated bacterial killing.
HBO is also helpful in treating gas gangrene as
the organisms cannot survive in such a high PO2
environment.
6.3.3.3 Air Emboli
Based on Boyle’s law, gas volume is inversely
proportional to pressure. Therefore, the “bubble
volume” in cases of air emboli and decompres-
sion sickness is reduced within the highly pres-
surized HBO chamber, helping to relieve small
vessel obstruction and restore blood flow to com-
promised tissue beds.
6.3.3.4 Toxicity/Complications
Complications of HBO can include seizures,
gas embolization, pneumomediastinum, pneu-
mothorax, perforated tympanic membranes, and
oxygen toxicity (reversible myopia, decreased
pulmonary compliance). Extreme care must be
taken to avoid fires and explosions at such high
partial pressures of oxygen.
Essentials to Remember
• The most important factor in determin-
ing if an oxygen gas delivery system is
sufficient to meet a patient’s inspiratory
demand is the gas flow rate.
• The three key components of respiratory
control are sensors, central control, and
effectors (muscles of respiration).
• Pulmonary vasodilators decrease pul-
monary artery pressure and can halt or
reverse the vascular changes related to
elevated pulmonary vascular resistance.
• Decreased oxygen delivery to the organs
and tissues of the body results from
inadequate cardiac output, low arterial
oxygen saturation level, inadequate
hemoglobin concentration, or low PaO2.
134 P.C. Rimensberger et al.

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