HIGH FREQUENCY VENTILATION 497
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118. Lakatta EG, Levy D. Arterial and cardiac aging: major
shareholders in cardiovascular disease enterprises: Part I:
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119. O’Rourke M. Arterial stiffness, systolic blood pressure, and
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120. Stergiopulos N, Westerhof N. Role of total arterial compli-
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121. Stergiopulos N, Westerhof N. Determinants of pulse
pressure. Hypertension 1998;32:556–559.
122. Sunagawa K, Maughan WL, Burkhoff D, Sagawa K. Left
ventricular interaction with arterial load studied in isolated
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123. Sunagawa K, Maughan WL, Sagawa K. Optimal arterial
resistance for the maximal stroke work studied in isolate
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124. Burkhoff D, Sagawa K. Ventricular efficiency predicted by
an analytical model. Am J Physiol 1986;250:R1021–R1027.
125. Kelly R, Ting C, Yang T, Liu C, Lowell W, Chang M, Kass D.
Effective arterial elastance as index of arterial vascular load
in humans. Circulation 1992;86:513–521.
126. Segers P, Stergiopulos N, Westerhof N. Relation of effective
arterial elastance to arterial system properties. Am J
Physiol Heart Circ Physiol 2002;282:H1041–H1046.
127. De Tombe PP, Jones S, Burkhoff D, Hunter WC, Kass DA.
Ventricular stroke work and efficiency both remain nearly
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128. Asanoi H, Sasayama S, Kameyama T. Ventriculoarterial
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129. Sasayama S, Asanoi H. Coupling between the heart and
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130. Stergiopulos N, Meister JJ, Westerhof N. Determinants of
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See also BIOIMPEDANCE IN CARDIOVASCULAR MEDICINE; BLOOD PRESSURE
MEASUREMENT; FLOWMETERS, ELECTROMAGNETIC; MONITORING, HEMODYNAMIC.
HEMODYNAMIC MONITORING. See MONITORING,
HEMODYNAMIC.
HIGH FREQUENCY VENTILATION
J. BERT BUNNELL
Bunnell Inc.
Salt Lake City, Utah
INTRODUCTION
High frequency ventilators (HFVs) were designed to elim-
inate many of the problems that conventional ventilators
breathe normally, we draw gas into the lungs by creating a
negative pressure with our diaphragm. Iron lungs were
created to replicate that activity, and they worked very
well for thousands of polio patients. However, when
patients are sealed off in airtight iron lungs numerous
practical problems unrelated to breathing arise.
Positive pressure ventilators made assisting ventilation
much easier. Attaching the ventilator to the patient’s lungs
via an endotracheal (ET) tube greatly simplified patient
care. But, lungs, especially premature lungs, are not
designed to tolerate much positive pressure.
The lungs of prematurely borne infants have yet to be
fully formed, and they lack the surfactant that enables
alveoli to expand with very little pressure gradient. Hence,
a considerable pressure gradient must be applied to venti-
late them. Applying that pressure from the outside in, as
conventional ventilators (CVs) have been doing since the
early 1970s, causes problems. Tiny infant’s airways get
distended, alveoli are ruptured, and inflammatory sensors
are triggered. Even if an infant receives artificial surfac-
tant to lessen the need for assisted ventilation, and they
grow new lung fast enough to survive, they may well
develop chronic lung disease at a time when most of us
were just taking our first breaths. Most premature infants
outgrow their chronic lung disease, but many struggle
mightily with every virus they encounter in their first
few years of life, and they have an increased incidence of
neurodevelopmental problems, such as cerebral palsy.
Some infants lose those struggles and die of pneumonia.
Acute respiratory distress syndrome (ARDS) is the pri-
mary problem for mechanical ventilation of adults. This
disease affects
50 people per 100,000 with a mortality of
30–50%, and there have been few improvements in this
mortality rate over the past several decades.
High frequency ventilators were developed in response
to problems associated with CVs, but HFVs do not try to
replicate normal breathing. They assist ventilation using
much smaller tidal volumes delivered at rates
10 times
higher than normal. Animal and clinical studies indicate
that smaller tidal volumes cause less lung injury (1,2).
Swedish anesthesiologists in the 1970s turned up the
rate of their anesthesia ventilators to enable them to use
smaller breaths to assist patients during neurosurgery (3).
Their regular ventilators caused pulsations in blood pres-
sure, causing brain movement every time the ventilator
pushed in a breath, which was an obvious problem during
microsurgery.
Auto accident victims whose heads went through car
windshields also pose problems during surgery when
access to the lungs has to pass right through the area of
the face and neck where major reconstruction is required.
So, another anesthesiologist, Dr. Miroslav Klain, began
sticking needles into patients’ necks to gain access to their
tracheas, and he made it work by delivering very tiny
breaths at very rapid rates (4).
The HFVs have shown great promise in supporting
premature infants where fragile, underdeveloped and sur-
factant deficient lungs need to be gently ventilated until
growth and maturation allow the newborn to catch up both
anatomically and physiologically. In newborn infants,
498 HIGH FREQUENCY VENTILATION
where various modes of positive pressure ventilation have
produced lung injury, HFVs have been widely accepted.
Early studies using HFV to treat adults with severe ARDS
have also shown promise in lessening lung injury and
improving survival (5,6).
This article will review our current understanding of
how HFVs work, the types of HFV equipment that are
available for treating infants and adults, the results of
several key animal and clinical studies that indicate how
to optimize applications of HFVs, and what controversies
remain to be resolved before HFVs can be considered as a
primary mode of ventilation.
THEORETICAL BASIS FOR HFV: HOW HFVs WORK
High frequency ventilators are different from all other
types of mechanical ventilators. They do not mimic normal
breathing; rather, they facilitate gas exchange in a manner
similar to panting in animals.
There are two elements to explaining how HFVs work
with the higher than normal frequencies and smaller than
normal tidal volumes. We begin with the assumption that
ventilation or CO2 elimination is proportional to minute
volume or frequency times tidal volume, as
 
V CO2 / V min ¼ f  VT ð1Þ
 
where V CO2 ¼ rate of carbon dioxide elimination; V min ¼
minute volume; f ¼ ventilator frequency; and VT ¼ tidal
volume.
If the practical limits of the high frequency end of this
relationship are considered, there must be a lower limit on
tidal volume size that will effectively provide alveolar ven-
tilation. That lower limit is related to the effective or phy-
siologic dead space of the lungs by the following equation:

V A ¼ f  ðVT  VD Þ ð2Þ
 There is a mechanical advantage to ventilating lungs at
where V A ¼ alveolar ventilation, and VD ¼ effective or phy-
siologic dead space.
Thus, as tidal volume approaches the size of the effective
dead space of the lungs, ventilation of the alveoli becomes nil.
Physiologic Dead Space and the Lower Limit of Tidal Volume
Anatomic dead space of mammalian lungs is generally
considered to be 2 mL kg1 body weight (7). When one
breathes normally, effective or physiologic dead space must
be at least as large as anatomic dead space, because one
pushes the dead space gas back into the alveoli ahead of the
fresh gas during inhalation. What happens in the panting
animal is another matter, as Henderson and associates
described in 1915 (8).
Henderson et al. (8) demonstrated that panting animals
breathe very shallowly as well as rapidly. They hypothe-
sized that physiologic dead space changes at rapid respira-
tory rates in mammals, and they measured these effects on
themselves. They also performed a series of experiments
using smoke to demonstrate how inhaled gas penetrates
through the anatomic dead space with rapid inhalations in
a manner that makes physiologic dead space become less
than anatomic dead space (Fig. 1).
Figure 1. Henderson’s smoke experiment. (a) A long thin spike or
jet stream of smoke shoots downstream when suddenly blown into
a glass tube. (b) The jet stream disappears when flow stops and
diffusion takes place. (c) This effect can be duplicated in the
opposite direction if fresh gas is drawn back into the smoke filled
tube with a sudden inhalation. (d) Imperfections in the tube walls
(such as a bulb) have little effect on the shape of the jet stream.
(Adapted with permission from Ref. 8, p. 8. # 1915, American
Physiology Society.)
Regardless of how much physiologic dead space can be
reduced in the panting animal, there is still the matter of
providing adequate alveolar ventilation as defined by Eq. 2.
Thus, the extent to which smaller tidal volumes can be
used to ventilate the alveoli has to be balanced by an
increase in breathing frequency, as defined by Eq. 1.
Panting animals breathe very rapidly, of course, but
humans do not pant as a rule. So, how can the benefits of
increasing ventilator frequency for humans be explained?
The Natural Frequency of the Lungs
frequencies higher than normal breathing frequency. This
phenomenon was revealed by a diagnostic technique for
measuring airway resistance called forced oscillations (9).
Applying forced oscillations to measure airway resis-
tance requires a person to hold a large bore tube in their
mouth and allow small volumes of gas to be oscillated in
and out of their lungs by a large loudspeaker. The fre-
quency of oscillations produced by the speaker is varied
through a spectrum from low (
1 Hz) to high (
60 Hz),
and the pressure amplitudes of the oscillations are mea-
sured along with the flow rate of the gas that is passing in
and out of the lungs (Fig. 2 depicts the test set up).
Although the volume of gas moving in and out of the
lungs is a constant, pressure amplitude varies with fre-
quency and is minimized at the resonant or natural
frequency of the lungs.
The concept that the lungs have a natural frequency is
explained by consideration of lung mechanics. There are
three elements to lung impedance (those things that
impede the flow of gas in and out of the lungs): airway
resistance, lung compliance, and inertance. We normally
are not concerned about inertance, since it is concerned
with the energy involved in moving the mass in the system,

Constant volume generator
P
.
V
(loudspeaker)
. prominent physiologists and bioengineers tackled the ana-
Figure 2. Measuring airway resistance at the resonant or natural
frequency of the lungs using forced oscillations. (Used with per-
mission. # 2003, Bunnell Inc.)
most of which is gas, and gas does not have much mass.
Therefore, it does not take much energy to overcome inertance
when one breathes: unless one is breathing very rapidly.
In the forced oscillations determination of airway resis-
tance, the point of minimum pressure amplitude marks the
frequency at which the energy necessary to overcome the
elasticity of the lungs is supplied by the energy temporarily
stored in the inertial elements of the system (i.e., the gas
rushing in). (We normally measure lung elasticity inver-
sely as lung compliance.) As the lungs recoil at the end of
the gas-in phase, the elasticity of the lungs imparts its
energy to turn the gas around and send it back out to the
loudspeaker.
When the natural frequency or resonance is reached,
the speaker and lungs exchange the gas being forced in and
out of the lungs with ease. The lungs and the speaker
accept the gas and recoil at just the right times to keep the
gas oscillating back and forth with minimal energy
required to keep the gas moving. At this point, the only
element impeding gas flow is frictional airway resistance,
which works against the gas coming in and going out. Its
value can be calculated by dividing pressure amplitude by
the gas flow rate when pressure amplitude is minimized.
The smaller the lungs are, the higher the natural fre-
quency. The natural frequency of adult lungs is
4 Hz,
while that of premature infant lungs is closer to 40 Hz.
Putting Two and Two Together: How Can We HFV?
Combining the two concepts that describe the relationships
of gas velocity, physiologic dead space, breathing fre-
quency, and lung mechanics led us to HFV. We reported
that one can then achieve adequate minute ventilation and
compensate for very small tidal volumes in paralyzed
animals by increasing ventilatory frequency to several
hundred breaths per minute in 1978 (10). Pushing small
volumes of gas into the lungs at high velocities reduced
effective dead space volume and pushed the lower limit of
effective tidal volume below anatomic dead space volume
HIGH FREQUENCY VENTILATION 499
(
2 mL kg1). Increasing frequency to near resonant fre-
quency also allowed us to minimize airway pressure.
As HFVs were developed and clinical use in newborn
intensive care units (NICUs) became widespread in the
1980 and 1990s, numerous theories and experiments
refined our concepts of how it all works. A number of
lysis and interpretation of gas exchange within the lungs
during HFV while clinicians were seeking to identify appro-
priate applications of the new technique and all its intri-
cacies. A few notable contributions will be discussed here.
Fredberg (11) and Slutsky et al. (12) analyzed mechan-
isms affecting gas transport during high frequency oscilla-
tion, expanding traditional concepts of convection and
diffusion to include their combined effects, and termed the
collection: augmented transport. Their analyses and those of
Venegas et al. (13) and Permutt et al. (14) revealed that our
traditional appreciation of the relationship between minute
volume and CO2 elimination must be modified during HFV
to reflect the increased contribution of tidal volume, as
VCO2 / f a  VTb ð3Þ
where the exponent b is greater than the exponent a. For
practical purposes, most people now accept this relation-
ship as

V CO2 / f  VT2 ð4Þ
Slutsky also explored the limitations of HFV by mea-
suring the effect of bronchial constriction on gas exchange.
When the peripheral airways of dogs were constricted by
administration of histamine, HFOV was no longer as effec-
tive at higher frequencies. (This issue is discussed later
when the effectiveness of various types of HFVs for differ-
ent pathophysiologies are explored.)
Venegas and Fredberg explored the importance of fre-
quency during HFV in their classic paper of 1994, subtitled:
‘‘Why does high frequency ventilation work?’’ (15). They
found that the resonant frequency of the smallest prema-
turely born infant with RDS (respiratory distress syn-
drome) is approximately 40 Hz. At that frequency, the
minimum pressure amplitude is required to ventilate the
lungs. However, the shape of theoretical curves of pressure
amplitude measured at the carina versus frequency for
infants with various lung conditions is most interesting as
illustrated in Fig. 3, which was constructed using their
concepts.
Figure 3 illustrates four essential considerations con-
cerning the application of HFV for newborn infants.
1. Decreasing lung compliance moves the optimal fre-
quency for HFV to the right (i.e., toward higher
frequencies).
2. Increasing airway resistance moves the optimal fre-
quency for HFV to the left (i.e., toward lower fre-
quencies); and
3. There is diminishing value in applying HFV for
infants at frequencies above ~ 10 Hz as far as airway
pressure is concerned.
4. Choosing to operate at the ‘‘corner frequency’’ is an
appropriate choice for HFV since there is little benefit
500 HIGH FREQUENCY VENTILATION
40
Preemie with
30 RDS and PIE
fc
f
opt
fc
20
PIP Preemie with RDS
(cm H2O)
fopt
10
Preemie with
normal lungs
10 20
Frequency (Hz)
Figure 3. Theoretical peak carinal pressures for infants with
normal lungs and lungs with poor compliance (RDS), poor airway
resistance (asthma), and both conditions (RDS þ PIE). Note how
infants with RDS are well served using the corner frequency (fc) of

10 Hz (600 breaths per minute, bpm). Larger patients will exhibit
curves with nearly identical shapes, but they will all be shifted to
the left. (Adapted with permission from Ref. 15.)
above that frequency and more chance for gas trap-
ping. Venegas and Fredberg define corner frequency
as that frequency above which airway pressure
required to provide adequate ventilation no longer
rapidly decreases.
In other words, ventilating premature babies at 10
breaths s1 is practically as efficient as ventilating them
at their theoretical resonant frequency of 40 ‘‘breaths’’ s1,
where the danger of gas trapping is greatly increased.
Patients with increased airway resistance require more
careful consideration of the decreased benefits of exceeding
the corner frequency and are more safely ventilated at
lower frequencies.
One can calculate the resonant and corner frequencies if
values of lung compliance (CL), airway resistance (Raw),
and inertance (I) are known, but that is rarely the case with
patients in intensive care. Venegas and Fredberg provided
the following formulas:
qffiffiffiffiffiffiffi
f0 ¼ 1=ð2p C̄I Þ ð5Þ
where f0 ¼ resonant frequency, and
fc ¼ 1=ð2pCRÞ
where fc ¼ corner frequency. (Plug in typical values for lung
compliance, inertance, and airway resistance of a pre-
mature infant, 0.5 mL cm1 H2O, 0.025 cm H2O L s2,
and 50 cm H2O L1 s1, respectively, and f0 ¼ 45 s1 and
fc ¼ 6.4 s1.)
Finally, Venegas and Fredberg illustrated the value of
using appropriate levels of positive end-expiratory pres-
sure (PEEP). The PEEPs of 5–10 cm H2O dramatically
decrease the pressure amplitude necessary to ventilate
premature infants at all frequencies when lung compliance
is normal, and at all frequencies above
6 Hz when lung
compliance is reduced.
High-frequency PEEP / HFV valve
Constant valve PEEP or
pressure synchronized
or flow
closure
Patient Exhaust
Figure 4. Basic design of HFPPVs. (Used with permission.
# 2003, Bunnell Inc.)
HFV EQUIPMENT
30
Design Classifications
Figures 4–7 illustrate four different ways HFVs have been
created. Figure 4 illustrates high frequency positive-
pressure ventilation (HFPPV), which is basically a CV that
operates at HFV rates. Early devices worked in this man-
ner, but they seldom worked at the very high frequencies
used with infants.
Figure 5 illustrates high frequency flow interruption
(HFFI), where positive pressure oscillations are created by
releasing gas under pressure into the breathing circuit via
an HFV valve mechanism. The valve may be a solenoid
valve or valves, a spinning ball with a hole in it, and so on.
Early HFVs used long, small diameter exhaust tubes to
increase impedance to gas flow oscillating at HFV frequen-
cies in the expiratory limb so that the HFV oscillations
would preferentially flow in and out of the patient.
High frequency oscillatory ventilators (HFOVs) work in
a similar manner to HFFIs, as shown in Fig. 6, except that
the pressure oscillations in the patient’s breathing circuit
are caused by an oscillating piston or diaphragm. Again,
the impedance of the expiratory limb of the circuit tubing
must be higher than the impedance of the patient and his
ET tube when the gas flowing through the circuit is
oscillating at HFV frequencies. The major difference
between HFOV and HFFI is that pressure in the venti-
lator circuit during HFOV oscillates below atmospheric
pressure in an effort to actively assist the patient’s expira-
tion. (This topic is discussed further below when gas
trapping is addressed.)
Finally, Fig. 7 illustrates high frequency jet ventilation
(HFJV), where inspiratory gas is injected into the patient’s
ET tube via a jet nozzle. Jet nozzles have been fashioned
out of needles or built into special ET tubes or ET tube
adapters as discussed below.
Each HFV approach introduces fresh gas into the
ð6Þ patient’s airway at about 10 times the patient’s normal
breathing frequency. The last three designs incorporate a
separate constant flow of gas that passes by the patient’s
High-frequency
Constant
flow-interrupting valve
pressure IMV / PEEP valve
PEEP or IMV
pressure
Constant flow
Exhaust
Patient
Figure 5. Basic design of HFFIs. (Used with permission. # 2003,
Bunnell Inc.)

Oscillating piston or diaphragm
Paw valve
Constant flow
Exhaust
Patient
Figure 6. Basic design of HFOVs. (Used with permission. # 2003,
Bunnell Inc.)
ET tube and out a large orifice valve to control baseline
PEEP and mean airway pressure in the circuit. The
patient may also breathe spontaneously from this gas
stream, which may be provided by a built-in mechanism
or by a separate conventional ventilator. Conventional
IMV (intermittent mandatory ventilation) may be com-
bined with HFV in this way. Additional hybrid devices
that are more difficult to characterize have also been
created, but the currently most common used HFVs are
HFOVs, HFJVs, and conventional ventilators with built-in
HFOV modules.
In the early 1980s, the FDA (U.S. Food and Drug
Administration) decided that 150 breaths min1 would
be the lower limit of what they would define as an
HFV, and they placed rigorous Class III restrictions on
any ventilator that operates above that frequency. As a
result, there have been only six HFVs approved for use in
the United States, three for infants and children, two for
adults, and one HFV that was granted Class II approval
(i.e., not needing proof of safety and efficacy since it
was substantially equivalent to devices marketed before
1976, the date U.S. law was amended to require proof of
safety and efficacy before new products can be marketed).
At least four other HFVs are available outside the United
States.
Of the FDA approved devices, two HFVs have been
withdrawn from the market by the major corporation that
acquired the smaller companies that developed them.
Therefore, we are left with one HFJV, one HFOV for
infants and children, one HFOV for children and adults,
and a Class II HFV hybrid device designed for patients of
all sizes. These four devices will be discussed in more detail
below.
HFJV: High Frequency Jet Ventilators
The HFJVs inject inspired gas into the endotracheal tube
via a jet nozzle. The Bunnell LifePulse High Frequency
High-frequency
Flow-interrupting valve
Constant
pressure Jet
IMV / PEEP valve
nozzle
Constant flow
Exhaust
Patient
Figure 7. Basic design of HFJVs. (Used with permission. # 2003,
Bunnell Inc.)
HIGH FREQUENCY VENTILATION 501
Paw Pressure
Figure 8. Bunnell life pulse HFV. (Used with permission.
# 2003, Bunnell Inc.)
Ventilator is the only HFJV currently available for inten-
sive care in the United States (Fig. 8). It was designed for
infants and children up to
10 years of age and operates at
rates between 240 and 660 bpm. It is also used in tandem
with a conventional ventilator, which provides for the
patient’s spontaneous breathing, delivery of occasional
sigh breaths, and PEEP.
The LifePulse is a microprocessor controlled, pressure
limited, time cycled ventilator that delivers heated and
humidified breaths to the ET tube via a LifePort adapter
(Fig. 9). A small Patient Box placed close to the patient’s
head contains an inhalation valve and pressure transducer
for monitoring airway pressures in conjunction with the
LifePort adapter. Peak inspiratory pressure (PIP) is feed-
back controlled by regulating the driving pressure (servo
pressure) behind the jet nozzle. More detailed information
on the device can be found on the manufacturer’s website:
www.bunl.com.
The theory of operation behind the LifePulse is that
pulses of high velocity fresh gas stream down the center of
the airways, penetrating through the dead-space gas, while
exhaled gas almost simultaneously moves outward in the
annular space along the airway walls. This countercurrent
action facilitates mucociliary clearance while it minimizes
effective dead space volume.
The pressure amplitude (DP) of LifePulse HFJV breaths
is determined by the difference between PIP and the CV-
controlled PEEP. Its value is displayed continuously on the
LifePulse front panel along with mean airway pressure,
PEEP or IMV
PIP, PEEP, and Servo Pressure.
pressure Servo Pressure on the LifePulse is a direct reflection of
the gas flow needed to reach the set PIP, so it varies with
the patient’s changing lung mechanics. Alarm limits are
automatically set around the Servo Pressure to alert the
operator to significant changes in the patient’s condition
as well as the tubing connecting the patient to the HFJV.
502 HIGH FREQUENCY VENTILATION
Figure 9. LifePort ET tube adapter
for HFJV. (Used with permission. #
2003, Bunnell Inc.)
A low limit alarm would infer that the patient’s lung
compliance or airway resistance has worsened, and the
LifePulse is using less gas (i.e., smaller tidal volumes) to
reach the set PIP in that circumstance. A high limit alarm
would infer that the patient’s condition has improved, larger
tidal volumes are being delivered, and the operator should
consider weaning PIP in order to avoid hyperventilation.
Alarm limits are also automatically set around moni-
tored mean airway pressure.
HFOV: High Frequency Oscillatory Ventilators
The SensorMedics 3100A HFOV for infants and children
and its sister model, the 3100B for adults, are the only pure
HFOVs currently available in the United States. Sinusoi-
dal oscillatory ventilation is produced by an electromagne-
tically driven floating piston with adjustable frequency and
amplitude. Inspiratory gas is supplied as bias flow, which
escapes from the very large diameter (1.5 in. ID, 38 mm)
patient breathing circuit via a traditional dome valve that
controls mean airway pressure. All pressures are moni-
tored at the connection to the ET tube. The SensorMedics
3100A HFOV is illustrated in Fig. 10 and more information
is available at www.sensormedics.com.
The 3100 HFOVs operate on the principle that high
frequency oscillations that are in tune with the natural
frequency of the patients lungs will preferentially move in
and out of the lungs, as opposed to the exhaust system of
the patient circuit. Haselton and Scherer illustrated a new
gas transport principle that applies to HFOV (16).
Differences in the velocity profiles of inspiration and
expiration during HFOV created by the branching archi-
tecture of the lungs enables inspiratory gas to advance
down the center of the airways while exhaled gas moves up
along the airway walls as the piston of the HFOV pulls the
gas back. The net effect of many oscillations is similar to,
but less pronounced than, the flow characteristics of HFJV
flow in the airways. Fresh gas tends to flow down the center
of the airways while exhaled gas recedes back along the
airway walls.

Figure 10. SensorMedics 3100A high frequency oscillatory ven-
tilator. (Used with permission. # 2003, SensorMedics Inc.)
The 3100 HFOVs have six control settings:
1. Frequency, which is adjusted to suit patient size and
lung time constants.
2–4. Bias gas flow rate, Mean Pressure Adjust and Mean
Pressure Limit, which together set mean airway
pressure.
5. Power, which sets DP.
6. % Inspiratory Time, which sets I:E (inspiratory to
expiratory time ratio; typically set at 33%).
Mean airway pressure is the primary determinant of
oxygenation, and DP is the primary determinant of tidal
volume and ventilation (CO2 removal). However, all con-
trols are open-loop: increasing frequency decreases tidal
volume and visa versa, and changing bias gas flow rate or
power may change mean airway pressure. Mean airway
pressure is monitored in the HFOV circuit, so changes
there are apparent, but changes in tidal volume due to
setting changes or changes in a patient’s lung mechanics
are not apparent. Given the squared relationship between
tidal volume and CO2 removal noted above, changes in
frequency move PaCO2 in the opposite direction of what one
would anticipate with conventional ventilation. (Increasing
frequency increases PaCO2; decreasing frequency decreases
PaCO2.) Thus, continuous or frequent monitoring of
arterial PaCO2 is recommended during HFOV, as it is
with all HFVs and conventional ventilation of premature
infants due to the potential for cerebral injury associated
with hyperventilation (more on that topic later).
HFFIs and Other Hybrids
Conventional infant ventilators with built-in HFV mod-
ules, such as the Dräger Babylog 8000 plus (Dräger
Medical AG & Co. KGaA) and the popular Infant Star
Ventilator, which will no longer be supported by its man-
ufacturer after May 2006, have been widely used in the
HIGH FREQUENCY VENTILATION 503
United States, Canada, Europe, and Japan. In general,
these hybrid HFVs are not as powerful as the stand-alone
HFVs, so their use is limited to smaller premature infants
(<2 kg). The VDR Servolator Percussionator (Percussio-
naire Corporation, Sand Point ID), however, was designed
to ventilate adults as well as premature infants. (Detailed
information on these devices can be viewed on the manu-
facturers’ websites: www.draeger-medical.com and www.
percussionaire.com.) The mechanical performances of these
devices vary widely, as do their complexities of operation
and versatilities as infant ventilators. (See the section
Equipment Limitations.)
Design Philosophy for Clinical Applications
The philosophy for controlling arterial blood gases with
HFVs is similar to that used with pressure-limited con-
ventional ventilation, especially when HFVs are used to
treat homogeneous lung disorders such as RDS (respira-
tory distress syndrome) in prematurely born infants. The
alveoli of these surfactant-deficient lungs must be opened
with some type of recruitment maneuver and kept open
with appropriate mean airway pressure (Paw) or PEEP in
order for the lungs to make oxygen available to the blood
stream. Ventilation is accomplished at a frequency propor-
tionate to the patient’s size and lung mechanics using a
peak airway pressure or pressure amplitude above PEEP
that creates a tidal volume that produces an appropriate
arterial PCO2. Pulse oximeters, which report the oxygen
percent saturation of arterial blood, are great indirect
indicators of when lungs have opened up, because oxyge-
nation is highly dependent on the number of alveoli that
are open and participating in gas exchange with the blood
stream. Chest wall motion is a good indirect indicator of
ventilation since it reflects the amount of gas that is
passing in and out of the lungs.
The usual approach to initiation of HFV is to choose a
frequency that is appropriate for the size of the patient and
his lung mechanics, starting with 10 Hz or 600 bpm for the
smallest premature infant with RDS and working down-
ward as the size of the patient increases and lung
mechanics improve. A good rule of thumb is to choose a
frequency 10 times greater that the patient’s normal
breathing frequency, which would put HFV for adults at
rates <200 bpm. Higher rates may be used with HFOV
since exhalation is nonpassive, but gas trapping can still
result unless mean airway pressure is kept high enough to
keep the airways open during the active exhalation phase.
Operating an HFOV with a 33% inspiratory time (I:E ¼ 1:2)
lessens negative pressure during exhalation compared to
longer I-times (e.g., I:E ¼ 1:1) thereby decreasing the
potential for causing airway collapse.
With HFJV, the shortest possible inspiratory time
(
0.020 s) usually works best; it maximizes inspiratory
velocity, which helps reduce effective dead space, and
minimizes I:E, which allows more time for exhalation to
avoid gas trapping. These characteristics also minimize
mean airway pressure, which is very useful when treating
airleaks and for ventilation during and after cardiac sur-
gery. The high velocity inspirations also enable ventilation
of patients with upper airway leaks and tracheal tears.
504 HIGH FREQUENCY VENTILATION
Treatment of obstructive lung disorders absolutely
requires longer exhalation times, so HFV must be used
at lower frequencies on these patients. HFJV I:E varies
from 1:3.5 to 1:12 as frequency is reduced from 660 to
240 bpm when inspiratory time is held constant at its
shortest value.
The HFV is not intended and may in fact be contra-
indicated for patients with asthma, unless helium–oxygen
mixtures become part of the mix (17).
Once a frequency and duty cycle (% I-time or I:E) is
chosen, airway pressure settings (PIP, PEEP, or DP) are set
to provide HFV tidal volumes that noticeably move the
chest. If chest wall movement is not apparent, ventilation
is probably not adequate. Use of transcutaneous CO2 mon-
itoring is of great benefit here.
Finally, mean airway pressure (Paw) or PEEP must be
optimized. Too little Paw or PEEP will lead to atelectasis
and hypoxemia, and too much Paw or PEEP will interfere
with cardiac output. One of the true benefits of HFV,
however, is that higher Paw and PEEP can be used without
increasing the risk of iatrogenic lung injury. (The small
HFV tidal volumes do not create the same potential for
creating alveolar ‘‘stretch’’ injury as larger CV tidal
volumes do.) Pulse oximeters can be great indirect indica-
tors of appropriate lung volume, but one must be vigilant in
detecting signs of decreased cardiac output.
Conventional ventilation is sometimes required or
available for tandem use with certain HFVs. The CV
breaths are most useful with nonhomogeneous lung dis-
orders and to facilitate alveolar recruitment with atelec-
tatic lungs. The usual strategy is to reduce CV support
when starting HFV (assuming the patient is on CV prior to
HFV) to 5–10 bpm while optimal Paw and PEEP is being
sought, and then reduce CV support further.
Now some of the performance differences in HFV equip-
ment and how those differences may affect successful HFV
implementation will be examined.
HFV Equipment Limitations
There have been few head-to-head comparisons of HFV
equipment. The most recent comparison were by Hatcher
et al. and Pillow et al. where they compared several neo-
natal HFOVs and found wide variations in performance,
complexity, and versatility (18,19). Pillow et al. concluded
that the clinical effects of manipulating ventilator settings
may differ with each HFOV device. In particular, the
pressure amplitude required to deliver a particular tidal
volume varies with device, and the effect of altering fre-
quency may result in very different effects on tidal volume
and PaCO2.
The first rigorous analysis of HFVs was undertaken by
Fredberg et al. in preparation for the HiFi Study (20). They
bench tested eight HFVs in an effort to provide the clin-
icians who were to participate in the study comparative
data that they could use to select an HFV for use in their
study. (They selected the Hummingbird HFOV, manufac-
tured by MERA of Japan.) Despite the wide diversity of
ventilator designs tested, certain common features
emerged. In almost all devices, delivered tidal volume
was sensitive to endotracheal tube size and airway resis-
tance and invariant with respiratory system compliance.
These results supported the theoretical basis for why high
frequency ventilation may be a better treatment for RDS
compared to pressure-limited CV (conventional ventila-
tion), because low lung compliance is its paramount patho-
physiologic feature.
These HFV bench tests also found that tidal volume
decreased with increasing frequency with all HFOVs
where I:E (inspiratory to expiratory time ratio) was held
constant and was invariant with HFJV and HFFI devices
where I-time was held constant. Peak inspiratory flow
rates for a given tidal volume and frequency were signifi-
cantly higher with the HFJV and HFFI as well. Proximal
airway pressure was also a poor indicator of distal pressure
with all devices.
Two other studies compared HFJV to HFOV. Boros and
associates compared the pressure waveforms measured at
the distal tip of the endotracheal tube of the Bunnell
LifePulse HFJV and the Gould 4800 HFOV (precursor to
the SensorMedics 3100A HFOV) in normal, paralyzed, and
anesthetized cats (21). They found that the HFOV required
higher PIP, DP, and Paw to get the same PaCO2, PaO2, and
pH compared to HFJV. Likewise, PaCO2 was higher and
pH and PaO2 were lower with HFOV when the same
airway pressures were used. However, different frequen-
cies were used with the two ventilators; 400 bpm with
HFJV and 900 bpm (15 Hz) with HFOV.
Zobel and associates also found that HFJV was effective
at lower airway pressure compared to HFOV (22). They
used a piglet model of acute cardiac failure and respiratory
failure and also measured airway pressure at the distal tip
of the endotracheal tube. The HFJV used was an Acutronic
AMS-10001 (Acutronic Medical Systems AG, Switzerland)
operating at 150 bpm with an I:E of 1:2. The HFOV was a
SensorMedics 3100A operating at 10 Hz and 1:2.
Why do HFOVs (presumably) operate at higher Paw
compared to HFJV? The answer to this question may be
related to gas trapping, HFV rates, and what happens
during exhalation. In both of the animal studies just dis-
cussed, HFJV rate was considerably lower than HFOV
rate. Exhalation is passive during HFJV, so lower rates
must be employed to allow sufficient exhalation time to
avoid gas trapping. The HFOVs suck the gas back out of the
lungs during the expiratory phase, and the physiologic
consequence can be, not surprisingly, airway collapse.
However, the Paw employed during HFOV determines
the importance of this effect.
Bryan and Slutsky set the tone for the future of HFVs
when they noted that this mode of ventilation is ideally
designed for treatment of patients with poor lung compli-
ance (23). The higher Paw required to match the patho-
physiology of such patients also serves to splint the airways
open during HFOV so that the choking effect of active
expiration is mitigated.
In conclusion, both modes of HFV can cause gas trap-
ping; they just do it by different mechanisms. The HFOV
can choke off airways when Paw is insufficient to mitigate
the effect of active expiration, and HFJV will trap gas when
expiratory time is insufficient to allow complete exhalation
of inspired tidal volume. One cannot lower Paw during
HFOV beyond the point where choking is made evident by
 HIGH FREQUENCY VENTILATION 505

a rise in a patient’s PCO2. With HFJV, one should not HFV APPLICATIONS IN NEONATES AND CLINICAL
increase frequency beyond the point where PEEP moni- OUTCOMES
tored in the endotracheal tube, as it is with the Bunnell
LifePulse, begins to rise inadvertently. If the automatically Homogeneous Atelectatic Lung Disease (e.g., RDS) and
set upper alarm limit on mean airway pressure with the Prevention of Lung Injury
LifePulse is activated, there is a good chance that this
Ever since the completion of the first multicenter, rando-
rise in Paw is due to inadvertent PEEP. The remedy for
mized, controlled HFV trial was published in 1989, report-
that circumstance is to decrease HFJV frequency, which
ing no benefit for premature infants with RDS and an
lengthens exhalation time and allows the PEEP to fall
increased risk of severe cerebral injury (26), the choice
back to set level.
of HFV to prevent lung injury in preterm infants has been
hotly debated. Some recent trails have demonstrated that
Airway Pressure Monitoring During HFV
if HFVs are implemented within hours of a premature
While airway pressures were monitored at the distal tip of infant’s birth with the proper strategy, results are positive.
the ET tube in the animal studies noted above, monitoring Other recent studies have not been positive.
at this location is seldom done currently, because the Hi-Lo The HiFi Trial, as the first multicenter, randomized,
ET tubes (formerly manufactured by Mallinckrodt, Inc.) controlled trial was labeled, was criticized for the general
are no longer available. Thus, airway pressure monitoring lack of clinical experience of the investigators and failure to
is done either at the standard ET tube adapter connection adhere to the most appropriate strategy for recruiting and
during HFOV or at the distal tip of the special LifePort maintaining appropriate lung volume (15). Later multicen-
adapter during HFJV. In either case, the pressure wave- ter, randomized controlled trials conducted in the 1990s
form measured deep in the lungs at the alveolar level is using both HFJV and HFOV demonstrated significant
greatly damped (Fig. 11). Gerstmann et al. reported that reductions in chronic lung disease (CLD) measured at 36
measurement of pressure amplitude in the alveoli of rab- weeks postconceptional age (PCA) in this patient population
bits during HFOV at 15 Hz was only 10% of that measured with practically no difference in adverse effects (27,28).
proximal to the ET tube (24). (There was a slightly higher incidence of PIE in the experi-
Meaningful monitoring of airway pressure during mental group of the HFOV study.) The demographics and
HFOV is limited to mean airway pressure, and that is only results of these two trials are illustrated in Tables 1 and 2.
representative of mean alveolar pressure in the absence of The results of the HFJV study were criticized for a lack
gas trapping, as noted above. Relative values of pressure of well-defined ventilator protocols for the conventionally
amplitude at the proximal end of the ET tube are indicative ventilated control group, whereas protocols for both the
of tidal volume size, and they are typically expressed as HFOV and SIMV control groups in the HFOV study, con-
such by the various HFOVs. ducted several years later, were well conceived and mon-
Peak inspiratory pressure (PIP) and PEEP as well as itored during the study. Therefore, it is interesting to note
Paw are measured during HFJV at the distal tip of the that the major outcome measures of CLD at 36 weeks PCA in
LifePort ET adapter. The PEEP is representative of alveo- the control groups of the two studies were almost identical.
lar PEEP at this location in the absence, again, of gas Other HFV studies revealed an increase in severe cere-
trapping. However, the PIP at this location is a gross bral injury that appears to be related to hyperventilation
overestimate of peak pressure in the alveoli. Mean airway and hypocarbia during HFV (29–32). Other criticisms of
pressure may slightly overestimate mean alveolar pres- recent trials with negative or equivocal results include the
sure as shown by the study of Perez-Fontan et al. (25). same strategy issues plus choice of HFV devices, limited
time on HFV before weaning back to CV, and so on (33).
Because of these mixed results, HFVs have yet to be
Trachea & Proximal Airways Distal Airways & Alveoli generally accepted for early treatment of premature
20 infants with RDS and prevention of lung injury.
15
P CMV
10 Table 1. Demographics of Two Multicenter, Randomized
Paw
5 Controlled Trials with HFOV and HFJV
0 Amplitude fixed; Paw fixed.
HFJV HFOV
20 Design/Demographics Studya Study10
15 HFOV
P Paw Treatment Groups HFJV CV HFOV SIMV
10
5
Number of Patients 65 65 244 254
0 Amplitude attenuates; Paw fixed when I:E = 1:1. Mean Birth Weight, kg 1.02 1.02 0.86 0.85
20
Mean Gestational Age 27.3 27.4 26.0 26.1
15 HFJV Age at Randomization, h 8.1 8.3 2.7 2.7
P
10 Paw 1 min/5 min Apgar Scores 3.5/7 4/7 5/7 5/7
5 FIO2 at Entry 0.62 0.69 0.57 0.60
0 Amplitude attenuates; PEEP fixed; Paw slightly declines. Mean Airway Pressure 10 10 8.2 8.3
at Entry
Figure 11. HFV Airway Pressure Waveform Dampening. (Used
a
with permission. # 2003, Bunnell Inc.) See Ref. 9.
506 HIGH FREQUENCY VENTILATION

Table 2. Significant Respiratory and Clinical Outcomes of HFOV and HFJV Early Application
Trials on Premature Infants with RDS
HFOV Study HFJV Study
Significant Respiratory and
Clinical Outcomes HFOV SIMV HFJV CV

Alive w/o CLD at 36 weeks PCA 56% 47% 68% 48%

p ¼ 0.046 p ¼ 0.037
Age at extubation, days 13 21 -
p < 0.001
Crossovers or Exitsa 25/244 (10%) 49/254 (19%) 3/65 (5%) 21/65 (32%)
p ¼ 0.07 p < 0.01
Success after Crossover 14/21 (67%) 0/3 (0%)
p ¼ 0.06
Supplemental O2 27% 31% 5.5% 23%
p ¼ 0.37 p ¼ 0.019
PIE 20% 13%
p ¼ 0.05
Pulmonary Hemorrhage 2% 7% 6.3% 10%
p ¼ 0.02 p > 0.05
a
Similar failure criteria were prospectively defined in both studies. Those who met the criteria in the HFJV study were
crossed over to the other mode, while those who met the criteria in the HFOV study exited the study and were treated with
whatever mode of ventilation the investigators deemed appropriate, including HFJV (personal communication, David
Durand, MD). Data on all patients were retained in their originally assigned group in both studies.

Homogeneous Restrictive Lung Disease (e.g., Congenital
Diaphragmatic Hernia)
While theories support use of HFV in cases where the lungs
are uniformly restricted by acute intra-abdominal disease or
postsurgically in infants with congenital diaphragmatic her-
nia, omphalocele, or gastroschisis, there are no randomized
controlled trials due to the rarity of these disorders. Despite
this lack of controlled trials, HFV has been widely accepted as
an appropriate treatment for this category of lung disease
due to the futility of CV treatment in severe cases.
Keszler et al. demonstrated improved gas exchange and
better hemodynamics with HFJV in an animal model of
chest wall restriction (34) and later reported improved
ventilation and hemodynamics in a series of 20 patients
with decreased chest wall compliance (35). Fok et al.
reported improved gas exchange with HFOV in eight simi-
lar patients who were failing CV (36).
Nonhomogeneous Atelectatic and Restrictive Lung Disease
(e.g., RDS with Tension PIE)
Pulmonary interstitial emphysema (PIE) in the prema-
ture infant creates a non-homogeneous lung disease:
parts of the lungs are collapsed as a result of surfactant
deficiency while other parts become overexpanded with
gas trapped in interstitial areas. Air leaks like PIE ori-
ginate most commonly in premature infants near the
terminal bronchial (37). As gas dissects into interstitial
spaces, it invades and dissects airway and vascular walls
moving towards the larger airways and vessels and the
pleural space where pneumothoraces are formed (38).
While positive-pressure CV may successfully penetrate
such restricted airways, the consequence may well be
accumulation of trapped gas in the alveoli and subsequent
alveolar disruption, which produces the classical picture
of PIE on X ray.
The HFJV quickly gained a reputation for superior treat-
ment of PIE in the early days of its clinical application. A
multicenter randomized trial of HFJV compared to rapid
rate (60–100 bpm), short I-time (0.20–0.35 s) CV for the
treatment of PIE confirmed anecdotal findings of faster
and more frequent resolution of PIE on HFJV. Survival
in the stratified group of 1000–1500 g birth weight infants
was most evident (79% with HFJV vs. 44% with CV;
p < 0.05). There was no difference in the incidence of adverse
side effects.
There is, as yet, no comparable randomized trial of
HFOV treatment for PIE. While anecdotal success has
been reported, attempts to show an advantage with HFOV
in a randomized controlled trial have so far been unsuc-
cessful. It may be that the physical characteristics of the
two types of HFVs coupled with the pathophysiologic
characteristics of PIE are the reasons for this lack of
success. Recall that one difference between HFV devices
reported in the pre-HiFi bench studies by Fredberg et al.
was that HFJVs squirt gas into the lungs at much higher
flow rates compared to HFOV. That fact may make HFJV
more sensitive to airway patency compared to HFOV.
Since CV breath distribution may be more affected by
lung compliance while HFV breaths may be more affected by
airway resistance, especially HFJV breaths with their high
velocity inspirations, the distribution of ventilation in the
nonhomogeneous PIE lung may be markedly affected by
mode of ventilation. While the path of least resistance for CV
breaths may lead to more compliant, injured areas of the
lungs, HFJV breaths may automatically avoid injured areas
where airway and vascular resistances are increased.
Therefore, HFJV breath distribution may favor relatively
normal airways in the uninjured parts of the lungs where
ventilation/perfusion matching is more favorable.
The CV tidal volumes delivered with higher PEEP and
Paw may dilate airways enough to help gas get into

restricted areas in babies with PIE, but those larger tidal
volumes take longer to get back out. Much smaller HFV
tidal volumes are more easily expired, especially those that
were unable to penetrate the restricted airways where the
lungs are injured.
Upper Airway Fistulas and Pneumothoraces
Theoretically, the small tidal volumes, high inspiratory
velocities, and short inspiratory times of HFJV are ideally
suited for treating pneumothoraces and broncho-pleural
and tracheal-esophageal fistulae. Gonzalez et al. found
that gas flow in chest tubes, inserted in a series of infants
with pneumothoraces, dropped an average of 54% when six
infants were switched from CV to HFJV (39). Their mean
PaCO2 dropped from 43 to 34 Torr at the same time that
their peak and mean airway pressures measured at the
distal tip of the ET tube dropped from means of 41–28 and
15 to 9.7 cm H2O, respectively.
Goldberg et al. (40) and Donn et al. (41) similarly
reported improved gas exchange and reduced flow through
tracheal–esophageal fistulas.
Homogeneous Obstructive Lung Disease (e.g., Reactive
Airway Disease, Asthma)
The HFV should theoretically not be of much benefit in
treating lung disorders such as asthma wherein airway
resistance is uniformly increased. Low rates and long
expiration times should be more effective. However, recent
work with HFJV and helium-oxygen mixtures (heliox)
demonstrated interesting potential for treating such dis-
orders in patients requiring no more than 80% oxygen.
Tobias and Grueber improved ventilation in a one-year
old infant with respiratory syncytial virus and progressive
respiratory failure related to bronchospasm with HFJV by
substituting a mixture of 80% helium/20% oxygen for
compressed air at the air/oxygen blender (42). They
hypothesized that the reduced density of helium compared
to nitrogen enhanced distal gas exchange. Gupta and
associates describe another case where HFJV and heliox
rescued a 5 month old infant with acute respiratory failure
associated with gas trapping, hypercarbia, respiratory
acidosis, and air leak (43). The combination of HFJV with
heliox led to rapid improvements in gas exchange, respira-
tory stabilization, and the ability to wean the patient from
mechanical ventilation.
Nonhomogeneous Obstructive Lung Disease (e.g., MAS) and
ECMO Candidates
Clinical studies of infants with meconium aspiration syn-
drome (MAS) provide support for the use of HFV with this
type of lung disease. These patients are potential candidates
for extracorporeal membrane oxygenation (ECMO), so ability
to avoid ECMO is a typical outcome variable in such studies.
Clark et al. randomized 94 full-term infant ECMO
candidates to HFOV or CV in a multicenter study (44).
Prospectively defined failure criteria were met by 60% of
those infants randomized to CV while only 44% of those
randomized to HFOV failed. Cross-overs to the alternate
mode by those who failed were allowed, and 63% of those
HIGH FREQUENCY VENTILATION 507
who failed CV were rescued by HFOV, while only 23% of
those who failed HFOV were rescued by CV. (The latter
comparison was statistically significant.) Overall, 46% of
the infants who met ECMO criteria required ECMO.
A similar single-center study of HFJV versus CV
involved 24 ECMO candidates with respiratory failure
and persistent pulmonary hypertension of the newborn
(PPHN) (45). Most of the infants in the HFJV-treated
group (8 of 11) and 5 of 13 of the conventionally treated
infants had either MAS or sepsis pneumonia. Treatment
failure within 12 h of study entry occurred in only two of the
HFJV-treated infants versus seven of the conventionally
treated infants. The ECMO was used to treat 4 of 11 HFJV
infants versus 10 of 13 control infants. Zero of nine surviv-
ing HFJV-treated infants developed chronic lung disease
compared to four of 10 surviving controls ( p ¼ 0.08). Sur-
vival without ECMO in the HFJV group was 5 of 11 (45%)
versus 3 of 13 (23%) in the control group. There was no
statistical significance in any of these comparisons due to
the small number of patients.
The degree to which pathophysiology predicts positive
outcomes with respect to the ability of HFVs to rescue
infants that become ECMO candidates has been explored
in two additional clinical studies. Baumgart et al. evalu-
ated their success with HFJV prior to instituting an ECMO
program in 73 infants with intractable respiratory failure
who by age and weight criteria may have been ECMO
candidates (46). They found survival after HFJV treatment
to be much higher in infants with RDS and pneumonia
(32/38, 84%) compared to MAS/PPHN (10/26, 38%) or con-
genital diaphragmatic hernia (3/9, 33%). All patients initi-
ally responded rapidly to HFJV as measured by oxygen
index (O.I., calculated as mean airway pressure in cm H2O
multiplied by fraction of inhaled O2 divided by PaO2 in
Torr). However, that improvement in survivors was rea-
lized and sustained during the first 6 h of HFJV treatment.
Paranka et al. studied 190 potential ECMO candidates
treated with HFOV during 1985–1992 (47). All patients
were born at 35 weeks gestational age or more and devel-
oped severe respiratory failure, as defined by an arterial to
alveolar oxygen ratio ðPðAaÞO2 Þ < 0:2 or the need for a peak
pressure of >35 cm H2O on CV. Fifty-eight percent (111
patients) responded to HFOV and 42% (79 patients) were
placed on ECMO. Gas exchange improved in 88% of the
infants with hyaline membrane disease (RDS), 79% of
those with pneumonia, 51% with meconium aspiration,
and 22% of those with congenital diaphragmatic hernia.
They also found failure to demonstrate an improvement in
PðAaÞO2 after six hours on HFOV to be predictive of failure.
During and After Cardiac Surgery
The ability of HFJV to hyperventilate while using lower
mean airway pressure is a great asset when treating
patients with cardiac problems. During surgery, the small
tidal volumes and low mean airway pressure allow the
surgeon to move the lungs out of the way, in order to
visualize and work on the heart. After surgery, HFJV
can gently hyperventilate the patient to encourage
increased pulmonary blood flow while mean airway pres-
sure is kept down (48–51).
508 HIGH FREQUENCY VENTILATION
PPHN and Nitric Oxide Therapy
Kinsella et al. demonstrated the potential of HFV to
enhance delivery of nitric oxide (NO) for the treatment
of PPHN in a large, multicenter, randomized controlled
trial (52). Nitric oxide delivered with HFOV to infants with
significant parenchymal lung disease was more effective
than NO delivered by CV. NO has also been delivered
successfully with HFJV (53). However, NO must be admi-
nistered via the HFJV circuit in order for the patient to
realize any beneficial effect from the gas (54). Inhaled NO
does not work with HFJV when administered exclusively
through the conventional ventilator circuit (55).
HFV APPLICATIONS IN CHILDREN AND ADULTS
While the bulk of the research and application of HFV has
been aimed at the benefit of infants to date, the sheer
number of potential applications for children and adults
is far greater. Unfortunately, the number of HFVs avail-
able to treat adults is severely limited. There is only one
instrument currently available in the United States spe-
cifically designed for ARDS in children and adults, the
SensorMedics 3100B. (The Percussionaire VDR4-F00008
ventilator also provides HFV for adults. It was approved as
a Class II device by the FDA.)
Acute respiratory distress syndrome is the obvious tar-
get for HFV treatment in adult intensive care. This syn-
drome affects
50 per 100,000 population with a mortality
of 30–50%. It is a clinical syndrome of noncardiogenic
pulmonary edema associated with pulmonary infiltrates,
stiff lungs, and severe hypoxemia (56). Although the
pathology of ARDS involves a number of features similar
to RDS in infants, such as hyaline membranes, endothelial
and epithelial injury, loss of epithelial integrity, and
increased alveolar-capillary permeability, it may have a
much greater inflammatory component.
The only treatment shown to positively impact mortal-
ity over the past several decades came from the ARDSnet
Trial where CVs were used with a low tidal volume
ventilatory strategy designed to reduce iatrogenic lung
injury (57). Comparative treatments in this multicenter
study of 861 patients included an experimental group
where mean tidal volumes for the first 3 days of their
treatments were 6.2 mL kg1 body weight and a control
group where tidal volumes were 11.8 mL kg1. The experi-
mental group had lower mortality and fewer days on
mechanical ventilators.
With ARDSnet trial pointing in the general direction
HFV Clinical Trails with Children and Adults
The importance of starting early with HFV on adults and
children with ARDS was highlighted in several anecdotal
and pilot trials. Smith et al. treated 29 children with severe
ARDS complicated by pulmonary barotrauma with HFJV
(58). Twenty (69%) survived, and the only statistically
significant difference between survivors and nonsurvivors
was the mean time on CV before initiating HFJV (3.7 days
in survivors vs. 9.6 days in nonsurvivors). Fort et al.
similarly found that survivors in a pilot study of HFOV
for adults with ARDS were on CV 2.5 days before initiation
of HFOV, while nonsurvivors were on CV for 7.2 days (59).
Expected survival in the pilot study was <20%, actual
survival was 47%.
Arnold et al. compared HFOV to CV in children with
respiratory failure (60). Optimizing lung volume was
emphasized in both the experimental and control groups.
The strategy for optimizing lung volume in the CV group
was to lengthen inspiratory times and increase PEEP in
order to decrease required PIPs. They found significant
improvement in oxygenation in the HFOV group as well as
a lower need for supplement oxygen at 30 days postenroll-
ment.
A recent prospective trial of HFOV for ARDS had simi-
lar results. Mehta et al. treated a series of 24 adults with
severe ARDS with HFOV (61). Five of the patients were
burn victims. Within 8 h of HFOV initiation, FIO2 and
PaCO2 were lower and PaO2/FIO2 was higher than base-
line values during CV throughout the duration of the trial.
An obvious focus was placed on recruiting and maintaining
adequate lung volume while on HFOV, since Paw was also
significantly higher than that applied during CV through-
out the HFOV trial. Unfortunately, this increase in Paw
was associated with significant changes in hemodynamic
variables including an increase in pulmonary artery occlu-
sion pressure (at 8 and 40 h) and central venous pressure
(at 16 and 40 h), and a reduction in cardiac output through-
out the study. Thus, Paw may not have been optimized.
However, 10 patients were successfully weaned from
HFOV and 7 survived. Again, there was a statistically
significant difference in the time spent on CV prior to
initiation of HFV: 1.6 days for survivors versus 5.8 days
for the nonsurvivors.
Noting the importance of early intervention, Derdak
et al. designed a multicenter, randomized, controlled trial
comparing the safety and effectiveness of HFOV versus CV
in adults with less severe ARDS (62). (The authors nick-
named their trial: the MOAT Study.) Inclusion criteria
of smaller tidal volumes, it is not surprising that recent
HFV trials appear very promising, especially since HFV
investigators focused on NICU patients and worked their
way up the learning curve. The most important lesson
learned, and one that took many years to learn in the
treatment of infants, was the importance of recruiting and
maintaining adequate lung volume during HFV. Adult
trials of HFV for ARDS now begin with a Paw 5 cm H2O
greater than that currently being used with CV. Just as
was learned with infants, it is safe to use higher PEEPs
and mean airway pressures with HFVs smaller tidal
volumes.
included PaO2/FIO2  200 mmHg (26.66 kPa) on 10 cm
H2O PEEP, and 148 adults were evenly randomized.
Applied Paw was significantly higher in the HFOV group
compared with the CV group throughout the first 72 h. The
HFOV group showed improvement in PaO2/FIO2 at <16 h,
but this difference did not persist beyond 24 h. Thirty day
mortality was 37% in the HFOV group and 52% in the CV
group ( p ¼ 0.102). At 6 months, mortality was 47% in the
HFOV group and 59% in the CV group ( p ¼ 0.143). There
were no significant differences in hemodynamic variables,
oxygenation failure, ventilation failure, barotraumas, or
mucus plugging between treatment groups.
 HIGH FREQUENCY VENTILATION 509

The MOAT Study indicates that HFOV is safe and (63). The meta-analysis showed that use of HFV was
effective for ARDS, and the FDA approved the SensorMe- associated with an increased risk of PVL (odds ratio ¼ 1.7
dics 3100B for ARDS. Outcome data from this study are 1.7 with a confidence interval of 1.06–2.74), but not IVH or
comparable to those of the ARDSnet Trial. The control
group in the MOAT study was not ventilated with tidal
volumes as small as those used in the experimental group
of the ARDSnet trial (6–10 vs. 6.2 mL kg1), but they were
generally smaller than the ARDSnet control group
(11.8 mL kg1). Mortality at 30 days in the MOAT Study
was not quite as good as that in the ARDSnet Trial (37 vs.
31%, respectively), but sepsis was much more prevalent in
the MOAT Study compared to the ARDSnet Trial (47 vs.
27%, respectively).
STATUS OF HFV, RISKS, AND OUTLOOK FOR THE FUTURE
Are HFVs Safe and Effective?
Use of HFVs for newborn infants and adults began in the
early 1980s. Fifteen randomized controlled trials with
infants and about one-half that many randomized studies
with children and adults were conducted over the next 20þ
years. Over 1000 articles about HFV have been published.
Yet, there are still questions about HFV safety and efficacy.
There are certainly adequate data to suggest that HFVs
are effective in lessening chronic lung injury. The fact that
not all studies have been successful in this regard is a
reflection of differences in infant populations, ventilator
strategies, and devices used. There is little argument that
use of antenatal steroids, exogenous surfactant, and ven-
tilator strategies using smaller tidal volumes have greatly
improved mortality and morbidity of premature infants.
Not surprisingly, as clinicians have become more suc-
cessful with HFV and other small tidal volume strategies,
the age of viability of premature infants has gone down.
Thus, the challenge of preventing chronic lung disease in
NICU patients never gets easier, because the patients keep
getting more premature.
What Are the Risks Associated with HFV in the NICU?
The greatest controversy in consideration of HFVs as a
primary mode of ventilation of premature infants is safety,
particularly whether HFV use increases the risk of cere-
bral injury. Clark et al. evaluated the probability of risk
of premature infants suffering from intraventricular
hemorrhage (IVH) or periventricular leukomalacia
(PVL) by conducting a meta-analysis of all prospective
randomized controlled trials of HFV published by 1996
PIP
Paw
PEEP
Higher P Lower P Higher P Lower P
Higher Paw Lower Paw Higher Paw Higher Paw
Hypocapnia Good PaCO2 Hypocapnia Good PaCO2
Good PaO2 Hypoxemia Good PaO2 Good PaO2
severe (grade 3) IVH. In addition, since the largest study
in the group by far was the HiFi Trial (14), where imple-
mentation strategy was reputed to be less than optimal,
they repeated the analysis without that study. When the
results of the HIFI study were excluded, there were no
differences between HFV and conventional ventilation in
the occurrence of IVH or PVL.
Since 1996, seven additional randomized controlled
trials of early use of HFV have been conducted on 1726
patients. Only one of the newer studies demonstrated a
possible increased risk of cerebral injury (64), and that
study included 273 patients or 16% of the total in these
7 studies. Thus, a more current meta-analysis would be
even more convincingly positive today, and one could even
say that there is little evidence of increased risk of cerebral
injury during HFV. Why then, is this matter still contro-
versial?
The risk of causing cerebral injury in premature infants
is associated with hyperventilation and hypocarbia as
noted earlier. There will never be a randomized controlled
trial to prove cause and effect here, for obvious reasons.
Therefore, all we can do is try to avoid hyperventilation and
hypocarbia and see if outcomes get better over time.
Avoiding hyperventilation and hypoxemia first requires
proper monitoring. Pulse oximetry, transcutaneous CO2
monitoring, and continuous or frequent arterial blood gas
monitoring are essential during HFV. Control of PaCO2
during HFV often requires optimization of PEEP, Paw, and
pressure amplitude (DP) as shown in Fig. 12. The HFVs are
noted for their ease of blowing off CO2 at lower airway
pressures compared to CV, so PEEP and Paw must often be
increased above those used during CV, if hypoxemia is to be
avoided.
With HFOV, one often adjusts mean airway pressure
without knowing the resulting baseline pressure or PEEP,
whereas with HFJV, PEEP is adjusted to get an appro-
priate Paw. Therefore, one must not be fearful of higher
PEEP when higher mean airway pressure is required.
PEEP as high as 10 cm H2O is not unusual when HFJV
is being used to treat premature infants.
One must also recognize that raising PEEP will reduce
DP when PIP is held constant, as shown in Fig. 12, which
causes both PaO2 and PaCO2 to rise.
Other safety concerns with early use of HFVs for pre-
venting lung injury are interference with cardiac output by
using too much PEEP or Paw. Since interference with
P
Figure 12. Adjusting pressure waveforms to correct
arterial blood gases. (Used with permission. # 2003,
Bunnell Inc.)
510 HIGH FREQUENCY VENTILATION

venous return by elevated intrathoracic pressure raises
intracranial pressure, there is associated fear of causing
IVH by this mechanism as well.
A related issue, for those HFVs with that capability, is
using too many CV breaths or using overly large CV tidal
volumes during HFV. The latter use increases the risk of
causing lung injury when HFV is implemented with higher
PEEP.
Optimizing PEEP and minimizing the risk of using too
many CV breaths during HFV can be achieved at the same
time. The following flowchart for finding optimal PEEP
during HFJV illustrates this point (Fig. 13).
The flowchart in Fig. 13 is based on the concept that CV
breaths will be most effective in opening up collapsed
alveoli, while PEEP or baseline pressure will prevent
alveoli from collapsing during exhalation. The longer I
times and tidal volumes of CV breaths provide a greater
opportunity to reach the critical opening pressure of col-
lapsed alveoli, and if PEEP is set above the critical closing
pressure of those alveoli, they will remain open throughout
the ventilatory cycle. Once PEEP is optimized, there is less
value in using CV in tandem with HFV.
Although Fig. 13 was designed for use during HFJV, its
principles are equally applicable to HFOV when CV may
not be available. In this case, mean airway pressure is
raised until an improvement in oxygenation makes it
apparent that alveolar recruitment has occurred. At that
point, it should be possible to decrease mean airway pres-
sure somewhat without compromising oxygenation. How-
ever, the appropriate strategy here would be to set a goal
for lowering the fraction of inhaled oxygen (FIO2) before
attempting to lower Paw. In this way, one should avoid
inadvertently weaning Paw too fast and risking cata-
strophic collapse of alveoli. An appropriate FIO2 goal in
this circumstance might be 0.3–0.4 depending on the vul-
nerability of the patient to high airway pressures and the
magnitude of the mean airway pressure present at the
time.
The final risk to be mentioned here will be the greatest
risk associated with HFV: inadequate humidification and
airway damage. In unsuccessful applications of HFV in
infants in the early 1980s, necrotizing tracheal bronchitis
(NTB) was frequently noted at autopsy (65). First discov-
ered during HFJV, it was subsequently discovered during
HFOV as well (66). Fortunately, the development of better
humidification systems coupled with earlier implementa-
tion of HFV seems to have eradicated this problem as an
extraordinary adverse side effect. None of the 14 rando-
mized controlled trials has found an increase in NTB
associated with HFV treatment.
Humidification during HFV is challenging, especially
for HFOVs that use high gas flow rates and HFJVs. Gas
humidified under pressure will not hold as much water as
unpressurized gas, so HFJVs must humidify their inspira-
tory gas at higher than normal temperatures in order to
reach anything near 100% relative humidity at body tem-
perature.
Bunnell Incorporated’s HFJV addressed this inherent
problem by minimizing the driving pressure behind their
jet nozzle using an inspiratory pinch valve in a little box
placed near the patient’s head. The pinch valve reduces the
pressure drop through that part of the system because of

Starting Assumptions:
1. Patient is on HFJV + CV with 5 – 10 IMV bpm, PEEP < 8 cm H2O.
2. Patient is being monitored with a pulse oximetry.

Switch CV to CPAP mode.

Does SaO2 drop? NO

PEEP is high enough, for the moment.
(Wait 1- 5 min.)
Hours later…
YES
Does FIO2 NO
PEEP is too low.
need to be increased?

Switch back to IMV. YES

Increase PEEP by 1 – 2. Add IMV at 3-5
bpm as necessary until FIO2 can be
reduced, then go back to CPAP mode.
Increase PEEP by 1 – 2.
Figure 13. Optimal PEEP flowchart. (Used with permis-
sion. # 2005, Bunnell Inc.) (Warnings: Lowering PEEP
may improve SaO2 in some cases. Optimal PEEP may be
Wait for SaO2 to return Keep PEEP at this level
lower in patients with active air leaks or hemodynamic
to acceptable value. until FiO2 < 0.30
problems. Do not be shocked if optimal PEEP ¼ 8  12 cm
H2O. Using IMV PIP with high PEEP is hazardous. Do not
assume high PEEP causes overexpansion.)
 HIGH FREQUENCY VENTILATION 511

the relatively large internal diameter (ID) of the tubing in tidal volumes at higher flow rates compared to HFV for
the valve (0.13 in., 3.2 mm). Placing the pinch valve within infants. Humidification of HFV gases is crucial as was
35 cm of the patient where inspired gas is delivered via a learned with the early trials in infants, and gas is more
jet nozzle embedded in a special ET tube adapter also difficult to humidify under pressure, as discussed above.
enables the LifePulse Ventilator to deliver its tiny tidal The most challenging mode of HFV in this respect is HFJV,
volumes without much driving pressure. (A typical driv- since it takes elevated pressure to push gas through a jet
ing pressure needed for HFJV with the LifePulse on a nozzle. Perhaps this is one reason for the lack of success of
premature infant is between 1.5 and 3.5 psi.) The HFVs the only HFJV for adults approved by the FDA for use with
that work at higher pressures and gas flow rates some- adults (the APT 1010 Ultrahigh Frequency Ventilator,
times provide humidity with liquid water. (See Acutronic developed by the Advanced Pulmonary Technologies,
jet ventilation systems on their website: www.acutronic- Inc., Glastonbury, CT). Humidification with this device
medical.ch.) was only provided via supersaturated entrained gas. How-
ever, the same corporation that pulled this product off the
Working Within the Limitations of HFVs in the NICU market is also planning to discontinue manufacturing the
Infant Star HFV for infants, and that ventilator had no
The HFVs have been widely accepted for treating newborn
such humidification issues. Thus, it appears likely that
infants with lung injury. Whether HFV will ever be widely
these products were discontinued for other (i.e., business)
accepted as a primary mode of ventilation is another
reasons.
matter. There have been many advances in conventional
There is also danger of operator error when any machine
ventilator therapy over the past several years and, to a
is used by untrained or unskilled operators. Given the
certain extent, techniques used to optimize HFVs have
tendency for some hospitals to only use HFVs as last resort
been applied to CVs (67).
rescue ventilators, one must consider those types of risks.
Like most therapies, the skill with which HFV is imple-
Since HFOV is most successful in homogeneous lung dis-
mented is probably the most critical determinant of clinical
orders, it only makes sense for it to be used relatively early
success. Starting HFV on patients sooner rather than
in the course of ARDS before significant lung injury results
waiting for worsening lung disease to become nearly hope-
from CV treatment. Once the patient’s condition deterio-
less is also extraordinarily important. Having written
rates into ARDS complicated by airleaks, chances for
protocols defining the patient population and how HFV
HFOV success may be significantly decreased.
is optimized for that patient population can also be very
Treating children and adults with HFVs also has to take
helpful.
optimal frequency into account. The primary determinant
Early-to-moderately early stage treatment of homoge-
of optimal frequency is lung compliance, which is primarily
neously noncompliant lungs is the most obvious choice as
determined by the patient’s size. An adult’s lung is larger
an appropriate indication for HFV. If hyperventilation and
than that of a child, which is larger than that of a term
gas trapping are avoided and appropriate resting lung
newborn, which is larger than that of a preemie. Thus,
volume is achieved, better outcomes should result. The
HFV frequency should be reduced as patient size increases.
ability of all HFVs to ventilate lungs using less pressure,
Optimal HFV for adults may occur at 150 bpm, whereas
independent of lung compliance, is nearly universal as long
operation at that frequency with infants would not even be
as the lungs are not too large for the ventilator’s output.
considered HFV.
Many of the HFV modes built into CVs are not powerful
Given the evidence that HFJVs have been more success-
enough to ventilate even a term infant, so operators need to
ful with nonhomogeneous lung disorders in infants, as
know the relative output capacities of their HFVs.
described above, it would seem likely that HFJVs would
Using HFVs as rescue ventilators usually means that
find a role for treating adult patients with ARDS as well.
the underlying lung disorder has become nonhomogeneous
Unfortunately, the application of HFJV for adults has been
or even obstructive. Ironically, most clinicians will only use
tarnished by a lack of success in very early studies.
HFVs as rescue ventilators even though these disorders
Carlon et al. conducted a randomized controlled trial
are much harder to treat with HFV. Gas trapping is a much
of HFJV versus volume-cycled CV on adults with acute
greater risk with heterogeneous obstructive disorders, and
respiratory failure (69). While they reported patients fail-
it may be avoided via use of small HFV tidal volumes.
ing on CV improved more rapidly and in greater number
However, even HFV tidal volumes can be trapped if expira-
when switched to HFJV compared to those who were
tory times are not several times greater than inspiratory
failing on HFJV and crossed to CV, there were no advan-
times. The HFJVs with their very short I:E ratios and very
tages with respect to survival and total duration of stay
high velocity inspiratory flows have been demonstrated to
in the ICU. Thus, they concluded that HFJV offered no
be more effective with these types of lung disease. Com-
obvious benefits over CV. The study was published in
bined CV and HFJV have also been shown to work even
1983, long before there was much appreciation of the need
better than pure HFJV in severe nonhomogeneous lung
to optimize PEEP and maintain adequate lung volume
disorders (68).
during HFV. One wonders what results would come from
a similar trial 20 years later, but such a trial will probably
What Are the Risks and Limitations Associated with HFV
never happen now. The cost, time, and effort of seeking
in Treating Children and Adults?
FDA approval for any Class III device is so high now, that
The only risks unique to HFV for children and adults are HFJV may never find its way back into an adult ICU in
those associated with the necessity for delivering larger the United States.
512 HIGH FREQUENCY VENTILATION
What Is the Outlook for HFV in the Future?
The HFVs evolved as people discovered problems with
trying to replicate breathing in compromised patients.
Unlike conventional ventilation, HFV is designed to facil-
itate gas exchange rather than mimic how people breathe
normally. The differences between HFV and CV have led to
creative solutions for many of the problems that investi-
gators set out to solve, but they have also created their own
problems.
It was discovered how HFVs can ventilate much more
effectively than CV, and in the process, it was discovered
how hypocapnia can lead to severe cerebral injury in pre-
mature infants.
The HFV still uses positive pressure where we create
negative pressure to draw gas into the lungs. So, the
problems related to use of ET tubes and its bypassing
the normal humidification system of the body (i.e., the
nose) are still there.
The HFV uses much smaller tidal volumes than CV,
so the damage we have come to call volutrauma has
lessened. In the process, it was discovered that more mean
airway pressure or PEEP is required to keep sick lungs
open while they are being ventilated. Then it was dis-
covered that the new problems were associated with too
much pressure in the thorax interfering with cardiac
output.
So, HFVs do not solve all the problems, and they require
increased vigilance to avoid creating new problems. How-
ever, the basic differences between HFV and CV provide a
very reliable alternative to CV in circumstances where
those differences are critical to survival.
The HFV tidal volumes are minimally affected by lung
compliance and maximally affected by airway resistance
when they are delivered via a jet nozzle. Therefore, in lung
disorders where these conditions dictate treatment success
or failure, wise users of HFVs have been very successful.
When HFV users are not adequately trained or aware of
the differences in HFV gas distribution caused by lung
pathophysiology, success can be elusive.
Premature infants with RDS represent a large popula-
tion with the potential of leading long and rich lives if they
survive their first months of life with undamaged or even
minimally damaged lungs and brains. Many randomized
controlled trials have demonstrated the potential of HFVs
to help these infants realize that potential.
The tens of thousands of adults who succumb to ARDS
every year also have the potential of increased survival
with less morbidity thanks to HFVs. These patients, when
successfully treated with an HFV, will be considered res-
cued from a well-recognized disorder with a chronically
high mortality rate.
Given the skill and training needed to master HFVs,
their use may be considered risky indefinitely. As HFVs
and associated monitoring equipment become better
designed to help their users optimize assisted ventilation,
HFV use should increase and evolve into earlier, more
prophylactic applications to prevent lung injury. The HFVs
are inherently a kinder, gentler form of mechanical venti-
lation. Hopefully, their true potential will someday be
realized.
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