Reflections on Pediatric High-Frequency

Oscillatory Ventilation From a Physiologic Perspective

Martin CJ Kneyber MD PhD, Marc van Heerde MD PhD, and Dick G Markhorst MD PhD

Introduction
Clinical Experiences
Critical Appraisal of the HFOV Strategy Employed
Indications for and Timing of HFOV
Best HFOV Approach and Oscillator Settings for Oxygenation
Best HFOV Approach and Oscillator Settings for Ventilation
Monitoring During HFOV
Spontaneous Breathing During HFOV
Conclusions

Mechanical ventilation using low tidal volumes has become universally accepted to prevent
ventilator-induced lung injury. High-frequency oscillatory ventilation (HFOV) allows pulmonary
gas exchange using very small tidal volume (1–2 mL/kg) with concomitant decreased risk of at-
electrauma. However, its use in pediatric critical care varies between only 3% and 30% of all
ventilated children. This might be explained by the fact that the beneficial effect of HFOV on
patient outcome has not been ascertained. Alternatively, in contrast with present recommendations,
one can ask if HFOV has been employed in its most optimal fashion related especially to the
indications for and timing of HFOV, as well as to using the best oscillator settings. The first was
addressed in one small randomized study showing that early use of HFOV, instead of rescue use,
was associated with improved survival. From a physiologic perspective, the oscillator settings could
be refined. Lung volume is the main determinant of oxygenation in diffuse alveolar disease, sug-
gesting using an open-lung strategy by recruitment maneuvers, although this is in practice not
custom. Using such an approach, the patient can be oscillated on the deflation limb of the pressure-
volume (P-V) curve, allowing less pressure required to maintain a certain amount of lung volume.
Gas exchange is determined by the frequency and the oscillatory power setting, controlling the
magnitude of the membrane displacement. Experimental work as well as preliminary human data
have shown that it is possible to achieve the smallest tidal volume with concomitant adequate gas
exchange when oscillating at high frequency and high fixed power setting. Future studies are needed
to validate these novel approaches and to evaluate their effect on patient outcome. Key words:
HFOV; ALI/ARDS; obstructive airway disease; oxygenation; ventilation. [Respir Care 2012;57(9):1496 –
1504. © 2012 Daedalus Enterprises]

Dr Kneyber is affiliated with the Department of Pediatrics, Division of Correspondence: Martin CJ Kneyber MD PhD, Department of Pedi-
Pediatric Intensive Care, Beatrix Children’s Hospital, University Medical atrics, Division of Pediatric Intensive Care, Beatrix Children’s Hos-
Center Groningen, Groningen, the Netherlands. He is also, along with pital, University Medical Center Groningen, Internal Postal Code
Drs van Heerde and Markhorst, affiliated with the Department of Pedi- CA80, PO Box 30.001, 9700 RB Groningen, The Netherlands. E-mail:
atrics, Division of Pediatric Intensive Care, VU University Medical Cen- [email protected].
ter, Amsterdam, the Netherlands.
The authors have disclosed no conflicts of interest. DOI: 10.4187/respcare.01571

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 REFLECTIONS ON PEDIATRIC HFOV FROM A PHYSIOLOGIC PERSPECTIVE

Introduction of specific lung diseases and data from animal as well as

bench studies.
Mechanical ventilation (MV) is intimately linked with
Clinical Experiences
the daily care of critically ill children admitted to the pe-
diatric ICU. Indications for MV include diffuse alveolar
The effect of HFOV on mortality was compared with
disease (DAD) including acute lung injury, or ARDS. Al-
conventional MV in 2 randomized controlled trials (RCTs)
though life-saving, MV is also linked with ventilator-
(Table).28 – 42 The largest of the 2 was performed 15 years
induced lung injury (VILI) and the development of mul-
ago, in 5 centers, during a 3.5 year period.28 In this cross-
tiple system organ failure.1 This has led to the concept of
over study, 58 patients with acute respiratory failure or
lung-protective ventilation, which has become standard of
pulmonary barotrauma, and an oxygenation index (OI)
care nowadays.2 High-frequency oscillatory ventilation ⬎ 13, demonstrated by 2 consecutive measurements over
(HFOV) is, at least theoretically, an ideal tool for lung- a 6 hour period, were randomized to either HFOV (n ⫽ 29)
protective ventilation, as it allows pulmonary gas exchange using a strategy of aggressive increase in CDP targeted at
using very small tidal volume (VT) and decreases the risk SpO2 ⱖ 90% with FIO2 ⱕ 0.6, or conventional mechanical
of atelectrauma.3–15 Animal studies have pointed out that ventilation (n ⫽ 29), using a strategy utilizing PEEP and
HFOV might be preferable over conventional MV, given limited inspiratory pressures. Patients with obstructive air-
its more beneficial effects on oxygenation, lung compli- way disease (OAD), intractable septic or cardiogenic shock,
ance, attenuation of the pulmonary inflammation and his- or non-pulmonary terminal diagnosis were excluded. Tar-
tologic injury, and better alveolar stability.16,17 HFOV al- geted blood gas values were equal for each group. The
lows the decoupling of oxygenation and ventilation. main finding was that HFOV did not improve survival
Simplified, oxygenation is dependent on lung volume, (HFOV 66% vs 59%) or total ventilator days (HFOV
which is controlled by the continuous distending pressure 20 ⫾ 27 vs 22 ⫾ 17), compared with conventional me-
(CDP). The CDP is depicted by the oscillator as mean chanical ventilation, when the data were analyzed by ini-
airway pressure. CO2 clearance (V̇CO2) is relatively inde- tial assignment. However, the percentage of survivors re-
pendent of lung volume, but influenced by oscillatory fre- quiring supplemental oxygen at 30 days was significantly
quency (f) and the square of VT (V̇CO2 ⫽ F ⫻ VT2).18 –22 lower in the HFOV group (21% vs 59%, P ⫽ .039). Fur-
The 3100 A/B HFO ventilator (SensorMedics, Yorba thermore, mortality was only 6% (n ⫽ 1/17) in patients
Linda, California) is the most commonly used HFOV de- who were exclusively managed on HFOV, whereas it was
vice in pediatrics. With this system, pressure oscillations 42% (n ⫽ 8/19) for patients who failed conventional me-
with a frequency of 3–15 Hz are superimposed upon a chanical ventilation and were transitioned to HFOV. Yet,
CDP in a square-wave manner. The CDP is generated by mortality in patients who were exclusively managed with
a fixed fresh gas flow/bias flow leaving the ventilator cir- conventional mechanical ventilation was 40% (n ⫽ 4/10).
cuit by an expiratory balloon valve. A membrane super- Samransamruajkit et al reported the results of a small
imposes high-frequency pressure oscillations around the single-center study comparing HFOV (n ⫽ 7 patients)
CDP. The oscillatory pressure amplitude is highly attenu- with conventional mechanical ventilation (n ⫽ 9 patients)
ated over the ETT and the airways, and results in the with ARDS in a 2-year study period.29 Survival was higher
delivery of a very small VT, usually lower than anatomical with HFOV (71%), compared with conventional mechan-
dead space.23 Because of this small VT, there is a de- ical ventilation (44%), and predicted by plasma levels of
creased risk of entering the so-called non-safe zones within soluble intercellular adhesion molecule 1.
the pressure-volume loop of the diseased lung.22 Both RCTs have not been repeated so far, but various
The use of HFOV in pediatric critical care varies be- institutions have described their (limited) experiences with
tween 3% and 30% of all ventilated children.23–27 This HFOV (see the Table).30 – 43 Overall survival varied be-
relatively low use may be explained by several factors. tween 40% and 90%. The largest cohort study came from
First, lack of equipment or disbelief of the attending phy- a collaborative of 10 pediatric centers reporting 232 pa-
sician because of the absence of sound evidence of effect. tients.35 Duration of conventional mechanical ventilation
Second, and perhaps even more importantly, many aspects prior to HFOV was between 2.2 ⫾ 4.2 to 4.5 ⫾ 3.1 days,
of pediatric HFOV remain to be explored, including among whereas patients with preexisting lung injury were managed
others the identification of patients who are most likely to for up to 11.4 ⫾ 45.5 days before transfer to HFOV. Thirty-
benefit from HFOV, timing of HFOV (early vs rescue), day mortality ranged from 30% for patients with respiratory
optimal oscillator settings, and monitoring during HFOV. syncytial virus lower respiratory tract disease, to 59% for
The purpose of this paper is to review published clinical patients with congenital heart disease. Mortality was in-
experiences with HFOV and to reflect on how its use dependently predicted by the OI 24 hours after start of
might be improved in light of the physiological properties HFOV and the presence of immunocompromise. The ap-

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 Table. Summary of Clinical Experiences With High-Frequency Oscillatory Ventilation in Critically Ill Children

1498
Study Recruitment Survival
First Author n Inclusion Criteria Initial HFOV Settings Outcome Predictor(s)
Period Maneuver (%)
Randomized Clinical Trials
Arnold28 3.5 years 58 OI ⬎ 13 or pulmonary barotrauma Frequency: 5–10 Hz No 66 HFOV vs 59 OI at 24 hours
⬎ grade 1 Amplitude: chest wall wiggle
29
Samransamruajkit 1 month 16 ARDS Frequency: weight-dependent No 71 HFOV vs 44 Soluble intercellular adhesion
Amplitude: 10 ⬎ peak molecule 1 (sICAM-1)
pressure on conventional
mechanical ventilation

Cohort Studies
Slee-Wijffels30 6 years 53 Patients with diffuse alveolar disease Frequency: weight-dependent Yes 64 Not reported
REFLECTIONS

and small airway disease Amplitude: chest wall wiggle

Lochindarat31 3 years 21 Patients with ARDS with OI ⬎ 10 Unknown Unknown 52.4 Survival predicted by OI at 24
ON

and PaO2/FIO2 ⬍ 200 mm Hg hours

Watkins32 5.5 years 100 Not reported Unknown Unknown 45* Not reported
Sarnaik33 45 months 31† Severe acute respiratory failure Frequency: 8–10 Hz No 74 Death predicted by pre-HFOV
(PaO2/FIO2 ⬍ 150 mm Hg) with Amplitude: 40 cm H2O OI ⱖ 20 and failure to
PEEP ⱖ 8 cm H2O, and/or decrease by 20% at 6 hours
PaCO2 ⱖ 60 mm Hg of HFOV
Berner34 10 years 13 Confirmed respiratory syncytial Frequency: 8–12 Hz Yes 100 Not reported
virus bronchiolitis Amplitude: chest wiggle
35
Arnold 1.5 years 232 Not reported Frequency: 5–10 Hz Yes 53.4‡ Death independently predicted by
Amplitude: chest wall wiggle immunodeficiency and OI at
24 hours of HFOV. Chronic
lung disease independently
PEDIATRIC HFOV FROM

predicted by presence of sepsis

and OI at 24 hours of HFOV
A

Brogan36 5 years 66 Not reported Frequency: weight-dependent No 39.4 Presence of non-pulmonary organ
Amplitude: chest wall wiggle failure associated with death
Martinon Torres37 3 months 6 OI ⬎ 13 Frequency: weight-dependent Yes 40 Not reported
Power: 40
38
Ben Jaballah 4 years 20 Weight ⱕ 35 kg, FIO2 ⬎ 0.6 Frequency: weight-dependent Yes 75 Not reported
Amplitude: chest wall wiggle
Duval39 4 years 35 Diffuse alveolar disease and small Frequency: weight-dependent Yes 88.6 Not reported
airway disease Amplitude: chest wall wiggle
Anton40 1.5 years 19 Patients with ARDS with PaO2/FIO2 Not reported Unknown 73.7 Initial OI ⬎ 20 and failure
⬍ 200 mm Hg to decrease by 20% at 6 hours
predicted death
Rosenberg41 Unknown 12§ OI ⬎ 13, gross air leak, Frequency: weight-dependent No 41.7 In non-survivors OI increased
PHYSIOLOGIC PERSPECTIVE

weight ⬍ 35 kg Amplitude: chest wall wiggle after 24 hours of HFOV

Fedora42 Unknown 26 ARDS, stratification by duration of Frequency: weight-dependent Yes 42 Early HFOV (ⱕ 24 hours)
conventional ventilation Amplitude: chest wall wiggle associated with significant
improvement in mortality

* Authors reported a decrease in mortality over time.

† 20 patients were managed with high-frequency oscillatory ventilation (HFOV), the remaining with high-frequency jet ventilation.
‡ Overall survival is shown. Authors reported differences in survival rate depending upon the underlying cause of the acute respiratory failure.
§ 7 patients were managed with HFOV, the remaining with high-frequency jet ventilation.
OI ⫽ oxygenation index

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plicability of the OI as a predictor for patient outcome despite the application of maximal lung-protective con-
during HFOV has been confirmed by others.31,41 Some ventional mechanical ventilation (ie, limiting peak inspira-
have linked failure of the OI to improve by at least 20% tory pressures to 30 –35 cm H2O and sufficient level of
6 hours after transition to HFOV with adverse outcome.33,40 PEEP) in children with acute lung injury/ARDS. Alter-
The use of HFOV in pulmonary conditions with in- natively, the OI can be used, although a specific threshold
creased airway resistance and prolonged time constants, needs to determined. For patients with OAD no guideline
such as virus-induced OAD, remains a subject of debate is available for when to consider HFOV. Based upon our
because of the assumed risk of dynamic air-trapping re- own experiences we consider HFOV when refractory re-
sulting from inadequate egress of air during expiration, spiratory acidosis persists despite maximum conservative
as seen in high-frequency jet ventilation. However, the measures such as nebulization or intravenous administra-
SensorMedics 3100 A/B oscillator has an active expira- tion of bronchodilators, use of heliox, or use of external
tory phase. Nevertheless, several institutions have re- PEEP to stent occluded airways.
ported safe and beneficial use of HFOV in this patient In our opinion there are no known contraindications for
population.30,34,35,37,39,44 HFOV, although its safety has been questioned in patients
It can thus be concluded that at present a beneficial with severe traumatic brain injury, based upon the assump-
effect of HFOV on mortality has not been established. tion that the high intrathoracic pressures are propagated
This may be explained by various factors. First, the knowl- toward the brain and impede the cerebral circulation. How-
edge on lung-protective ventilation has significantly in- ever, this has been refuted by both animal and clinical
creased over the past years. It is now universally accepted data.45,46
that a low VT should be applied. However, the study by
Arnold and colleagues28 was conducted in the era prior to Best HFOV Approach and Oscillator Settings
the ARDS Network trial. In their study, the authors did for Oxygenation
not specify the VT used on conventional mechanical ven-
tilation. Similar criticisms can be made toward the study Lung volume is the main determinant of oxygenation in
by Samransamruajkit et al,29 so that it is not unthinkable DAD during HFOV. Simplified, the PaO2 increases linearly
that patients on conventional mechanical ventilation were with lung volume up to a certain point when alveoli be-
subjected to high VT. Second, both RCTs were not pow- come overdistended.47 This suggests that an open-lung strat-
ered to detect statistically significant differences in mor- egy (ie, opening up the lung and keeping it open) in DAD
tality. by (repeated) recruitment maneuvers (RM) should be con-
sidered when switching to HFOV. Furthermore, pressure
Critical Appraisal of the HFOV Strategy Employed oscillations are less dampened in lungs with ongoing at-
electasis, thus exposing the conducting airways to higher
Alternatively, the question could also be raised whether injurious pressure swings.48 Animal work has indeed shown
HFOV was applied in its most optimal fashion. These improved lung compliance and less hyaline membrane
issues (among others) include identification of the patient formation when such strategies were applied.15,49,50 How-
who will benefit the most from HFOV, the timing of cross- ever, in both pediatric RCTs, as well as in nearly half of
over from conventional mechanical ventilation to HFOV, all observational cohort studies, there is no mention of
as well as determining the best oscillator settings. RMs being performed.28,29,31–33,36,40,41 Also, there is much
ongoing scientific debate related to use and efficacy of
Indications for and Timing of HFOV RMs. Not all lung diseases are recruitable, and in general
the potential for lung recruitability is highly variable.51
The indications for HFOV are ill-defined and usually Furthermore, there are so far no clinical studies establish-
depend upon the personal preference of the attending phy- ing the beneficial effects of RMs during HFOV, let alone
sician. In general, HFOV is considered only as a rescue determining the best RM.
approach when conventional mechanical ventilation fails. The latter has been addressed in one study in which 4
One group of investigators have evaluated the early use of different RM approaches were compared: a step-wise pres-
HFOV instead of using it as rescue therapy.42 In their sure increase over 6 min; a 20 s sustained dynamic infla-
small observational study of 26 patients, it was found that tion (either one or repeated 6 times); and a standard ap-
the group of patients who was transitioned to HFOV within proach (setting mean airway pressure direct at start).52
24 hours of conventional mechanical ventilation had a This study showed that a step-wise pressure increase pro-
significantly higher 30-day survival rate (58.8 vs 12.5%). duced the greatest increase in lung volume and resolution
We suggest that HFOV should be considered if oxygen- of atelectasis. Thus, this study suggests that the stepwise
ation remains severely impaired (in our institution defined increase pressure approach might be considered for opti-
by SpO2 ⬍ 88% and/or PaO2 ⬍ 50 mm Hg with FIO2 ⬎ 0.6) mizing lung volume during HFOV, as it incorporates not

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 REFLECTIONS ON PEDIATRIC HFOV FROM A PHYSIOLOGIC PERSPECTIVE

only pressure but also adequate duration of the RM. The quency (f), in Hertz (Hz), inspiratory to expiratory ratio,
clinical benefits of RMs during HFOV have been addressed position of the membrane, endotracheal tube (ETT) length
in a recently completed phase II trial in critically ill adults and diameter, and the presence of ETT leakage.20,66,67
comparing HFOV with and without RMs (www.clinical- The ETT constitutes the major work load to the oscil-
trials.gov NCT00399581). Unfortunately, a pediatric coun- lator and is an important determinant of VT.68,69 VT is
terpart is lacking, but the adult results are eagerly awaited. proportional to the ETT inner cross-sectional area, because
Another, at least theoretical, benefit of RMs is that it the impedance of the ETT exceeds the impedance of the
allows oscillating the patient on the deflation limb of the lung.70,71 Increasing diameter (inner diameter 2.5– 4.0 mm)
P-V curve, thereby (partially) avoiding injurious hyper- of the ETT increases pressure transmission.62
inflation and atelectasis.22,53–59 By doing so, less CDP is The manufacturer’s manual recommends setting f and
needed to maintain a certain lung volume on the inflation power according to the patient’s age, ventilator settings,
limb, because of the hysteresis of the respiratory system. and observation of chest wiggle. This recommendation has
In our view and practice, this can be achieved in clinical been adopted into clinical practice, using the f and power
practice in patients with DAD by initially setting the CDP in a weight and age-dependent manner in both RCTs, as
3–5 cm H2O above the mean airway pressure on conven- well as in the observational cohort studies.28 –30,33–39,41,42
tional mechanical ventilation, as the distal CDP is lower We propose that these recommendations may be re-
than the set proximal CDP.60,61 Then the CDP should be fined. From a physiological perspective it seems more
increased stepwise over a certain period of time until the appropriate to use the highest possible f in DAD. First,
point where oxygenation (either the SpO2 or the PaO2) does f determines the rate of oscillations and directly influences
not improve at a fixed FIO2 (suggestive of approximating the VT. Hence, the higher the f, the smaller the VT, be-
total lung capacity). Also, with increasing compliance the cause changes in f are inversely proportional to the distal
⌬P depicted by the oscillator may decrease; hence, it may oscillatory pressure amplitude. Consequently, it becomes
be indicative for approximating total lung capacity when easier to stay within the limits of the safe zone (ie, the zone
⌬P increases again.62 The next step would be to reduce the with the smallest risk of injurious hyperinflation or atel-
CDP to the point where oxygenation starts to decrease ectasis) of the P-V loop. Second, collapsed lung regions
after initial improvement (suggestive of derecruitment). are more easily opened at higher f.72 Third, the delivered
The ⌬P depicted by the oscillator may initially decrease, VT is more equally distributed, as it becomes less depen-
but may increase again when derecruitment on the defla- dent on regional compliance at higher f.73 Lastly, the square
tion limb occurs. Ultimately, the CDP will finally set block waveform is better preserved, allowing a more con-
2– 4 cm H2O above this point. We have adopted such an stant VT.74,75 Needless to say, it is necessary to maintain an
approach in our clinical practice. A positive effect of sus- appropriate CDP when setting the f.
tained inflations prior to the stepwise increase in CDP has The next question, then, is what could be considered as
not been demonstrated.52,63 optimal f. Venegas and Fredberg have proposed that how
HFOV may also be considered in patients with refrac- f needs to be set depends upon the so-called corner fre-
tory OAD. However, in these patients the purpose of the quency (Fc) of the lung, Fc ⫽ 1/(2␲RC), where R is re-
stepwise increase in CDP is to splint open and stent the sistance and C compliance.59 Fc defines the optimal fre-
airways to a certain point when the PaCO2 starts to drop, in quency at which there is adequate gas transport during
order to prevent relatively healthy alveoli being exposed to HFOV in combination with the least injurious pressures,
high pressures once the airways are open.64 Importantly, and is influenced by the underlying disease (Figure). It is
the novel approach toward optimizing oxygenation as dis- increased in lung diseases characterized by short time con-
cussed needs to be studied for safety and effectiveness. stants and low compliance, such as in DAD. This implies
that at higher f, alveoli are ventilated at a lower pressure
Best HFOV Approach and Oscillator Settings cost of ventilation, as opposed to lung diseases character-
for Ventilation ized by prolonged time constants (for example OAD).
Importantly, f is intimately linked with ⌬P. Basically,
The V̇CO2 is determined by patient-related characteris- the higher the ⌬P, the larger the VT. Yet, we (unpublished
tics and oscillator settings. The first include compliance data) and others have observed in bench test studies that
and resistance of the respiratory system.62,65 With reduced VT was smaller when combining high f (15 Hz) and high
compliance in unresolved atelectasis there is a marked power (set to achieve a ⌬P of 90), compared with low f
increase in transmission of the peak-to-trough ⌬P to the (5 Hz) and low power settings, as the distal pressure am-
alveoli and bronchi. Increased resistance decreases the plitude was much lower but still associated with a suffi-
transmission of the peak-to-trough ⌬P over the airways cient V̇CO2.76 These findings were in agreement with the
to the alveoli.62 Oscillator settings include oscillatory work from Hager and co-workers. They have measured VT
power setting (magnitude of membrane displacement), fre- in adult patients with ARDS managed on HFOV and found

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 REFLECTIONS ON PEDIATRIC HFOV FROM A PHYSIOLOGIC PERSPECTIVE

informative to assess if targets of ventilation (ie, permis-

sive hypercapnia [pH ⬎ 7.15–7.25]) are being met. Trans-
cutaneous CO2 (PtCO2) monitoring may be used as a non-
invasive alternative.79 Developments are being made with
respect to electrical impedance tomography and respira-
tory inductance plethysmography incorporated in the
Bicore II as tools for the determination of the optimal
CDP.80,81
We have recently begun to explore the use of respira-
tory inductance plethysmography in guiding the stepwise
increase in CDP. Alternatively, the optimal CDP may be
recognized when both lung compliance and OI (calculated
by CDP ⫻ FIO2 ⫻ 100/PaO2) are optimal.82 The benefit of
the OI over the PaO2/FIO2 ratio is that it takes the degree of
Figure. Corner frequency (Fc) of the lung in patients with decreased ventilator settings (as summarized by the mean airway
compliance, such as acute lung injury/ARDS and increased resis- pressure) into account. Van Genderingen and co-workers
tance, such as obstructive airway disease. Fc (graphically depicted
by the dot) defines the optimal frequency at which there is ade-
found that the lowest OI during the RM indicated at which
quate gas transport during HFOV in combination with the least CDP the oxygenation was considered to be optimal; this
injurious pressures. It is defined by 1/2␲RC, where R is resistance also indicated the point on the deflation limb of the P-V
and C compliance. (From Reference 59, with permission.) curve where physiologic shunt fraction was the lowest.83
The oscillatory pressure ratio (OPR) may also aid in the
identification.65 OPR is defined as the ratio of the distal
smaller VT with the combination high f and high power and proximal ETT pressure swings. To calculate the OPR
setting.69 The use of these higher f did not impair gas it is necessary to measure the tracheal pressure. In a 3.0 mm
exchange.77 ETT neonatal respiratory distress syndrome simulated
Importantly, how are these theoretical benefits trans-
model, OPR decreased when the CDP was increased (sug-
lated into clinical practice? At present it is impossible to
gestive of lung recruitment) but increased when the CDP
detect the Fc and thus impossible to identify the optimal f.
was increased further. This suggested hyperinflation. The
Furthermore, what ⌬P should be targeted? Based upon our
OPR was the lowest at maximum compliance. The OPR
own experiences, we propose using the highest f in com-
bination with a fixed power setting that is associated with was also affected by frequency, ⌬P, and ETT inner diam-
acceptable CO2 elimination (in our view pH ⬎ 7.25) in eter. The OPR was further evaluated in an animal model of
patients with DAD. For patients with OAD the initial f acute lung injury.84 One of the main findings of this study
should theoretically be between 5 and 7 Hz. The ⌬P should was that, after lung recruitment, similar oxygenation with
not exceed 70 –90, because higher pressures may theoret- smaller pressure swings could be achieved with a lower
ically expose the proximal airways to injurious pressures. CDP set by the deflation limb of the P-V curve rather than
Again, this novel approach toward optimizing ventilation the inflation limb. The clinical use of these potential aids,
during HFOV requires further evaluation for its safety and however, needs to be established.
efficacy. For instance, it has been suggested that the use of
high amplitudes might lead to gas trapping due to the
Spontaneous Breathing During HFOV
development of so-called choke points causing expiratory
flow limitation, especially at low CDP.78 However, the
occurrence of choke points has never been demonstrated. Maintaining spontaneous breathing during HFOV im-
proves oxygenation and regional ventilation.85,86 Sponta-
Monitoring During HFOV neous breathing during HFOV is feasible for small chil-
dren but becomes more difficult when the patient demands
At present, physicians have the SpO2, blood gas analysis, high inspiratory flows. The maximal possible bias flow
⌬P, and chest radiography at their disposal for evaluating delivered by the oscillator may be well below the needs of
the response of a patient to HFOV. It is often advised to the patient. This will lead to increased work of imposed
obtain chest radiographs to evaluate the optimal lung in- breathing, as shown by our group in a bench test model.87
flation. However, such an approach has never been vali- Because of this, many older children on the oscillator are
dated, and we therefore do not routinely obtain chest ra- likely to need sedatives and neuromuscular blockade dur-
diographs. Repeated daily blood gas analyses may be ing their illness, prohibiting spontaneous breathing.

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 REFLECTIONS ON PEDIATRIC HFOV FROM A PHYSIOLOGIC PERSPECTIVE

Conclusions macrophages in surfactant depleted piglets. Pediatr Res 2004;55(2):

339-346.
14. Rotta AT, Gunnarsson B, Fuhrman BP, Hernan LJ, Steinhorn DM.
The beneficial effect of HFOV on outcome in critically Comparison of lung protective ventilation strategies in a rabbit model
ill children remains unclear. However, based upon the phys- of acute lung injury. Crit Care Med 2001;29(11):2176-2184.
iologic properties of the oscillator, one can ask if HFOV 15. McCulloch PR, Forkert PG, Froese AB. Lung volume maintenance
has been employed in its most optimal fashion. We sug- prevents lung injury during high frequency oscillatory ventilation
in surfactant-deficient rabbits. Am Rev Respir Dis 1988;137(5):
gest that in patients with diffuse alveolar disease, convert
1185-1192.
to HFOV early in the disease course; employ an open-lung 16. Imai Y, Nakagawa S, Ito Y, Kawano T, Slutsky AS, Miyasaka K.
strategy using (repeated) RMs; and use the highest fre- Comparison of lung protection strategies using conventional and
quency and high fixed power setting, providing that ade- high-frequency oscillatory ventilation. J Appl Physiol 2001;91(4):
quate gas exchange is maintained. For patients with OAD, 1836-1844.
HFOV may be considered to open up and stent the air- 17. Carney D, DiRocco J, Nieman G. Dynamic alveolar mechanics and
ventilator-induced lung injury. Crit Care Med 2005;33(Suppl 3):
ways. Importantly, future studies are needed to validate S122-S128.
these novel approaches and to evaluate their effect on 18. Schindler M, Seear M. The effect of lung mechanics on gas trans-
patient outcome. port during high-frequency oscillation. Pediatr Pulmonol 1991;11(4):
335-339.
19. Boynton BR, Hammond MD, Fredberg JJ, Buckley BG, Villa-
REFERENCES nueva D, Frantz ID, III. Gas exchange in healthy rabbits during
high-frequency oscillatory ventilation. J Appl Physiol 1989;66(3):
1. Tremblay LN, Slutsky AS. Ventilator-induced lung injury: from the
1343-1351.
bench to the bedside. Intensive Care Med 2006;32(1):24-33.
20. Slutsky AS, Kamm RD, Rossing TH, Loring SH, Lehr J, Shapiro
2. Esan A, Hess DR, Raoof S, George L, Sessler CN. Severe hypox-
AH, et al. Effects of frequency, tidal volume, and lung volume on
emic respiratory failure: part 1: ventilatory strategies. Chest 2010;
CO2 elimination in dogs by high frequency (2-30 Hz), low tidal
137(5):1203-1216.
volume ventilation. J Clin Invest 1981;68(6):1475-1484.
3. Imai Y, Slutsky AS. High-frequency oscillatory ventilation and
ventilator-induced lung injury. Crit Care Med 2005;33(Suppl 3): 21. Kamitsuka MD, Boynton BR, Villanueva D, Vreeland PN, Frantz
S129-S134. ID, III. Frequency, tidal volume, and mean airway pressure combi-
4. Slutsky AS, Drazen FM, Ingram RH Jr, Kamm RD, Shapiro AH, nations that provide adequate gas exchange and low alveolar pres-
Fredberg JJ, et al. Effective pulmonary ventilation with small- sure during high frequency oscillatory ventilation in rabbits. Pediatr
volume oscillations at high frequency. Science 1980;209(4456): Res 1990;27(1):64-69.
609-671. 22. Froese AB. High-frequency oscillatory ventilation for adult respira-
5. Bohn DJ, Miyasaka K, Marchak BE, Thompson WK, Froese AB, tory distress syndrome: let’s get it right this time! Crit Care Med
Bryan AC. Ventilation by high-frequency oscillation. J Appl Physiol 1997;25(6):906-908.
1980;48(4):710-716. 23. Santschi M, Jouvet P, Leclerc F, Gauvin F, Newth CJ, Carroll CL,
6. Aspros AJ, Coto CG, Lewis JF, Veldhuizen RA. High-frequency et al; PALIVE Investigators; Pediatric Acute Lung Injury and Sepsis
oscillation and surfactant treatment in an acid aspiration model. Investigators (PALISI) Network; European Society of Pediatric and
Can J Physiol Pharmacol 2010;88(1):14-20. Neonatal Intensive Care (ESPNIC). Acute lung injury in children:
7. Shimaoka M, Fujino Y, Taenaka N, Hiroi T, Kiyono H, Yoshiya I, therapeutic practice and feasibility of international clinical trials.
I. High frequency oscillatory ventilation attenuates the activation of Pediatr Crit Care Med 2010;11(6):681-689.
alveolar macrophages and neutrophils in lung injury. Crit Care 1998; 24. Erickson S, Schibler A, Numa A, Nuthall G, Yung M, Pascoe E,
2(1):35-39. et al. Acute lung injury in pediatric intensive care in Australia and New
8. Muellenbach RM, Kredel M, Said HM, Klosterhalfen B, Zollhoefer Zealand: a prospective, multicenter, observational study. Pediatr Crit
B, Wunder C, et al. High-frequency oscillatory ventilation reduces Care Med 2007;8(4):317-323.
lung inflammation: a large-animal 24-h model of respiratory distress. 25. Flori HR, Glidden DV, Rutherford GW, Matthay MA. Pediatric
Intensive Care Med 2007;33(8):1423-1433. acute lung injury: prospective evaluation of risk factors associated
9. Nakagawa R, Koizumi T, Ono K, Yoshikawa S, Tsushima K, Otagiri with mortality. Am J Respir Crit Care Med 2005;171(9):995-1001.
T. Effects of high-frequency oscillatory ventilation on oleic acid- 26. Randolph AG, Meert KL, O’Neil ME, Hanson JH, Luckett PM,
induced lung injury in sheep. Lung 2008;186(4):225-232. Arnold JH, et al. The feasibility of conducting clinical trials in in-
10. Sugiura M, McCulloch PR, Wren S, Dawson RH, Froese AB. fants and children with acute respiratory failure. Am J Respir Crit
Ventilator pattern influences neutrophil influx and activation in Care Med 2003;167(10):1334-1340.
atelectasis-prone rabbit lung. J Appl Physiol 1994;77(3):1355-1365. 27. Zimmerman JJ, Akhtar SR, Caldwell E, Rubenfeld GD. Incidence
11. Jian MY, Koizumi T, Yokoyama T, Tsushima K, Kubo K. Compar- and outcomes of pediatric acute lung injury. Pediatrics 2009;124(1):
ison of acid-induced inflammatory responses in the rat lung during 87-95.
high frequency oscillatory and conventional mechanical ventilation. 28. Arnold JH, Hanson JH, Toro-Figuero LO, Gutierrez J, Berens RJ,
Inflamm Res 201;59(11):931-937. Anglin DL. Prospective, randomized comparison of high-frequency
12. Takata M, Abe J, Tanaka H, Kitano Y, Doi S, Kohsaka T, et al. oscillatory ventilation and conventional mechanical ventilation in
Intraalveolar expression of tumor necrosis factor-alpha gene during pediatric respiratory failure. Crit Care Med 1994;22(10):1530-1539.
conventional and high-frequency ventilation. Am J Respir Crit Care 29. Samransamruajkit R, Prapphal N, Deelodegenavong J, Poovorawan
Med 1997;156(1):272-279. Y. Plasma soluble intercellular adhesion molecule-1 (sICAM-1) in
13. der Hardt K, Kandler MA, Fink L, Schoof E, Dotsch J, Branden- pediatric ARDS during high frequency oscillatory ventilation: a
stein O, et al. High frequency oscillatory ventilation suppresses in- predictor of mortality. Asian Pac J Allergy Immunol 2005;23(4):
flammatory response in lung tissue and microdissected alveolar 181-188.

1502 RESPIRATORY CARE • SEPTEMBER 2012 VOL 57 NO 9

 REFLECTIONS ON PEDIATRIC HFOV FROM A PHYSIOLOGIC PERSPECTIVE

30. Slee-Wijffels FY, van der Vaart KR, Twisk JW, Markhorst DG, 48. Sakai T, Kakizawa H, Aiba S, Takahashi R, Yoshioka T, Iinuma K.
Plotz FB. High-frequency oscillatory ventilation in children: a single- Effects of mean and swing pressures on piston-type high-frequency
center experience of 53 cases. Crit Care 2005;9(3):R274-R279. oscillatory ventilation in rabbits with and without acute lung injury.
31. Lochindarat S, Srisan P, Jatanachai P. Factors effecting the outcome Pediatr Pulmonol 1999;27(5):328-335.
of acute respiratory distress syndrome in pediatric patients treated 49. Bond DM, McAloon J, Froese AB. Sustained inflations improve
with high frequency oscillatory ventilation. J Med Assoc Thai 2003; respiratory compliance during high-frequency oscillatory ventilation
86(Suppl 3):S618-S627. but not during large tidal volume positive-pressure ventilation in
32. Watkins SJ, Peters MJ, Tasker RC. One hundred courses of high rabbits. Crit Care Med 1994;22(8):1269-1277.
frequency oscillatory ventilation: what have we learned? Eur J Pediatr 50. Bond DM, Froese AB. Volume recruitment maneuvers are less del-
2000;159(1-2):134. eterious than persistent low lung volumes in the atelectasis-prone
33. Sarnaik AP, Meert KL, Pappas MD, Simpson PM, Lieh-Lai MW, rabbit lung during high-frequency oscillation. Crit Care Med 1993;
Heidemann SM. Predicting outcome in children with severe acute 21(3):402-412.
respiratory failure treated with high-frequency ventilation. Crit Care 51. Gattinoni L, Caironi P, Cressoni M, Chiumello D, Ranieri VM,
Med 1996;24(8):1396-1402. Quintel M, et al. Lung recruitment in patients with the acute respi-
34. Berner ME, Hanquinet S, Rimensberger PC. High frequency oscil- ratory distress syndrome. N Engl J Med 2006;354(17):1775-1786.
latory ventilation for respiratory failure due to RSV bronchiolitis. 52. Pellicano A, Tingay DG, Mills JF, Fasulakis S, Morley CJ, Dar-
Intensive Care Med 2008;34(9):1698-1702. gaville PA. Comparison of four methods of lung volume recruitment
35. Arnold JH, Anas NG, Luckett P, Cheifetz IM, Reyes G, Newth CJ, during high frequency oscillatory ventilation. Intensive Care Med
et al. High-frequency oscillatory ventilation in pediatric respiratory 2009;35(11):1990-1908.
failure: a multicenter experience. Crit Care Med 2000;28(12): 53. Boynton BR, Villanueva D, Hammond MD, Vreeland PN, Buckley
3913-3919. B, Frantz ID, III. Effect of mean airway pressure on gas exchange
36. Brogan TV, Bratton SL, Meyer RJ, O’Rourke PP, Jardine DS. Non- during high-frequency oscillatory ventilation. J Appl Physiol 1991;
pulmonary organ failure and outcome in children treated with high- 70(2):701-707.
frequency oscillatory ventilation. J Crit Care 2000;15(1):5-11. 54. Goddon S, Fujino Y, Hromi JM, Kacmarek RM. Optimal mean
37. Martinon Torres F, Rodriguez Nuñez A, Jaimovich DG, Martinon airway pressure during high-frequency oscillation: predicted by the
Sanchez JM. [High-frequency oscillatory ventilation in pediatric pa- pressure-volume curve. Anesthesiology 2001;94(5):862-869.
tients. protocol and preliminary results]. An Esp Pediatr 2000;53(4): 55. Luecke T, Meinhardt JP, Herrmann P, Weisser G, Pelosi P, Quintel
305-313. Article in Spanish. M. Setting mean airway pressure during high-frequency oscillatory
38. Ben Jaballah N, Khaldi A, Mnif K, Bouziri A, Belhadj S, Hamdi A, ventilation according to the static pressure: volume curve in surfac-
et al. High-frequency oscillatory ventilation in pediatric patients with tant-deficient lung injury: a computed tomography study. Anesthe-
acute respiratory failure. Pediatr Crit Care Med 2006;7(4):362-367. siology 2003;99(6):1313-1322.
39. Duval EL, Markhorst DG, Gemke RJ, van Vught AJ. High-frequency 56. Kacmarek RM, Malhotra A. High-frequency oscillatory ventilation:
oscillatory ventilation in pediatric patients. Neth J Med 2000;56(5): what large-animal studies have taught us! Crit Care Med 2005;
177-185. 33(Suppl 3):S148-S154.
40. Anton N, Joffe KM, Joffe AR. Inability to predict outcome of acute 57. Markhorst DG, van Genderingen HR, van Vught AJ. Static pressure-
respiratory distress syndrome in children when using high frequency volume curve characteristics are moderate estimators of optimal
oscillation. Intensive Care Med 2003;29(10):1763-1769. airway pressures in a mathematical model of (primary/pulmonary)
41. Rosenberg RB, Broner CW, Peters KJ, Anglin DL. High-frequency acute respiratory distress syndrome. Intensive Care Med 2004;30(11):
ventilation for acute pediatric respiratory failure. Chest 1993;104(4): 2086-2093.
1216-1221. 58. Tingay DG, Mills JF, Morley CJ, Pellicano A, Dargaville PA. The
42. Fedora M, Klimovic M, Seda M, Dominik P, Nekvasil R. Effect of deflation limb of the pressure-volume relationship in infants during
early intervention of high-frequency oscillatory ventilation on the high-frequency ventilation. Am J Respir Crit Care Med 2006;173(4):
outcome in pediatric acute respiratory distress syndrome. Bratisl Lek 414-420.
Listy 2000;101(1):8-13. 59. Venegas JG, Fredberg JJ. Understanding the pressure cost of venti-
43. Dobyns EL, Anas NG, Fortenberry JD, Deshpande J, Cornfield DN, lation: why does high-frequency ventilation work? Crit Care Med
Tasker RC, et al. Interactive effects of high-frequency oscillatory 1994;22(Suppl 9):S49-S57.
ventilation and inhaled nitric oxide in acute hypoxemic respiratory 60. Chan V, Greenough A, Giffin F. Disease severity and optimum
failure in pediatrics. Crit Care Med 2002;30(11):2425-2429. mean airway pressure level on transfer to high frequency oscillation.
44. Leipala JA, Sharma A, Lee S, Milner AD, Greenough A. An in vitro Pediatr Pulmonol 1994;17(3):178-182.
assessment of gas trapping during high frequency oscillation. Physiol 61. Pillow JJ, Neil H, Wilkinson MH, Ramsden CA. Effect of I/E ratio
Meas 2005;26(3):329-336. on mean alveolar pressure during high-frequency oscillatory venti-
45. David M, Markstaller K, Depta AL, Karmrodt J, Herweling A, Kemp- lation. J Appl Physiol 1999;87(1):407-414.
ski O, et al. Initiation of high-frequency oscillatory ventilation and 62. Pillow JJ, Sly PD, Hantos Z, Bates JH. Dependence of intrapul-
its effects upon cerebral circulation in pigs: an experimental study. monary pressure amplitudes on respiratory mechanics during high-
Br J Anaesth 2006;97(4):525-532. frequency oscillatory ventilation in preterm lambs. Pediatr Res 2002;
46. O’Rourke J, Sheeran P, Heaney M, Talbot R, Geraghty M, Costello 52(4):538-544.
J, et al. Effects of sequential changes from conventional ventilation 63. Muellenbach RM, Kredel M, Zollhoefer B, Wunder C, Roewer N,
to high-frequency oscillatory ventilation at increasing mean airway Brederlau J. Sustained inflation and incremental mean airway pres-
pressures in an ovine model of combined lung and head injury. Eur J sure trial during conventional and high-frequency oscillatory venti-
Anaesthesiol 2007;24(5):454-463. lation in a large porcine model of acute respiratory distress syn-
47. Suzuki H, Papazoglou K, Bryan AC. Relationship between PaO2 drome. BMC Anesthesiol 2006;6:8.
and lung volume during high frequency oscillatory ventilation. Acta 64. Kneyber MC, Plotz FB, Sibarani-Ponsen RD, Markhorst DG. High-
Paediatr Jpn 1992;34(5):494-500. frequency oscillatory ventilation (HFOV) facilitates CO2 elimination

RESPIRATORY CARE • SEPTEMBER 2012 VOL 57 NO 9 1503

 REFLECTIONS ON PEDIATRIC HFOV FROM A PHYSIOLOGIC PERSPECTIVE

in small airway disease: the open airway concept. Respir Med 2005; 76. Van de Kieft M, Dorsey D, Morison D, Bravo L, Venticinque S,
99(11):1459-1461. Derdak S. High-frequency oscillatory ventilation: lessons learned from
65. van Genderingen HR, Versprille A, Leenhoven T, Markhorst DG, mechanical test lung models. Crit Care Med 2005;33(Suppl 3):
van Vught AJ, Heethaar RM. Reduction of oscillatory pressure along S142-S147.
the endotracheal tube is indicative for maximal respiratory compli- 77. Fessler HE, Hager DN, Brower RG. Feasibility of very high-
ance during high-frequency oscillatory ventilation: a mathematical frequency ventilation in adults with acute respiratory distress syn-
model study. Pediatr Pulmonol 2001;31(6):458-463. drome. Crit Care Med 2008;36(4):1043-1048.
66. Scalfaro P, Pillow JJ, Sly PD, Cotting J. Reliable tidal volume 78. Bryan AC, Slutsky AS. Long volume during high frequency oscil-
estimates at the airway opening with an infant monitor during lation. Am Rev Respir Dis 1986;133(5):928-930.
high-frequency oscillatory ventilation. Crit Care Med 2001;29(10): 79. Tobias JD. Transcutaneous carbon dioxide monitoring in infants and
1925-1930. children. Paediatr Anaesth 2009;19(5):434-444.
67. Hamel DS, Katz AL, Craig DM, Davies JD, Cheifetz IM. Carbon 80. van Genderingen HR, van Vught AJ, Jansen JR. Regional lung vol-
dioxide elimination and gas displacement vary with piston position ume during high-frequency oscillatory ventilation by electrical im-
during high-frequency oscillatory ventilation. Respir Care 2005;50(3): pedance tomography. Crit Care Med 2004;32(3):787-794.
361-366. 81. Habib RH, Pyon KH, Courtney SE. Optimal high-frequency oscil-
68. Gavriely N, Solway J, Loring SH, Butler JP, Slutsky AS, Drazen JM. latory ventilation settings by nonlinear lung mechanics analysis. Am J
Pressure-flow relationships of endotracheal tubes during high- Respir Crit Care Med 2002;166(7):950-953.
82. Markhorst DG, Jansen JR, van Vught AJ, van Genderingen HR.
frequency ventilation. J Appl Physiol 1985;59(1):3-11.
Breath-to-breath analysis of abdominal and rib cage motion in sur-
69. Hager DN, Fessler HE, Kaczka DW, Shanholtz CB, Fuld MK, Si-
factant-depleted piglets during high-frequency oscillatory ventila-
mon BA, et al. Tidal volume delivery during high-frequency oscil-
tion. Intensive Care Med 2005;31(3):424-430.
latory ventilation in adults with acute respiratory distress syndrome.
83. van Genderingen HR, van Vught JA, Jansen JR, Duval EL, Mark-
Crit Care Med 2007;35(6):1522-1529.
horst DG, Versprille A. Oxygenation index, an indicator of optimal
70. Niederer PF, Leuthold R, Bush EH, Spahn DR, Schmid ER. High-
distending pressure during high-frequency oscillatory ventilation?
frequency ventilation: oscillatory dynamics. Crit Care Med 1994;
Intensive Care Med 2002;28(8):1151-1156.
22(Suppl 9):S58-S65.
84. van Genderingen HR, van Vught AJ, Duval EL, Markhorst DG,
71. Hirao O, Iguchi N, Uchiyama A, Mashimo T, Nishimura M, Fujino Jansen JR. Attenuation of pressure swings along the endotracheal
Y. Influence of endotracheal tube bore on tidal volume during high tube is indicative of optimal distending pressure during high-
frequency oscillatory ventilation: a model lung study. Med Sci Monit frequency oscillatory ventilation in a model of acute lung injury.
2009;15(1):MT1-MT4. Pediatr Pulmonol 2002;33(6):429-436.
72. Bauer K, Brucker C. The role of ventilation frequency in airway 85. van HM, Roubik K, Kopelent V, Plotz FB, Markhorst DG.
reopening. J Biomech 2009;29;42(8):1108-1113. Demand flow facilitates spontaneous breathing during high-frequency
73. Tsuzaki K, Hales CA, Strieder DJ, Venegas JG. Regional lung me- oscillatory ventilation in a pig model. Crit Care Med 2009;37(3):
chanics and gas transport in lungs with inhomogeneous compliance. 1068-1073.
J Appl Physiol 1993;75(1):206-216. 86. van HM, Roubik K, Kopelent V, Kneyber MC, Markhorst DG. Spon-
74. Custer JW, Ahmed A, Kaczka DW, Mulraeany DG, Simon BA, taneous breathing during high-frequency oscillatory ventilation im-
Easley RB. In vitro performance comparison of the Sensormedics proves regional lung characteristics in experimental lung injury. Acta
3100A and B high-frequency oscillatory ventilators. Pediatr Crit Anaesthesiol Scand 2010;54(10):1248-1256.
Care Med 2010;12(4):e176-e180. 87. van Heerde M, van Genderingen HR, Leenhoven T, Roubik K, Plotz
75. Meyer J, Cox PN, McKerlie C, Bienzle D. Protective strategies of FB, Markhorst DG. Imposed work of breathing during high-
high-frequency oscillatory ventilation in a rabbit model. Pediatr Res frequency oscillatory ventilation: a bench study. Crit Care 2006;
2006;60(4):401-406. 10(1):R23.

1504 RESPIRATORY CARE • SEPTEMBER 2012 VOL 57 NO 9