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\begin{document}

\title{Humidity during high-frequency oscillatory ventilation compared to
intermittent positive pressure ventilation in extremely preterm
neonates: an in-vitro and in-vivo observational study.}



\author[1]{Claude Danan}%
\author[1]{Manon Tauzin}%
\author[1]{Camille Jung}%
\author[1]{Xavier Durrmeyer}%
\author[1]{Laurence Caeymaex}%
\author[1]{Charles Treussart}%
\author[1]{Fabrice Decobert}%
\author[2]{Bruno Louis}%
\affil[1]{Centre Hospitalier Intercommunal de Creteil}%
\affil[2]{Universite Paris-Est Creteil Val de Marne}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Inappropriate humidification of inspired gas during
mechanical ventilation can impair lung development in extremely low
birthweight (ELBW) infants. Humidification depends on multiple factors,
such as the heater-humidifier device used, type of ventilation, and
environmental factors. Few studies have examined inspired gas
humidification in these infants, especially during high-frequency
oscillatory ventilation (HFOV). Our objective was to compare humidity
during HFOV and intermittent positive pressure ventilation (IPPV), in
vitro and in vivo. \textbf{Methods:} In-vitro and in-vivo studies used
the same ventilator during both HFOV and IPPV. The bench study used a
neonatal test lung and 2 heater-humidifiers with their specific
circuits; the in-vivo study prospectively included preterm infants born
before 28 weeks of gestation.~ \textbf{Results:} On bench testing, mean
absolute (AH) and relative (RH) humidity values were significantly lower
during HFOV than IPPV (RH~= 79.4\% \selectlanguage{ngerman}± 8.1\% vs 89.0\% ± 6.2\%,
P\textless{}0.001). Regardless of the ventilatory mode, mean relative
humidity significantly differed between the 2 heater-humidifiers (89.6\%
± 6.7\% vs 78.7\% ± 6.8\%, P=0.003). The in-vivo study included 10
neonates (mean~±~SD gestational age: 25.7 ± 0.9 weeks and birth weight:
624.4 ± 96.1 g). Mean relative humidity during HFOV was significantly
lower than during IPPV (74.6\% ± 5.7\% vs 83.0 ± 6.7\%, P=0.004).~
\textbf{Conclusion:} Relative humidity was significantly lower during
HFOV than IPPV, both in vitro and in vivo. The type of heater-humidifier
also influenced humidification. More systematic measurements of humidity
of inspired gas, especially during HFOV, should be considered to
optimize humidification and consequently lung protection in ELBW
infants.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Humidity during high-frequency oscillatory ventilation compared
to intermittent positive pressure ventilation in extremely preterm
neonates: an in-vitro and in-vivo observational study.}

Claude Danan\textsuperscript{1,2}, MD, Manon Tauzin\textsuperscript{1},
MD, Camille Jung\textsuperscript{3,4}, MD, PhD, Xavier
Durrmeyer\textsuperscript{1,2,3,5,6}, MD, PhD, Laurence
Caeymaex\textsuperscript{1,5}, MD, PhD, Charles
Treussart\textsuperscript{1}, MD, Fabrice Decobert\textsuperscript{1,2},
MD and Bruno Louis\textsuperscript{2}, MD.

Affiliations:

\textsuperscript{1} Neonatal Intensive Care Unit, Centre Hospitalier
Intercommunal de Creteil, Creteil, France

\textsuperscript{2} IMRB INSERM-Universite Paris Est Creteil, CNRS EMR
7000, Creteil, France

\textsuperscript{3} Clinical Research Centre, Centre Hospitalier
Intercommunal de Creteil, Creteil, France

\textsuperscript{4} Pediatrics, Centre hospitalier Intercommunal de
Creteil, Creteil, France.

\textsuperscript{5} Faculte de Sante, Universite Paris Est Creteil,
Creteil, France.

\textsuperscript{6} GRC CARMAS, IMRB, Universite Paris Est Creteil,
Faculte de Sante de Cr\selectlanguage{ngerman}éteil, Creteil,

Corresponding author: Claude Danan, claude.danan@chicreteil.fr

Address: Pédiatrie Néonatale, CHI Creteil, 40 avenue de Verdun,
94010-CRETEIL, France

Phone~: +33 1~570~234 65~; Cell~: +33 6~091~875 62~;~Fax~: +33 1~570~230
89

Co-authors

Manon Tauzin, MD: manon.tauzin@chicreteil.fr

Camille Jung, MD, PhD~: camille.jung@chicreteil.fr

Xavier Durrmeyer, MD, PhD~: xavier.durrmeyer@chicreteil.fr

Laurence Caeymaex, MD, PhD~: laurence.caeymaex@chicreteil.fr

Charles Treussart, MD~: charles.treussart@chicreteil.fr

Fabrice Decobert, MD~: fabrice.decobert@chicreteil.fr

Bruno Louis, PhD~: bruno.louis@inserm.fr

Financial support: No

Conflict of interest: No

Ethical Statement: authorized on 2020, 1\textsuperscript{st} December by
Comité d'Ethique de l'Hôpital Intercommunal de Creteil.

Keywords: ELBW, HFOV, Humidification

Abbreviated title: Airway humidification during HFOV in ELBW newborns

\textbf{Abstract}

\textbf{Background:} Inappropriate humidification of inspired gas during
mechanical ventilation can impair lung development in extremely low
birthweight (ELBW) infants. Humidification depends on multiple factors,
such as the heater-humidifier device used, type of ventilation, and
environmental factors. Few studies have examined inspired gas
humidification in these infants, especially during high-frequency
oscillatory ventilation (HFOV). Our objective was to compare humidity
during HFOV and intermittent positive pressure ventilation (IPPV), in
vitro and in vivo.

\textbf{Methods:} In-vitro and in-vivo studies used the same ventilator
during both HFOV and IPPV. The bench study used a neonatal test lung and
2 heater-humidifiers with their specific circuits; the in-vivo study
prospectively included preterm infants born before 28 weeks of
gestation.

\textbf{Results:} On bench testing, mean absolute (AH) and relative (RH)
humidity values were significantly lower during HFOV than IPPV (RH~=
79.4\% ± 8.1\% vs 89.0\% ± 6.2\%, P\textless{}0.001). Regardless of the
ventilatory mode, mean relative humidity significantly differed between
the 2 heater-humidifiers (89.6\% ± 6.7\% vs 78.7\% ± 6.8\%, P=0.003).
The in-vivo study included 10 neonates (mean~±~SD gestational age: 25.7
± 0.9 weeks and birth weight: 624.4 ± 96.1 g). Mean relative humidity
during HFOV was significantly lower than during IPPV (74.6\% ± 5.7\% vs
83.0 ± 6.7\%, P=0.004).

\textbf{Conclusion:} Relative humidity was significantly lower during
HFOV than IPPV, both in vitro and in vivo. The type of heater-humidifier
also influenced humidification. More systematic measurements of humidity
of inspired gas, especially during HFOV, should be considered to
optimize humidification and consequently lung protection in ELBW
infants.



\textbf{Introduction}

In extremely low birthweight infants (ELBW), pulmonary fluid clearance
and transcapillary water transport are crucial for pulmonary
development.\textsuperscript{1} The balance between inflammation, water
transport, and upper and deep airway humidification is critical and
plays a role in surfactant production and continued lung development
during the critical period when the preterm infant is dependent on
mechanical ventilation.\textsuperscript{2} A relatively small change
(increase or decrease) in the temperature or humidity of the inspired
gas may be sufficient to impair the preterm infant's pulmonary
function.\textsuperscript{3} Recommendations in this field come from
adult studies, are uncertain,\textsuperscript{4} and stipulate that
humidification must be maintained between 33 and 44 mg/L of absolute
humidity (AH) and 75\% to 100\% of relative humidity
(RH).\textsuperscript{5} Medical devices to heat and humidify the
airways have been optimized for conventional intermittent positive
pressure ventilation (IPPV) and can meet these humidification
recommendations. High-frequency oscillatory ventilation (HFOV) uses very
different settings than IPPV, often with high flow rates and always with
small tidal volumes (V\textsubscript{T}).\textsuperscript{6}

Even though Tarnow-Mordi \emph{et al.} first raised the problem of the
fragility of preterm patients with inadequate humidification in 1989,
very few studies have since addressed humidification in ELBW
infants.\textsuperscript{7} In 2009, Chikata \emph{et al.} and
Nagaya\emph{et al.} reported that humidification during HFOV bench
testing may be more problematic than during conventional
ventilation.\textsuperscript{8 9} More recently, Ralphe \emph{et
al.}dedicated a review to humidification during tracheal and noninvasive
ventilation for ELBW and insisted on the relation between
bronchopulmonary dysplasia and unsuitable
humidification.\textsuperscript{4} We think, however, that conclusions
based only on bench-test studies must also be examined in the light of
clinical and laboratory data. One animal study has highlighted an
interesting link between variation of humidification and lung
inflammatory responses.\textsuperscript{10} All of these
authors\textsuperscript{4 7-10} expressed regret about the lack of
studies of humidification during ventilation.

Humidification of the preterm patient's airways depends on multiple
factors such as the ventilator, circuits, heater-humidifier, ventilatory
mode and settings, and environmental factors.\textsuperscript{4} We
chose to study two of these: the heater-humidifier and the ventilatory
mode. Hence, our aims were, first, to bench test recent
heater-humidifiers during IPPV and HFOV, and, second, to compare
in-vitro and in-vivo humidification achieved in each mode. Our
hypothesis was that the specific parameters of HFOV could result in less
adequate humidification in this mode than during IPPV.

\textbf{Materials and methods:}

Our study comprised two phases: a bench-test study and a prospective
observational clinical study.

\emph{Phase one (n=12): Bench-test study}

The ventilator was the VN500 (Drager Lubeck, Germany) in volume
guarantee (VG) mode during both IPPV (IPPV-VG) and HFOV (HFOV-VG). The
ventilatory settings were the parameters usually used in clinical
settings for each mode and repeated at each set of experiments. During
IPPV, we targeted a V\textsubscript{T} of 4 mL with positive
end-expiratory pressure set at 4 mbar, frequency at 50/min and an
inspiratory time~of~0.3~seconds. During HFOV-VG, we targeted a
V\textsubscript{T}~of~2~mL, with frequency set at 12~Hz (720/min), mean
airway pressure at 12~mbar, and the inspiratory/expiratory time ratio~at
1:1 ( i.e., an inspiratory time of 0.042 sec).

The test lung was located in a Giraffe\selectlanguage{english}\textsuperscript{?} closed
incubator (GE Healthcare, USA) with heat set to 37deg C. The compliance of
the test lung was calibrated around 0.3~mL/mb +- 5\%, to be close to the
usual lung compliance of ELBW patients.\textsuperscript{11}

To test the influence of heating devices on humidification, we conducted
the experiments with 2 heater-humidifiers: the
MR850\selectlanguage{english}\textsuperscript{?}with a RT265\selectlanguage{english}\textsuperscript{?} as the
ventilator circuit, referred to hereafter as MR-A and the
MR950\selectlanguage{english}\textsuperscript{?} with the 950-N81\selectlanguage{english}\textsuperscript{?} circuit
(F\&P, Auckland, New Zealand), referred to as MR-B. The
heater-humidifiers were in automatic mode without any settings to
adjust. For the RT265 circuit, we used a 30~cm extension circuit without
wireless heating inside the incubator to leave the temperature sensor
outside the incubator. The RT 950-N81 circuit did not necessitate an
extension and was directly connected to the Y-piece.

We used the procedure described below to conduct 12 experiments (6 with
MR-A and 6 with MR-B). First, the ventilatory circuit was dried until
RH~\textless{}~2\% was reached. Then, we started ventilation and
humidification in the randomly selected ventilatory mode --- HFOV-VG or
IPPV-VG --- for at least one hour without recording. Humidity and
temperature recording started after one hour and lasted for 4 hours: 2
hours in the first ventilatory mode (IPPV-VG or HFOV-VG) and 2 hours in
the other mode. The first ventilatory mode was selected randomly, via
sealed envelopes.

\emph{Phase two: in-vivo study}

This prospective observational study took place between January 2021 and
January 2022 in the neonatal intensive care unit (NICU) of the Centre
Hospitalier Intercommunal de Creteil. We included ELBW born \selectlanguage{english}[?] 28 weeks
of gestational age with a body weight of less than 1500~g at the time of
the study and requiring mechanical ventilation. Patients were included
in the analysis when a recording of humidity was possible in both IPPV
and HFOV during their ventilatory support course. The choice of
ventilatory mode and ventilatory settings were left to the clinician's
expertise and were not modified due to the study. Parents were informed
of the study and stated that they did not object. The institutional
ethics committee approved the study on December 1, 2020. The number of
subjects to include could not be predicted because the difference of
inspired airway humidity between the two ventilatory modes has never
been described. Thus, the study duration was set at one year.

The standard Y-piece was replaced by a sterilized Y-piece equipped with
a hygrometer during nursing care to record the humidity and temperature.
This recording lasted for two hours for each patient and each
ventilatory mode. The Y-piece with the hygrometer was removed the next
time a nurse attended the baby. Ventilator settings, heater-humidifier
device information (chamber inlet and outlet temperature and flow rate),
ambient temperature, and barometric pressure were all collected during
the 2-hour recording. After a stabilization period, any intervention
(such as opening the incubator or changing ventilatory settings) during
the 2-hour recording period was recorded. Only MR-B was used as a heater
humidifier to adhere to the airway humidification protocol in the NICU.

\emph{Relative humidity and temperature measures}

For both in-vitro and in-vivo experiments, RH and temperature were
recorded in the Y-piece just before the endotracheal tube (ETT) with a
capacitive thermohygrometer and a sensor 4 mm in diameter (Testo
Hygrometer 635-2\selectlanguage{english}\textsuperscript{?} with sensor 2135\selectlanguage{english}\textsuperscript{?},
Forbach, France). The hygrometer was able to record data for a
predetermined period of time (4 hours for in-vitro-study and 2 hours for
in-vivo study) at a predetermined frequency (every 1 minute). The
recordings were converted into two curves: RH (in \%) and temperature
(in degC) with PC-software (Testo Comfort Software x35
professional\selectlanguage{english}\textsuperscript{?}, Forbach, France). For analysis, we
considered only the second hour of recording in each ventilatory mode.
The first hour was considered a stabilization period. AH (in mg/L) was
calculated with the following mathematical formula: (287.7 x RH x
Psat)/(T+273)\textsuperscript{12} with the saturated vapor pressure of
water (Psat) expressed as mm~Hg and temperature (T) as degC.

Beforehand, the introduction of the hygrometer into the Y-piece was
tested to make sure that there was no pressure change.

Statistical analysis:

Data were described as means and their standard deviations. We compared
relative and absolute humidity during IPPV versus HFOV during both the
in-vitro and in-vivo experiments. We compared humidity during IPPV
versus HFOV with two different heater-humidifiers (MR-A and MR-B) only
during in-vitro experiments. Paired Wilcoxon tests were used in the
bench tests to compare HFOV vs IPPV as the comparisons were made at the
same time with the same environmental conditions. Comparisons between
MR-A and MR-B used Mann-Whitney tests. In the in-vivo study, because the
two modes were tested at two potentially separated periods, we used
Mann-Whitney tests rather than paired tests. A \emph{P} -value~\selectlanguage{english}[?]~0.05
was considered significant.

\textbf{Results:}

\emph{Bench testing}

RH (Figure 1) and AH were significantly lower during HFOV than during
IPPV while temperature in the Y-piece was significantly higher during
HFOV than IPPV (Table 1). RH was significantly higher with MR-A than
MR-B, regardless of the ventilatory mode (89.6\% +- 6.7\% vs 78.7\% +-
6.8\%;~\emph{P~} = 0.003) and in each ventilatory mode (Table 1, Figure
1).

\emph{In-vivo study}

During the one-year study, 10 patients received both IPPV and HFOV and
were recorded in both ventilatory modes. Because six patients were
recorded in only one ventilatory mode, they were excluded from the
analysis. Patients included had a mean +-~SD gestational age at birth of
25.7 +-~0.9 weeks and a mean +-~SD birth weight of 624.4~+-~96.1 g. Twenty
recordings were made (10 in each ventilatory mode) at a mean +-~SD
postnatal age of 8.5 +- 7.7 days for HFOV and 10.9~+-~8.7~days for IPPV.
Patients' characteristics and ventilatory parameters at the time of
recording are summarized in Table 2.

RH during HFOV was significantly lower than during IPPV (Table~2).
Postnatal age, weight at the procedure, and environmental parameters
were comparable during HFOV and IPPV, but the heater-humidifier inlet
and outlet temperatures, flow rates, tidal volumes, and pressures
differed significantly (Table 2).

\textbf{Discussion:}

The two main objectives were to test the influence of the two
ventilatory modes and simultaneously two different modern
heater-humidifiers on humidification measured at the Y-piece. The two
main results of this study were that humidity was lower during HFOV than
during conventional ventilation and differed according to the
heater-humidifier model. Results for the two ventilatory modes were
consistent for the in-vitro study, with strictly controlled ventilatory
settings and ambient conditions, and the in-vivo study, with its various
ventilatory settings and ambient conditions. Several hypotheses may
explain these results. The first and most intuitive explanation for this
difference is that HFOV flow rates are much higher than IPPV flow
rates.\textsuperscript{13} At the same time, both the inlet and outlet
chamber temperatures were found to be higher in HFOV than IPPV. This
finding suggests that the heater-humidifier increases the heat of the
plate in order to increase the energy delivered by the
heater-humidifier, which should be proportional to the air volume
delivered by the ventilator. However, the heater-humidifier regulation
tends to stop the heater plate when the inlet chamber temperature is
high.\textsuperscript{13} In this situation, the water may be partially
heated and the gas insufficiently humidified and heated. Nonetheless,
the HFOV and IPPV chamber temperatures did not differ all that much
clinically, although they were statistically different. This difference
does not seem adequate to explain the temperature reduction of the
heating plate.\textsuperscript{13} A second explanation might be the
frequency difference. For the same duct diameter, the thermal losses of
the oscillatory flow increase with its
frequency.\textsuperscript{14}Thus we can expect that this increasing
loss will decrease temperature and AH. However, Nagaya \emph{et al.}
showed that the temperature change in the ETT did not depend on the
oscillatory frequency when the oscillatory volume was fixed; but, the
temperature did depend on the oscillatory volume when the oscillatory
frequency was fixed.\textsuperscript{15} It is also interesting to note
the previous observation during IPPV that AH decreases linearly with the
value of V\textsubscript{T},\textsuperscript{16} although the reasons
for this phenomenon remain unclear.

Recommendations to target a RH of inspired gas between 75\% and 100\%
come from recommendations for adults, but ventilation in ELBW patients
is very different from that in adults, due to the use of low tidal
volumes and high instrumental dead space. Because of these
particularities, humidity at the tip of the ETT is different from that
at the Y-piece.\textsuperscript{15} Thus, it might not be possible to
extrapolate adult recommendations on humidification to preterm neonates,
who might even need higher levels of humidity.

It is important to note that the mean RH during HFOV in our study was
below the recommended 75\%. Poor humidification may have a deleterious
effect on inflammation\textsuperscript{10 17} and on water
movements\textsuperscript{18} at the respiratory tract level as well as
at the cellular level. It may thus impair lung development as it can
induce such adverse events as atelectasis or plugged ETT and unplanned
extubations. The incidence of inadequate humidity as an associated risk
factor of pulmonary inflammation and consequently part of
ventilator-induced lung injury is poorly documented. The principal
reason for the lack of literature on this subject may well be the lack
of routine monitoring of humidity and temperature of inspired gases.
This study presents a method for exploring humidity and temperature at
the Y-piece during tracheal ventilation that could be routinely used for
in-vitro and in-vivo studies. Monitoring humidity at the Y-piece is a
first approach and is not yet sufficient to extrapolate the real
humidity level in the trachea.

The superiority of HFOV over IPPV for lung protection has not yet been
proven,\textsuperscript{19} although we might expect superiority due to
the use of lower tidal volumes\textsuperscript{6} in this ventilatory
mode in preterm patients.\textsuperscript{20} IPPV with volume guarantee
mode induces lower expression of early inflammation markers than
HFOV,\textsuperscript{21} which is contradictory to the expected
protective effect of HFOV. Our study suggest that inadequate
humidification could be a factor explaining potential excess
inflammation during HFOV. Another important result of this study is that
humidification is not easily predictable and depends not only on
ventilation mode but also on the type of circuit and the specific
heater-humidifier used.

Our study has several limitations. First, it is an observational study.
An interventional study, however, appears difficult to conduct, given
the variety of factors involved in determining the humidity level: the
medical devices used, the ventilatory settings, and ambient conditions.
In this in-vitro and in-vivo study, the only ventilator used was the
Drager VN500. One advantage of using a single ventilator is the
homogeneity of the study conditions, but its negative aspect is that we
cannot extrapolate these results to other ventilators. The specific flow
management of the VN500 during HFOV may influence the hygrometric
results as the flow is quadrupled during HFOV compared to conventional
IPPV. Nevertheless, because other ventilators do not systematically
provide flow rates, it seems difficult not to remain vague for the
moment. While waiting for humidity monitoring which is technically more
difficult, we think that flow rate monitoring should be systematically
reported for ventilators.

In conclusion, we found that during mechanical ventilation, humidity
measured in-vitro and in-vivo in ELBW preterm infants was lower with
HFOV than with IPPV and did not reach recommended values during HFOV.
Moreover, humidification values differed significantly according to the
humidifier device used. These results suggest that humidification
depends on ventilatory mode and heating devices and that HFOV requires a
specific humidification management. It is suggested that the systematic
control of humidity, temperature, and flow rate during mechanical
ventilation may optimize lung protection strategies.

\textbf{References:}

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\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/484463/articles/570251-humidity-during-high-frequency-oscillatory-ventilation-compared-to-intermittent-positive-pressure-ventilation-in-extremely-preterm-neonates-an-in-vitro-and-in-vivo-observational-study}

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\verb`Table 2.docx`  available at \url{https://authorea.com/users/484463/articles/570251-humidity-during-high-frequency-oscillatory-ventilation-compared-to-intermittent-positive-pressure-ventilation-in-extremely-preterm-neonates-an-in-vitro-and-in-vivo-observational-study}

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