\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Clinical Impact of Adaptive Servo-Ventilation on the Left Atrial
Pressure during Catheter Ablation in Sedated Patients with Atrial
Fibrillation}



\author[1]{Naohiko Kawaguchi}%
\author[1]{Atsushi Suzuki}%
\author[1]{Michio Usui}%
\author[1]{Shunji Yoshikawa}%
\author[1]{Shingo Watanabe}%
\author[1]{Ryota Maeno}%
\author[1]{Hirofumi Kujiraoka}%
\author[1]{Kuniyoshi Sato}%
\author[2]{Masahiko Goya}%
\author[3]{Tetsuo Sasano}%
\affil[1]{Tokyo Yamate Medical Center}%
\affil[2]{Tokyo Medical and Dental University Hospital}%
\affil[3]{Tokyo Medical and Dental University}%


\vspace{-1em}



  
  \date{May 19, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Introduction Sedation during pulmonary vein isolation (PVI) of atrial
fibrillation often provokes a decline in left atrial (LA) pressure (LAP)
under atmospheric pressure and increases the risk of systemic air
embolisms. This study aimed to investigate the efficacy of adaptive
servo-ventilation (ASV) on the LAP in sedated patients. Methods and
Results Fifty-one consecutive patients undergoing cryoballoon PVI were
enrolled. All patients underwent sedation using propofol throughout the
procedure. Sedation status was monitored by the bispectral index. After
the transseptal puncture and inserting the long sheath into the LA, the
LAP was measured via the sheath. Then, the ASV treatment was started,
and the LAP was re-measured. The LAP before and after the ASV support
was investigated. Before the ASV, the LAP during inspiratory phase was
significantly smaller than that during expiratory phase (4.9\selectlanguage{ngerman}±5.4 mmHg
vs. 14.0±5.2 mmHg, p\textless{}0.01). The lowest LAP was -2.2±5.1 mmHg
and was under 0 mmHg in 37 (73\%) patients. After the ASV, the LAP
during inspiratory phase significantly increased to 8.9±4.1 mmHg
(p\textless{}0.01), and lowest LAP to 4.7±5.9 mmHg (p\textless{}0.01).
The negative lowest LAP value became positive in 30/37(81\%) patients.
There were no statistical differences regarding obstructive sleep apnea
(OSA), obesity, gender, or other comorbidities between patients with and
without a negative lowest LAP after the ASV support. Conclusion ASV is
effective for increasing the LAP above 0 mmHg and might prevent air
embolisms during PVI. A negative LAP after the ASV was rare but occurred
in patients even without comorbidities such as OSA and obesity%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


Clinical Impact of Adaptive Servo-Ventilation on the Left Atrial
Pressure during Catheter Ablation in Sedated Patients with Atrial
Fibrillation

Naohiko Kawaguchi, MD\textsuperscript{*}, Atsushi Suzuki,
MD\textsuperscript{*}, Michio Usui, MD\textsuperscript{*}, Shunji
Yoshikawa, MD\textsuperscript{*}, Shingo Watanabe,
MD\textsuperscript{*}, Ryota Maeno, MD\textsuperscript{*}, Hirofumi
Kujiraoka, MD\textsuperscript{*}, Kuniyoshi Sato, MD\textsuperscript{*},
Masahiko Goya, MD\textsuperscript{+}, Tetsuo Sasano,
MD\textsuperscript{+}

\textsuperscript{*}Heart Center, Tokyo Yamate Medical Center, Tokyo,
Japan

\textsuperscript{+}Department of Cardiology, Tokyo Medical and Dental
University, Tokyo, Japan.

Address for correspondence: Atsushi Suzuki

3-22-1 Hyakunin-cho, Shinjuku-ward, Tokyo, Japan, 169-0073

Heart Center, Tokyo Yamate Medical Center, Tokyo, Japan

Telephone: +81-03-3364-0251

Fax: +81-03-3364-5663

E-mail: bellwood@msc.biglobe.ne.jp

Disclosures: None

\textbf{Abstract}

\textbf{Introduction}

Sedation during pulmonary vein isolation (PVI) of atrial fibrillation
often provokes a decline in left atrial (LA) pressure (LAP) under
atmospheric pressure and increases the risk of systemic air embolisms.
This study aimed to investigate the efficacy of adaptive
servo-ventilation (ASV) on the LAP in sedated patients.

\textbf{Methods and Results}

Fifty-one consecutive patients undergoing cryoballoon PVI were enrolled.
All patients underwent sedation using propofol throughout the procedure.
Sedation status was monitored by the bispectral index. After the
transseptal puncture and inserting the long sheath into the LA, the LAP
was measured via the sheath. Then, the ASV treatment was started, and
the LAP was re-measured. The LAP before and after the ASV support was
investigated.

Before the ASV, the LAP during inspiratory phase was significantly
smaller than that during expiratory phase (4.9\selectlanguage{ngerman}±5.4 mmHg vs. 14.0±5.2
mmHg, p\textless{}0.01). The lowest LAP was -2.2±5.1 mmHg and was under
0 mmHg in 37 (73\%) patients. After the ASV, the LAP during inspiratory
phase significantly increased to 8.9±4.1 mmHg (p\textless{}0.01), and
lowest LAP to 4.7±5.9 mmHg (p\textless{}0.01). The negative lowest LAP
value became positive in 30/37 (81\%) patients. There were no
statistical differences regarding obstructive sleep apnea (OSA),
obesity, gender, or other comorbidities between patients with and
without a negative lowest LAP after the ASV support.

\textbf{Conclusion}

ASV is effective for increasing the LAP above 0 mmHg and might prevent
air embolisms during PVI. A negative LAP after the ASV was rare but
occurred in patients even without comorbidities such as OSA and obesity.

Key words: ablation, adaptive servo ventilation, atrial fibrillation,
left atrial pressure, sedation

\textbf{Introduction}

Pulmonary vein isolation (PVI) is a widely accepted procedure for
catheter ablation of patients with atrial fibrillation (AF). For a
completion of the PVI, access to the left atrium (LA) is required, and a
transseptal puncture has usually been performed. The procedure in the LA
has a substantial risk of systemic embolisms including cerebral and
myocardial infarctions\textsuperscript{1-2}.

The PVI using a cryoballoon has emerged as an alternative ablation
procedure tool for radiofrequency (RF) ablation and its safety and
effectiveness have been proven\textsuperscript{3-4}. However, thrombi
and air embolic events during cryoballoon ablation have recently been
reported\textsuperscript{2, 5}. In terms of air embolic events during
the procedure, the creation of procedure related micro air bubbles has
been thought to be the most common factor\textsuperscript{6-7}. The
majority of micro air embolisms are silent, asymptomatic, and detected
by brain magnetic resonance imaging after the
procedure\textsuperscript{6, 8}. On the other hand, a large amount of an
air embolism during the catheter ablation procedure is rare, but could
be life-threatening\textsuperscript{1-2}. It is mainly caused by massive
air intrusion through a long sheath located in the LA and is prone to
occur at the time the intra LA pressure (LAP) drops to less than the
atmospheric pressure\textsuperscript{1, 9}.

Patients typically receive sedation during the PVI because the
procedures take several hours and often are inflictive. Sedation of
patients could inevitably result in an upper airway obstruction and
subsequently provoke apnea and snoring, which could reduce the intra
thoracic pressure and LAP. A decreased LAP to less than the atmospheric
pressure increases the risk of air intrusion into the vasculature
through a long sheath.

Adaptive servo-ventilation (ASV) (AutoSet CS; ResMed, Sydney) is a
noninvasive positive pressure ventilation and is designed to treat
sleep-disordered breathing\textsuperscript{10-11}. It provides a
positive expiratory airway pressure and inspiratory pressure support,
and automatically adjusts the airway ventilation volume based on the
analysis of the patient`s breathing effort. Although the efficacy of the
ASV therapy in patients with sleep-disordered breathing has been widely
accepted, the accurate efficacy of ASV for the LAP in sedated patients
remains unclear.

The aim of this study was to investigate the LAP in sedated patients
undergoing a cryoballoon PVI and to clarify the impact of the ASV on the
LAP during the procedure.

\textbf{Methods}

\textbf{Inclusion and exclusion criteria}

From October 2018 to September 2020, a cryoballoon PVI was performed in
patients with drug refractory AF. All patients received sedation and a
subsequent ASV treatment was applied during the procedure. Consecutive
patients undergoing a cryoballoon PVI with ASV support under sedation
were enrolled in this study. The LAPs before and after the ASV support
were sequentially evaluated in all these patients.

Exclusion criteria were severe valvular disease, hemodialysis, severe
coronary artery disease, a LA diameter \textgreater{} 55mm, and the
existence of a thrombus in the LA.

Written informed consent was obtained from all patients. This study
protocol was approved by the institutional review board of our institute
and conformed to the ethical guidelines of the 1975 Declaration of
Helsinki.

\textbf{Procedural management}

All patients received oral anticoagulants prior to the procedure. In
patients taking direct oral anticoagulants, the drugs were interrupted
on the day of the procedure and re-administered on the next morning
after the procedure. In patients taking warfarin, the warfarin therapy
was continued without interruption.

During the procedure, a single transseptal puncture was performed with
an RF needle (Baylis Medical Inc, Montreal, Quebec, Canada) and 8 Fr
long sheath (SL0, Abbott, Minneapolis, MN). Five thousand U of Heparin
was administered before the transseptal puncture and additionally given
to maintain an activated clotting time between 300 and 350 seconds.
After the transseptal puncture, an 8 Fr long sheath was exchanged for a
steerable 15 Fr sheath (Flexcath Advance, Medtronic, Minneapolis, MN).

\textbf{The LAP evaluation and ASV support}

The atmospheric pressure was set as 0 mmHg reference at a beginning of
the procedure. After the transseptal puncture and insertion of the 15 Fr
long sheath (FlexCath) in the LA, the LAP via the sheath was recorded on
a digital polygraph (RMC-5000, Nihon Corden, Tokyo, Japan)
(\textbf{Figure 1} ). The LAP was measured over more than three
consecutive respiratory cycles. The LAP during one respiratory cycle was
calculated as the average of the integral LAPs during one respiratory
cycle, and the LAP was defined as the average value of that over three
or more consecutive cycles. The LAP during the inspiratory and
expiratory phases also was defined in the same manner. The lowest LAP
was the minimum LAP during those respiratory cycles. Afterward, the ASV
treatment was initiated in all patients. As the setting for the ASV, an
expiratory positive airway pressure of 5 cmH\textsubscript{2}O and
inspiratory pressure support between 3 and 10 cmH\textsubscript{2}O were
used. Following the ASV treatment and confirmation of stable breathing
synchronized with the ASV, the LAP was re-measured.

\textbf{Sedation}

All patients received sedation throughout the procedure. At the
beginning of the procedure, an intravenous propofol bolus of 0.5 mg/kg
was administered, and a nasopharyngeal temperature probe was inserted
and located in the esophagus to measure the esophageal temperature
during the procedure. Maintenance of sedation was performed with a
continuous intravenous propofol administration with a dosage of
1.25\textasciitilde{}2 mg/kg/hr. As an analgesic, an intravenous drip
infusion of buprenorphine with a dosage of 1.0 \selectlanguage{greek}µ\selectlanguage{english}g/kg was also
administered at the beginning of the procedure and was properly added if
patients complained of pain. The bispectral index was continuously
monitored by a BIS monitoring system (A-3000 BIS XP Platform, Aspect
Medical Systems, Newton, MA) to evaluate the sedation level of the
patients. To maintain the BIS index level between 50 and 70, an
intravenous propofol bolus of 0.5 mg/kg was additionally administered,
and the dosage of the continuous intervenous propofol administration was
also adjusted according to the sedation level of the patients, if
necessary\textsuperscript{12-13}.

\textbf{Ablation procedure}

The method of the cryoballoon ablation has been previously
described\textsuperscript{8}. In brief, a steerable 15 Fr sheath
(Flexcath) and second-generation 28mm cryoballoon (Arctic Front Advance,
Medtronic) were inserted into the LA and advanced to the orifice of the
targeted PVs. Then, the cryoballoon PVI was started. The entire PVI
procedure was performed under ASV support.

\textbf{Statistical analysis}

Continuous data are expressed as the mean \selectlanguage{ngerman}± SD. Statistical comparisons
were performed using the Student's t-test and Fisher exact test, as
appropriate. Statistical significance was set at a value of P
\textless{}0.05. Statistical analysis was performed using Bell curve for
Excel (ver. 3.20).

\textbf{Results}

\textbf{Study population and baseline patient characteristics}

Fifty-one consecutive patients underwent the cryoballoon PVI. The mean
age was 65.8 ± 10.4 years old and 41 (80.4 \%) patients had a male
gender. The proportion of paroxysmal and non-paroxysmal AF was 27 (53.0
\%) and 24 (47.0 \%) patients, respectively. Two patients were diagnosed
with obstructive sleep apnea (OSA) and were introduced to continuous
positive airway pressure therapy. The patient characteristics are shown
in \textbf{Table 1} .

\textbf{LAP evaluation} (\textbf{Table 2} )

The LAPs were sequentially measured before and after the ASV support in
a total of 51 enrolled patients. The BIS value at the time of the LAP
measurement was similar between that before and after the ASV support
(67.7 ± 13.1 vs. 68.5 ± 12.7, p = 0.26). Out of 27 patients with
paroxysmal AF, the LAP was measured during sinus rhythm in 25 and during
AF in the remaining 2. In all 24 patients with non-paroxysmal AF, the
LAP was measured during AF or atrial flutter. There was no significant
difference in the average LAP between that before and after the ASV
support (10.9 ± 4.8 mmHg vs. 11.6 ± 3.7 mmHg, p = 0.14).

\textbf{LAP before the ASV}

The LAP during the inspiratory phase was 4.9 ± 5.4 mmHg and was
significantly lower than that during the expiratory phase (14.0 ± 5.2
mmHg, p \textless{} 0.01). The average lowest LAP was -2.2 ± 5.1 mmHg
(from 7 to -17 mmHg), which was recorded during the inspiratory phase in
all patients. Out of a total of 51 patients enrolled, 37 (72.5 \%) had a
lowest LAP value of \selectlanguage{english}[?] 0 mmHg. A male gender was frequently observed in
patients with a lowest LAP value of \selectlanguage{english}[?] 0 mmHg (negative lowest LAP) than
in those with a lowest LAP value of \textgreater{} 0 mmHg (33/37 vs.
8/14, p = 0.02). There were no significant differences regarding the BIS
index, body-mass index (BMI), prevalence of OSA, obesity (BMI
\textgreater{} 25 kg/m2), and other comorbidities between the patients
with and without a negative lowest LAP value (\textbf{Table 3A} ). The
BIS value at the time of the LAP measurement was similar between the two
groups (67.4 +- 12.5 vs. 68.7 +- 14.4, p = 0.54).

\textbf{LAP after the ASV}

After the ASV, the LAP during the inspiratory phase significantly
increased to 8.9 +- 4.1 mmHg as compared to that before the ASV (4.9 +-
5.4 mmHg) (p \textless{} 0.01) (\textbf{Figure 2} ). The \selectlanguage{greek}Δ \selectlanguage{english}lowest LAP
between that before and after the ASV support was 6.6 \selectlanguage{ngerman}± 5.2 mmHg. The
lowest LAP increased in 47/51 (92.2 \%) patients with the ASV, and
remained unchanged in the other four patients (\textbf{Figure 3} ). Out
of 37 patients with a negative lowest LAP value before the ASV, in 30
(81.1 \%) patients the lowest LAP value turned out to be positive after
the ASV. Even in the remaining seven patients, the lowest LAP increased
to 4.6 ± 3.5 mmHg, but it did not reach more than 0 mmHg (from -6 to 0
mmHg). There were no significant differences regarding the patient
characteristics or comorbidities between the patients with and without a
negative lowest LAP value after the ASV (\textbf{Table 3B} ). The BIS
value at the time of the LAP measurement was similar between the two
groups (65.0 ± 13.6 vs. 69.0 ± 12.5, p = 0.75). The male gender also was
not observed very frequently in the patients with a negative lowest LAP
value (7/7 vs. 34/41, p = 0.32).

\textbf{Expiratory LAP evaluation}

After the ASV, the expiratory LAP slightly decreased from 14.0 ± 5.2
mmHg to 12.7 ± 4.3 mmHg (p \textless{} 0.01). The \selectlanguage{greek}Δ\selectlanguage{english}expiratory LAP
difference between that before and after the ASV support was -1.3 \selectlanguage{ngerman}± 3.3
mmHg.

\textbf{Results of the cryoballoon PVI}

Out of a total of 204 enrolled PVs, all PVs were successfully isolated.
Although temporary right phrenic nerve paralysis was observed in two
patients during the cryoballoon ablation at the RSPV, the motion of the
diaphragm fully recovered by the first out patient visit. A groin
hematoma was observed in three patients. There were no other
complications during the procedure including systemic embolic events
such as cerebral and myocardial infarctions.

\textbf{Discussion}

The major findings in the present study were (1) the lowest LAP in
sedated patients dropped to less than the atmospheric pressure in
approximately 73\% of patients, (2) ASV increased the lowest LAP value
to positive in 81\% of the patients who had a negative lowest LAP value
before the ASV support, (3) there were no significant differences
regarding the patient characteristics including the prevalence of OSA,
BMI, and a male gender between the patients with and without a negative
lowest LAP value after the ASV support.

A drop in the LAP of less than the atmosphere pressure during the PVI
increases the risk of massive air intrusion during the procedure. The
hemostasis valve of the sheath plays an important role in the prevention
of air intrusion into the vasculature through a long sheath. However,
the valve could become open to the atmosphere while inserting a catheter
into the sheath via the valve, especially when inserting catheters with
complicated tip shapes such as circular mapping catheters or multipolar
catheters\textsuperscript{2, 6}. If the timing of the insertion of the
catheter is synchronized with a drop in the LAP to less than atmospheric
pressure, a massive air embolism is prone to occur. The continuous
maintenance of the LAP above the atmospheric pressure during the
procedure could absolutely decrease the risk of air intrusion. The
present study confirmed that the majority of the sedated patients
undergoing AF ablation had a negative LAP during the procedure, and to
the best of our knowledge, this is the first clinical study that has
demonstrated the efficacy of the ASV in the prevention of an LAP drop to
less than the atmospheric pressure. Although the present study evaluated
the LAP in patients undergoing a cryoballoon PVI, this result could be
applicable to all kinds of percutaneous catheter procedures which
require access into the LA.

In addition to providing a supply of positive expiratory pressure, ASV
has a unique algorithm that automatically supplies positive inspiratory
pressure according to an analysis of the patient`s breathing effort. It
could provide a stable respiration pattern. Although bronchial
intubation could certainly more effectively reduce the risk of air
intrusion and contribute to a stable LAP, it is invasive and requires
general anesthesia, however, the ASV treatment is easy to start and
finish. Therefore, an evaluation of the impact of ASV on the LAP could
be worthwhile.

\textbf{AF ablation with sedation}

The feasibility and safety of deep sedation during AF ablation has been
previously reported\textsuperscript{14-15}. However, intravenous
sedation with an anesthetic agent such as propofol causes respiratory
suppression due to upper airway collapse, and the anesthetic depth is
associated with the respiratory status\textsuperscript{16}.

As the sedation depth, anesthetic dosing was adjusted to maintain the
BIS value within a target range of 50-70 and actual average BIS value
before the ASV support was approximately 68, suggesting the sedation
depth was nearly moderate sedation\textsuperscript{12-13}. In patients
under the moderate sedation depth, it is generally considered that no
interventions are required to maintain a patent airway and spontaneous
ventilation is adequate\textsuperscript{17}. However, the present study
revealed that the 73\% of the sedated patients had negative lowest LAP
value before the ASV support. That suggested that the LAP could become
negative even in patients under moderate sedation. During the procedure,
the sedation level often resulted in a deeper sedation level than
initially intended. Therefore, the fact that the risk of air intrusion
might change depending on the sedation continuum should be noted.

Additionally, the introduction and maintenance of the sedation was
performed with an intravenous propofol administration. For an
intravenous anesthetic agent during AF ablation, propofol, midazolam,
dexmedetomidine are commonly used. Out of those anesthetic agents,
dexmedetomidine has a relatively less propensity for the induction of an
upper air way collapse in comparison to propofol \textsuperscript{12}.
If dexmedetomidine is administered for the anesthesia, the prevalence of
a negative LAP under sedation could be smaller.

\textbf{Evaluation of negative lowest LAP even after the ASV support}

The present study revealed the ability of the ASV treatment to increase
the LAP above the atmospheric pressure. On the other hand, the lowest
LAP was still negative in seven patients even with ASV support. Previous
reports demonstrated that OSA has been associated with an LAP decline
during sleep\textsuperscript{18}. Furthermore, obesity, a male gender,
hypertension, diabetes mellitus, and heart failure are thought to be
important risk factors for OSA\textsuperscript{19-20}. However, those
specific patient characteristics could not frequently be observed in
patients with a negative LAP after the ASV. In the present study, there
were two patients who had been diagnosed with OSA before the ablation
procedure, and that might have influenced the results.

We should be aware that a negative LAP after the ASV could be provoked
even in patients without OSA, obesity, or other risk factors.
Complications due to massive air intrusion could be fatal, and
therefore, not only the efficacy but the limitations of ASV on the LAP
must be taken into consideration. If further study reveals and predicts
the characteristics of the patients with a high risk of an ASV
refractory negative LAP, selective and prophylactic bronchial intubation
before the procedure could be effective in preventing air intrusion.

\textbf{Expiratory LAP}

In the patients under sedation, the inspiratory LAP was easily
influenced by a decline in the intra thoracic pressure, however, the
expiratory LAP theoretically would not. Therefore, the expiratory LAP in
patients under sedation was thought to be almost identical to the LAP in
those in an awake state.

The expiratory LAPs after the ASV were slightly lower than those before
the ASV. From the aspect of the mechanism of noninvasive positive
pressure ventilation, a positive expiratory pressure might reduce the
venosus return and decreased the LAP. However, whether a positive
expiratory pressure influences the LAP immediately after the initiation
of the ASV remains unclear and requires further investigation in terms
of the hemodynamic status.

\textbf{Study limitations}

This study was a single center trial and the study population was
relatively small. The LAP was not evaluated continuously because the
insertion of the cryoballoon into the long sheath was needed to perform
the PVI and an accurate LAP could not be evaluated during cryoballoon
ablation. The sedation status was variable even with the same dose of an
anesthetic agent, and the collapsibility of the upper airway also
changed during the procedure. An additional propofol bolus
administration as the patient status dictated easily deepen the sedation
status for a certain length of time. Therefore, the efficacy of the ASV
for the LAP could be variable and labile.

The present study did not perform polysomnography to evaluate the extent
of the OSA before the ablation procedure. Therefore, the prevalence of
OSA might have been underestimated. Further prospective studies that
enroll larger numbers of patients with OSA and investigate the LAP
change after the ASV treatment are expected.

\textbf{Conclusion}

The ASV treatment in sedated patients undergoing a PVI was effective for
increasing the LAP above the atmospheric pressure and might prevent
fatal air embolisms during the procedure. Furthermore, the LAP could
drop and become negative in patients under sedation even in those
without OSA, obesity, or other comorbidities.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Kuwahara T, Takahashi A, Takahashi Y, Kobori A, Miyazaki S, Takei A,
  Fujii A, Kusa S, Yagishita A, Okubo K, Fujino T, Nozato T, Hikita H,
  Sato A, Aonuma K. Clinical characteristics of massive air embolism
  complicating left atrial ablation of atrial fibrillation: lessons from
  five cases. Europace 2012, 14 (2), 204-8.
\item
  Cay S, Ozeke O, Ozcan F, Topaloglu S, Aras D. Coronary air embolism
  during cryoablation of atrial fibrillation: A catastrophic
  complication and its management. J Atr Fibrillation 2017 Oct 31; 10
  (3): 1728.
\item
  Aryana A, Singh SM, Kowalski M, Pujara DK, Cohen AI, Singh SK, Aleong
  RG, Banker RS, Fuenzalida CE, Prager NA, Bowers MR, D'Avila A, O'Neill
  PG. Acute and long-term outcomes of catheter ablation of atrial
  fibrillation using the second-generation cryoballoon versus
  open-irrigated radiofrequency: a multicenter experience. J Cardiovasc
  Electrophysiol 2015, 26 (8), 832-839.
\item
  Kuck KH, Brugada J, Furnkranz A, Metzner A, Ouyang F, Chun KR, Elvan
  A, Arentz T, Bestehorn K, Pocock SJ, Albenque JP, Tondo C. Cryoballoon
  or radiofrequency ablation for paroxysmal atrial fibrillation. N Engl
  J Med 2016, 374 (23), 2235-45.
\item
  Tsukahara K, Oginosawa Y, Fujino Y, Ohe H, Yamagishi Y, Iwataki M,
  Sonoda S, Kohno R, Otsuji Y. Abe H. Prevention of serious air embolism
  during cryoballoon ablation; risk assessment of air intrusion into the
  sheath by catheter selection and change in intrathoracic pressure: an
  ex vivo study. J Cardiovasc Electrophysiol 2019, 30 (12), 2944-2949.
\item
  Miyazaki S, Watanabe T, Kajiyama T, Iwasawa J, Ichijo S, Nakamura H,
  Taniguchi H, Hirao K, Iesaka Y. Thromboembolic risks of the procedural
  process in second-generation cryoballoon ablation procedures: analysis
  from real-time transcranial Doppler Monitoring. Circ Arrhythm
  Electrophysiol 2017, 10 (12).
\item
  Takami M, Fujiwara R, Kijima Y, Nagoshi R, Kozuki A, Mochizuki Y,
  Shibata H, Nakano S, Fukuyama Y, Fujimoto D, Kakizaki S, Masuko E,
  Kurimoto H, Kyo S, Miyata T, Shite J. Techniques for reducing air
  bubble intrusion into the left atrium during radiofrequency catheter
  and cryoballoon ablation procedures: An ex vivo study with a
  high-resolution camera. Heart Rhythm 2019, 16 (1), 128-139.
\item
  Nakamura T, Okishige K, Kanazawa T, Yamashita M, Kawaguchi N, Kato N,
  Aoyagi H, Yamauchi Y, Sasano T, Hirao K. Incidence of silent cerebral
  infarctions after catheter ablation of atrial fibrillation utilizing
  the second-generation cryoballoon. Europace 2017, 19 (10), 1681-1688.
\item
  Franzen OW, Klemm H, Hamann F, Koschyk D, von Kodolitsch Y, Weil J,
  Meinertz T, Baldus S. Mechanisms underlying air aspiration in patients
  undergoing left atrial catheterization. Catheter Cardiovasc Interv
  2008, 71 (4), 553-8.
\item
  Miyata M, Yoshihisa A, Suzuki S, Yamada S, Kamioka M, Kamiyama Y,
  Yamaki T, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh S,
  Takeishi Y. Adaptive servo ventilation improves Cheyne-Stokes
  respiration, cardiac function, and prognosis in chronic heart failure
  patients with cardiac resynchronization therapy. J Cardiol 2012, 60
  (3), 222-7.
\item
  Randerath WJ, Galetke W, Stieglitz S, Laumanns C, Schafer T. Adaptive
  servo-ventilation in patients with coexisting obstructive sleep
  apnoea/hypopnoea and Cheyne-Stokes respiration. Sleep Med 2008, 9 (8),
  823-30.
\item
  Kasuya Y, Govinda R, Rauch S, Mascha EJ, Sessler DI, Turan A. The
  correlation between bispectral index and observational sedation scale
  in volunteers sedated with dexmedetomidine and propofol. Anesth Analg
  2009, 109 (6), 1811-5.
\item
  Wang ZH, Chen H, Yang YL, Shi ZH, Guo QH, Li YW, Sun LP, Qiao W, Zhou
  GH, Yu RG, Yin K, He X, Xu M, Brochard LJ, Zhou JX. Bispectral index
  can reliably detect deep sedation in mechanically ventilated patients:
  a prospective multicenter validation study. Anesth Analg 2017, 125
  (1), 176-183.
\item
  Kottkamp H, Hindricks G, Eitel C, Muller K, Siedziako A, Koch J,
  Anastasiou-Nana M, Varounis C, Arya A, Sommer P, Gaspar T, Piorkowski
  C, Dagres N. Deep sedation for catheter ablation of atrial
  fibrillation: a prospective study in 650 consecutive patients. J
  Cardiovasc Electrophysiol 2011, 22 (12), 1339-43.
\item
  Salukhe TV, Willems S, Drewitz I, Steven D, Hoffmann BA, Heitmann K,
  Rostock T. Propofol sedation administered by cardiologists without
  assisted ventilation for long cardiac interventions: an assessment of
  1000 consecutive patients undergoing atrial fibrillation ablation.
  Europace 2012, 14 (3), 325-30.
\item
  Eastwood PR, Platt PR, Shepherd K, Maddison K, Hillman DR.
  Collapsibility of the upper airway at different concentrations of
  propofol anesthesia. Anesthesiology. 2005 Sep; 103 (3): 470-7.
\item
  Practice guidelines for moderate procedural sedation and analgesia
  2018: A report by the American society of anesthesiologists task force
  on moderate procedural sedation and analgesia, the American
  association of oral and maxillofacial surgeons, American college of
  radiology, American dental association, American society of dentist
  anesthesiologists, and society of interventional radiology.
  Anesthesiology. 2018 Mar; 128 (3): 437-479.
\item
  Condos WR Jr, Latham RD, Hoadley SR, Pasipoularides A. Hemodynamics of
  the Mueller maneuver in man: right and left heart micromanometry and
  doppler echocardiography. Circulation. 1987 Nov; 76 (5): 1020-8.
\item
  Heinzer R, Vat S, Marques-Vidal P, Marti-Soler H, Andries D, Tobback
  N, Mooser V, Preisig M, Malhotra A, Waever G, Vollenweider P, Tafti M,
  Haba-Rubio J. Prevalence of sleep-disordered breathing in the general
  population: the HypnoLaus study. Lancet Respir Med. 2015 Apr; 3 (4):
  310-8.
\item
  Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D`Agostino
  RB, Newman AB, Lebowitz MD, Pickering TG. Association of
  sleep-disordered breathing sleep apnea and hypertension in a large
  community based-study. Sleep Heart Health Study. JAMA. 2000 Apr 12;
  283 (14): 1829-36.
\end{enumerate}

\textbf{Table 1} : Clinical characteristics of the study population\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Number of patients, n & 51\tabularnewline
\midrule
\endhead
Age, years & 65.8 \selectlanguage{ngerman}± 10.4\tabularnewline
Male gender (\%) & 41 (80.4)\tabularnewline
BMI\textsuperscript{+}, kg/m2 & 24.4 \selectlanguage{ngerman}± 3.6\tabularnewline
Obesity (BMI \textgreater{} 25 kg/m2) (\%) & 20 (39)\tabularnewline
Obstructive sleep apnea (\%) & 2 (3.9)\tabularnewline
Non-paroxysmal AF\textsuperscript{*} (\%) & 24 (47.0)\tabularnewline
CHADS2 score & 1.0 \selectlanguage{ngerman}± 0.8\tabularnewline
Hypertension (\%) & 25 (49.0)\tabularnewline
Diabetes mellitus (\%) & 6 (11.8)\tabularnewline
Heart failure (\%) & 8 (15.7)\tabularnewline
Old cerebral infarction and TIA\textsuperscript{+} (\%) & 2
(3.9)\tabularnewline
BNP on the day before ABL, pg/mL & 95.9 \selectlanguage{ngerman}± 141.7\tabularnewline
LA\textsuperscript{§} diameter, mm & 41.2 \selectlanguage{ngerman}± 7.1\tabularnewline
LVEF\textsuperscript{¶}, \% & 62.1 \selectlanguage{ngerman}± 8.9\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textsuperscript{*}AF: atrial fibrillation

\textsuperscript{+}BMI: body-mass index

\textsuperscript{§}LA: left atrium

\textsuperscript{¶}LVEF: left ventricular ejection fraction

\selectlanguage{english}\textsuperscript{+}TIA: transient ischemic attack

\textbf{Table 2} : Comparison of the LAP and BIS value between that
before and after the ASV support\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Before the ASV\textsuperscript{*} & After the ASV & p
value\tabularnewline
\midrule
\endhead
Average LAP\textsuperscript{+}, mmHg & 10.9 \selectlanguage{ngerman}± 4.8 & 11.6 \selectlanguage{ngerman}± 3.7 &
0.14\tabularnewline
LAP during the inspiratory phase, mmHg & 4.9 \selectlanguage{ngerman}± 5.4 & 8.9 \selectlanguage{ngerman}± 4.1 &
\textless{}0.01\tabularnewline
Lowest LAP, mmHg & -2.2 \selectlanguage{ngerman}± 5.1 & 4.7 \selectlanguage{ngerman}± 5.9 &
\textless{}0.01\tabularnewline
Number of lowest LAPs [?] 0 mmHg (\%) & 37 (72.5) & 7 (13.7) &
\textless{}0.01\tabularnewline
LAP during the expiratory phase, mmHg & 14.0 \selectlanguage{ngerman}± 5.2 & 12.7 \selectlanguage{ngerman}± 4.3 &
\textless{}0.01\tabularnewline
BIS value at the time of the LAP measurement & 67.7 \selectlanguage{ngerman}± 13.1 & 68.5 \selectlanguage{ngerman}± 12.7
& 0.26\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{*}ASV: Adaptive Servo-Ventilation

\textsuperscript{+}LAP: left atrial pressure

\textbf{Table 3} : Comparison of the characteristics between the
patients with and without a negative lowest LAP value

Before the ASV support\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Lowest LAP [?] 0 & Lowest LAP \textgreater{} 0 & p value\tabularnewline
\midrule
\endhead
Number of patients, n & 37 & 14 &\tabularnewline
Age, years & 66.8 \selectlanguage{ngerman}± 9.9 & 63.3 \selectlanguage{ngerman}± 3.9 & 0.37\tabularnewline
Male gender (\%) & 33 (89) & 8 (36) & 0.02\tabularnewline
BMI\textsuperscript{+}, kg/m2 & 24.2 \selectlanguage{ngerman}± 2.7 & 24.8 \selectlanguage{ngerman}± 3.9 &
0.84\tabularnewline
Obesity (BMI \textgreater{} 25 kg/m2) (\%) & 15 (41) & 5 (36) &
1.0\tabularnewline
Obstructive sleep apnea (\%) & 2 (5) & 0 (0) & 1.0\tabularnewline
Non-Paroxysmal AF\textsuperscript{*} (\%) & 19 (51) & 5 (36) &
0.36\tabularnewline
CHADS2 score & 1.03 \selectlanguage{ngerman}± 0.75 & 0.93 \selectlanguage{ngerman}± 0.96 & 0.57\tabularnewline
Hypertension (\%) & 19 (51) & 6 (43) & 0.55\tabularnewline
Diabetes mellitus (\%) & 5 (14) & 1 (7) & 1.0\tabularnewline
Heart failure (\%) & 5 (14) & 3 (21) & 0.67\tabularnewline
Old cerebral infarction and TIA\textsuperscript{+} (\%) & 1 (3) & 1 (7)
& 0.48\tabularnewline
BNP, pg/mL & 87 \selectlanguage{ngerman}± 144.3 & 120.6 \selectlanguage{ngerman}± 132.7 & 0.75\tabularnewline
LA\selectlanguage{ngerman}\textsuperscript{§} diameter, mm & 41.0 \selectlanguage{ngerman}± 7.3 & 42.2 \selectlanguage{ngerman}± 6.4 &
0.70\tabularnewline
LVEF\selectlanguage{ngerman}\textsuperscript{¶}, \% & 62.3 \selectlanguage{ngerman}± 9.6 & 61.6 \selectlanguage{ngerman}± 6.4 &
0.43\tabularnewline
\bottomrule
\end{longtable}

(B) After the ASV support\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Lowest LAP [?] 0 & Lowest LAP \textgreater{} 0 & p value\tabularnewline
\midrule
\endhead
Number of patients, n & 7 & 44 &\tabularnewline
Age, years & 69.0 \selectlanguage{ngerman}± 13.9 & 65.3 \selectlanguage{ngerman}± 9.6 & 0.85\tabularnewline
Male gender (\%) & 7 (100) & 34 (77) & 0.32\tabularnewline
BMI\textsuperscript{+}, kg/m2 & 24.6 \selectlanguage{ngerman}± 4.9 & 24.3 \selectlanguage{ngerman}± 3.3 &
0.47\tabularnewline
Obesity (BMI \textgreater{} 25 kg/m2) (\%) & 4 (57) & 16 (36) &
0.41\tabularnewline
Obstructive sleep apnea (\%) & 1 (14) & 1 (2) & 0.20\tabularnewline
Non-Paroxysmal AF\textsuperscript{*} (\%) & 4 (57) & 20 (45) &
0.69\tabularnewline
CHADS2 score & 1.1 \selectlanguage{ngerman}± 0.8 & 0.98 \selectlanguage{ngerman}± 0.8 & 0.66\tabularnewline
Hypertension (\%) & 3 (43) & 22 (50) & 1.0\tabularnewline
Diabetes mellitus (\%) & 2 (29) & 4 (9) & 0.19\tabularnewline
Heart failure (\%) & 1 (14) & 7 (16) & 1.0\tabularnewline
Old cerebral infarction and TIA\textsuperscript{+} (\%) & 0 (0) & 2 (5)
& 1.0\tabularnewline
BNP, pg/mL & 86.1 \selectlanguage{ngerman}± 262.2 & 97.6 \selectlanguage{ngerman}± 92.9 & 0.35\tabularnewline
LA\selectlanguage{ngerman}\textsuperscript{§} diameter, mm & 42.3 \selectlanguage{ngerman}± 6.9 & 41.0 \selectlanguage{ngerman}± 7.1 &
0.44\tabularnewline
LVEF\selectlanguage{ngerman}\textsuperscript{¶}, \% & 64.6 \selectlanguage{ngerman}± 11.7 & 61.7 \selectlanguage{ngerman}± 8.3 &
0.84\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{*}AF: atrial fibrillation

\textsuperscript{+}BMI: body-mass index

\selectlanguage{ngerman}\textsuperscript{§}LA: left atrium

\textsuperscript{¶}LVEF: left ventricular ejection fraction

\selectlanguage{english}\textsuperscript{+}TIA: transient ischemic attack

\textbf{Figure legends}

\textbf{Figure 1} : The LAP waveform

Respiratory variations in the LAP waveform during the procedure were
observed, and the inspiratory LAP prominently dropped to less than the
atmospheric pressure (0 mmHg).

The average LAP, that during the inspiratory and expiratory phase, and
the lowest LAP were measured, respectively.

Exp: expiratory phase

Insp: inspiratory phase

LAP: left atrial pressure\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 2} : Representative case of the LAP between that before
(A) and after (B) the ASV support. The steep decline in the LAP during
the inspiratory phase completely resolved and the lowest LAP increased
to a positive value after the ASV support.

ASV: Adaptive Servo-Ventilation

LAP: left atrial pressure\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3} : Change in the lowest LAP between that before and
after the ASV support

ASV: Adaptive Servo-Ventilation

LAP: left atrial pressure\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2A/Figure-2A}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2B/Figure-2B}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

