The Laryngoscope

C 2013 The American Laryngological,

V
Rhinological and Otological Society, Inc.

An Animal Model of Obstructive Sleep Apnea in Rabbit

Myeong S. Yu, MD, PhD; Na R. Jung, MD, PhD; Kyoung H. Choi, MD, PhD; Kuiwon Choi, PhD;
Bong-Jae Lee, MD, PhD; Yoo-Sam Chung, MD, PhD

Objectives/Hypothesis: An animal model of obstructive sleep apnea (OSA) may help to investigate the pathophysiology
of this disorder and develop appropriate treatments. We investigated the feasibility of a rabbit model of OSA.
Study Design: Animal study.
Methods: Twelve New Zealand white rabbits were injected at the base of their tongues under endoscopic guidance with
liquid silicone (experimental group, n 5 6) or normal saline (control group, n 5 6). Polysomnography was performed before
and after injection. The development of OSA and changes in sleep parameters were compared between the two groups.
Results: Before injection, all rabbits showed normal breathing during sleep without hypopnea. In the silicone group, the
rabbits had a mean of 29.9 6 6.9 hypopneas/hour and a mean of 10.4 6 3.1 apneas/hour 1 month after silicone injection and
28.4 6 6.9 hypopneas/hour and 10.0 6 3.3 apneas/hour 3 months after silicone injection (P < 0.05). Mean total sleep time
decreased from 260.3 6 70.2 minutes at baseline to 152.5 6 38.8 minutes 1 month and 206.8 6 60.3 minutes 3 months after
injection, with a decrease in stage II sleep. In the saline group, however, there were no breathing events during sleep.
Conclusions: These results show that silicone injections into the tongue base of rabbits can result in OSA.
Key Words: Rabbit, animal model, obstructive sleep apnea, sleep.
Level of Evidence: N/A
Laryngoscope, 124:789–796, 2014

INTRODUCTION and structural features that give rise to a narrowed

Obstructive sleep apnea (OSA) is a sleep disorder
that involves a cessation or significant decrease in air-
flow while sleeping. It is characterized by repetitive
pauses in breathing during sleep and is usually associ-
ated with a reduction in blood oxygen saturation and
repetitive collapse of the pharynx during sleep in
patients with a relatively narrow upper airway.1 Recur-
rent hypoxemia and sleep fragmentation have been
related to inflammation, metabolic syndrome, hyper-
somnolence, mental deterioration, and cardiovascular
risks, including arrhythmias and systemic hyperten-
sion.2–5
Factors that decrease upper airway size or patency
during sleep such as old age, brain injury, decreased
muscle tone, increased soft tissue around the airway,
From the Department of Otolaryngology (M.S.Y.), Konkuk Univer-
sity Chungju Hospital, Konkuk University School of Medicine, Chungju;
the Department of Rehabilitation Medicine (N.R.J., K.H.C.), Asan Medical
Center, University of Ulsan College of Medicine and the Department of
Otolaryngology (B-J.L., Y-S.C.), Asan Medical Center, University of Ulsan
College of Medicine; and the Biomedical Research Institute (K.C.), Korea
Institute of Science and Technology, Seoul, Korea.
Editor’s Note: This Manuscript was accepted for publication
August 21, 2013.
This work was supported by the Public Welfare & Safety Research
program through the National Research Foundation of Korea (NRF) and
funded by the Ministry of Education, Science, and Technology (grant
2010–0020789) and the Asan Institute for Life Sciences, Seoul, Korea
(grant 09–354). The authors have no other funding, financial relation-
ships, or conflicts of interest to disclose.
Send correspondence to Yoo-Sam Chung, MD, PhD, Department of
Otolaryngology, Asan Medical Center, University of Ulsan College of
Medicine, 388-1 Pungnap-2dong, Songpa-gu, Seoul, Korea, 138–736.
E-mail: yschung@amc.seoul.kr
DOI: 10.1002/lary.24398
airway can lead to OSA. Although the clinical features
of OSA have been well characterized, many aspects of
its pathogenesis and pathophysiology are not yet fully
understood.6–8 Thus there is a need for suitable animal
models to study OSA. Animal models allow invasive pro-
cedures under well-controlled experimental conditions.
Basic research using experimental animals may help
further our understanding of the pathophysiological
mechanisms underlying OSA.
An ideal animal for an OSA model should be easy
to manipulate, relatively inexpensive, unrestrained, and
have small upper airways that can be easily obstructed.
Although a number of animal models have been pro-
posed,9–15 no model has satisfied all of these conditions.
The aim of this study was to develop and test the feasi-
bility of such an animal model for OSA. We hypothesized
that silicone injection into the tongue base of rabbits
would result in OSA. To address this hypothesis, we
developed a new animal model of OSA in rabbits by
injecting liquid silicone into the base of the tongue under
endoscopic guidance, and we will now describe the
results of this model.
MATERIALS AND METHODS
Animals and Electrode Implantation
Twelve female New Zealand White rabbits, with a mean
weight of 2.7 6 0.5 kg at baseline, 3.3 6 0.8 kg at 1 month, and
3.5 6 0.6 kg at 3 months after injection were used for all experi-
ments. In this study, we used female rabbits because they are
usually larger than male rabbits and easy to breed. Approval
from the Ethics Committee for Laboratory Animals of the Asan

Laryngoscope 124: March 2014 Yu et al.: Rabbit Model of Obstructive Sleep Apnea
789
Fig. 1. Schematic drawing of the site of liquid silicone injections at the tongue base (left). Endoscopic view of oral cavity of a rabbit in which
silicone was injected at the tongue base (asterisk) between the circumvallate papillae. [Color figure can be viewed in the online issue, which
is available at wileyonlinelibrary.com.]
Medical Center (AMC) was obtained prior to the study. All ani-
mal procedures were conducted in accordance with guidelines
published by the National Institutes of Health.16 Rabbits were
anesthetized with zolazepam (35 mg/kg, IM) and xylazine
hydrochloride (5 mg/kg, IM). After midline scalp incision, the
periosteum was divided over the frontoparietal region on both
sides of the head. Electroencephalogram (EEG)-recording elec-
trodes (Teflon-coated, multistranded stainless steel wire) were
placed over the frontal and parietal areas of the skull with
stainless steel screws (F3/P3–F4/P4). A reference electrode (Pz)
was implanted in the midline of the frontoparietal suture line.
Electrooculogram (EOG) recording electrodes (Teflon-coated,
multistranded stainless steel wire) were implanted extraorbi-
tally in the horizontal plane on both sides of the eyes. All elec-
trodes were secured to the skull with dental acryl cement and
connected to a nine-pin stainless steel connector (DE-9P, AMP).
Electromyography (EMG) electrodes (a pair of monopolar needle
electrodes) were inserted into the biceps femoris muscles. The
rabbits were administered amoxicillin (10 mg/kg, SQ) for 5 days
after electrode implantation. After 1 week of recovery, the rab-
bits were trained to sleep in the restraining apparatus for 2
weeks. During the first week of habituation, the rabbits were
trained to sleep in the prone position. During the second week,
the rabbits were habituated to sleep while they wore an
adapted mask, thoraco-abdominal bands (Protech, Velcro Strap;
Redmond, WA), and a foreleg pulse oximeter (Nonin, 2000SA
Wrap Sensor; Plymouth, MN). The rabbits were considered to
be habituated to the experimental conditions when they dis-
played normal sleep-wake cycles in the apparatus. Thereafter,
daily data recordings were taken for 1 month to test the stabil-
ity of sleep architecture.
Baseline Polysomnography
Polysomnography was performed on rabbits before induc-
tion of OSA using four EEG, two EOG, two EMG electrodes,
one abdominal belt sensor (inductance plethysmography), one
air flow sensor, and one oximeter. Polysomnography was per-
formed from 9 am to 7 pm using a polygraph (B&TEK, Stellate
Harmonie System; San Carlos, CA) with frequency ranges of
Laryngoscope 124: March 2014
790
1.5 Hz to 100 Hz for EEG, 0.5 Hz to 35 Hz for EOG, and 7 Hz
to 150 Hz for EMG recordings. Nasal and oral airflows were
recorded through an adapted ventilation face mask connected to
a pressure transducer system (Breabon, Ultima Pressure Sen-
sor; Kanata, Ontario, Canada). The flexible shell of the mask
was molded to conform to the rabbit’s mouth and nose. Respira-
tory efforts were monitored by respiratory inductance plethys-
mography; and blood oxygen saturation (SaO2) was measured
using a pulse oximeter with a probe attached to the shaved
foreleg of each rabbit. Sleep stages were classified as awake,
stage I, and stage II sleep stages, and were identified as
described previously.17 In the present study, respiratory events
were scored as hypopnea when there was a reduction of 50% to
90% in the nasal flow signal, recorded via an oronasal mask for
at least two breaths. Apnea was defined by a >90% reduction in
airflow at the nose and mouth for at least two breaths. Total
sleep time (TST) refers to the time a rabbit spent asleep in any
sleep stage.
Injection of Silicone and Saline/Postinjection
Polysomnography
Using endoscopic guidance, rabbits were injected with 1.5
mL to 3.0 mL liquid silicone (Dow Corning, Q7–9120 Silicone
Fluid; experimental group, n 5 6) or normal saline (control
group, n 5 6) into the base of the tongue once weekly (Fig.1).
Polysomnography was performed every week after injection to
evaluate the effect of injections on respiratory effort, apnea-
hypopnea index (AHI), TST, sleep stage, and SaO2. Silicone
injections were stopped when chronic regular hypopnea or
apnea developed; this was observed after a mean of three
injections (range, 2–4) with a mean cumulative injected vol-
ume of 5.6 6 1.9 mL liquid silicone. Saline was injected into
the base of the tongue in the same way as silicone injection.
The mean amount of saline injected into control rabbits was
5.0 6 1.2 mL.
Rabbits in the silicone group underwent postinjection poly-
somnography 1 and 3 months after induction of OSA, and rabbits
in the saline group underwent postinjection polysomnography
1 month after injection of saline.
Yu et al.: Rabbit Model of Obstructive Sleep Apnea
Fig. 2. Example of a baseline poly-
somnography recording. air-
flow 5 nasal pressure transducer;
effort 5 abdominal strain gauges;
EMG 5 electromyogram; F3/Pz, F4/Pz,
P3/Pz, P4/Pz 5 electroencephalogra-
phy leads; LOC and ROC 5 left and
right electrooculogram; SaO2 5 oxy-
gen saturation. [Color figure can be
viewed in the online issue, which is
available at wileyonlinelibrary.com.]
Histopathologic Examination
At 3 months after silicone injection, the assigned rabbits
were sacrificed and the tongue base was removed for pathologi-
cal inspection. Saline-injected rabbit were used to control the
normal histology of tongue base. The specimens were fixed in
10% buffered formalin. Serial coronal paraffin sections of each
specimen at 500-mm intervals were prepared and then stained
with hematoxylin and eosin (H&E) for light microscopic inspec-
tion. Histopathological assessment of the stained slides was
performed to determine the general tissue responses to silicone
or saline. Sections were assessed for the degree of inflamma-
tion, fibroblast proliferation, and foreign body reaction.
Statistical Analysis
Statistical analyses were performed using the SPSS soft-
ware (version 15.0; SPSS, Inc., Chicago, IL). Differences
between groups were analyzed by the Wilcoxon signed-ranks
test and Mann-Whitney U test. All data are reported as mean-
s 6 standard deviations (SDs). A P value < 0.05 was considered
statistically significant.
RESULTS
Baseline Recordings
At baseline, all 12 rabbits showed normal breathing
while awake or asleep, with no evidence of apnea or
Laryngoscope 124: March 2014
hypopnea (Fig 2). Mean length of sleep in restraining
cages was 240.8 6 48.6 minutes, and mean sleep latency
was 5.3 6 2.5 minutes. Sleep stage I occurred for
22.4% 6 5.7% of total sleep time (TST), sleep stage II for
76.8% 6 6.1%, and rapid eye movement (REM) sleep for
1.8% 6 1.7%. There were no significant differences
between the silicone and saline groups regarding sleep
parameters, hypopnea, and apnea at baseline (P > 0.05)
(Fig 3).
Postinjection Recordings
Rabbits in the silicone group showed obstructive
breathing events immediately after the injection of sili-
cone (Fig 4). One month after injection, although these
rabbits showed no significant changes in breathing
events while awake, all silicone group animals developed
disordered breathing during sleep. There was a decrease
in nasal airflow with an associated decrease in respira-
tory effort, and significant increases in hypopnea and
apnea were observed (Fig 5). One month after injection,
the rabbits had a mean of 29.9 6 6.9 hypopneas/h and a
mean of 10.4 6 3.1 apneas/h; after 3 months, these rab-
bits had a mean of 28.4 6 6.9 hypopneas/h and a mean of
10.0 6 3.3 apneas/h (Fig 3). Mean TST decreased from
260.3 6 70.2 minutes at baseline to 152.5 6 38.8 minutes
Yu et al.: Rabbit Model of Obstructive Sleep Apnea
791
Fig. 3. The effect of injection of silicone (w) and saline (•) on total sleep time (TST), sleep stage, apnea/hypopnea index (AHI), and minimal
blood oxygen saturation (SaO2). Values are means 6 SD.
after 1 month and 206.8 6 60.3 minutes after 3 months
(P 5 0.054). The mean percentage of sleep stage I at the
baseline was 21.8 6 4.1%, whereas the mean percentage
of sleep stage I in the silicon group at 1 and 3 months
after injection were 31.5 6 5.3 and 26.9 6 8.1%, respec-
tively (P 5 0.097). Although the percentage of sleep stage
I tended to increase and the percentage of sleep stage II
tended to decrease 1 month after silicone injection com-
pared to that of the baseline, these changes were not
statistically significant (P > 0.05) (Fig 3). Minimal SaO2
during sleep was lower after silicone injection than at
baseline. The minimal SaO2 at baseline and at 1 month
and 3 months after injection were 94.7 6 2.1, 81.5 6 6.7,
and 82.7 6 6.9, respectively (P 5 0.016) (Fig 3).
Rabbits in the control group showed obstructive
breathing events immediately the after injection of
saline (Fig. 4), but there were no significant changes in
breathing events during sleep after 1 month (Fig. 5).
Hypopnea (0 hypopnea/h), TST (221.8 6 27.1 vs.
210.8 6 21.9 min.), and minimal SaO2 (94.3 6 2.2% vs.
93.5 6 3.0%) were similar at 1 month compared to the
baseline (P > 0.05). Furthermore, there were no signifi-
cant changes in the proportions of sleep stages I and II
and REM sleep after saline injection (P > 0.05) (Fig 3).
There was a significant difference in the AHI after
injection between silicone and saline groups. One month
Laryngoscope 124: March 2014
792
after injection, the AHIs in the silicone and saline
groups were 40.3 6 14.0 and 0.0, respectively (P 5 0.002).
The TST of the silicone group at 1 month after injection
was 152.5 6 38.8, whereas that of the saline group was
210.8 6 21.9 (P 5 0.025). The minimal SaO2 was
81.5 6 6.7 and 93.5 6 3.0 in silicone and control groups,
respectively (P 5 0.004). There was no significant differ-
ence in the proportions of sleep stages between the sili-
cone and saline groups (P > 0.05) (Fig 3). Significant
narrowing of the oropharynx was noted 3 months after
silicone injection. Injection-associated histologic changes
in the tongue base are shown in Figure 6. Liquid silicone
occupied the subepithelial and intramuscular spaces 3
months after silicone injection. There was no evidence of
inflammation or fibrosis. No definite histologic changes
were noted in animals from the saline group.
DISCUSSION
An animal model of OSA may help to investigate
the pathophysiology of this disorder and develop appro-
priate treatments. The ideal animal for such a model
should be small, inexpensive, and easy to obstruct upper
airway. Here, we have shown that injecting silicone into
the upper airways of rabbits significantly modified air-
way anatomy. All six silicone-injected rabbits developed
Yu et al.: Rabbit Model of Obstructive Sleep Apnea
Fig. 4. Example of a polysomnogra-
phy recording immediately after injec-
tion under general anesthesia.
Airflow 5 nasal pressure transducer;
Effort 5 abdominal strain gauges;
EMG 5 electromyogram; F3/Pz, F4/Pz,
P3/Pz, P4/Pz 5 electroencephalogra-
phy leads; LOC and ROC 5 left and
right electrooculogram; SaO2 5 oxy-
gen saturation. [Color figure can be
viewed in the online issue, which is
available at wileyonlinelibrary.com.]
hypopnea, but not the six control saline-injected rabbits.
The silicone group also showed modifications in sleep
architecture, which may have been due to sleep frag-
mentation induced by disturbed breathing events. These
findings suggest that injection of silicone into rabbits is
a good animal model for breathing disorders during
sleep.
A number of animal models such as dogs, pigs, and
rats have been used to investigate the pathophysiology
of OSA. In addition, spontaneously occurring OSA has
been documented in the English bulldog and obese
pig.10,12,14,15 These animals developed OSA events,
which resulted from a remarkably similar pathogenesis
to that described in humans with OSA.18 The major limi-
tations in using these models have been the difficulty in
obtaining enough animals to establish a statistically
adequate sample for various types of studies; thus the
use of English bulldog or obese pigs in nonsurvival
research protocols is not possible. Intermittent airway
obstruction in tracheotomized dogs has also been studied
in order to understand the pathophysiology of OSA.11
Although the long-term application of this model has
provided important insights into the effects of repeated
airway occlusion during sleep, it does not account for
one major factor in the pathophysiology of human OSA,
the upper airway. A rat model in which rats breathe air
Laryngoscope 124: March 2014
with different oxygen concentrations has been used to
study the effects of respiratory disturbances during
OSA.19 However, these models do not allow us to investi-
gate the potential consequences of strenuous breathing
against an obstructed airway.8 Thus far the monkey is
the animal that best provides a model for human OSA.
In that model, OSA is induced by the injection of colla-
gen into the soft palate, posterior pharyngeal wall, and
base of the tongue.13 However, this model is hard to
manipulate, costly, and not suitable for studies requiring
large numbers of subjects. The advantages of using rab-
bits, as in our model, are their small size, low cost, and
relatively ease with which the upper airway can be
obstructed. Therefore, rabbits can be used in large stud-
ies on OSA.
In a preliminary study before developing an OSA
model using rabbits, we performed a study on the natu-
ral sleep patterns of rabbits under the same conditions
as in the present study. In the preliminary study, no dis-
ordered breathing developed more than two respiratory
cycles during normal sleep in rabbit. Therefore, we
defined hypopnea or apnea as a reduction in nasal flow
signal recorded via a nasal mask for at least two breaths
in the present study. Additionally, in the preliminary
study, rabbits were injected with silicone into various
parts of oropharynx, including the soft palate, uvula,
Yu et al.: Rabbit Model of Obstructive Sleep Apnea
793

tongue, and base of tongue. After several trials, we con-
cluded that the tongue base between the circumvallate
papillae was the most safe and effective injection site to
develop sleep disordered breathings in rabbits.
The present study has several limitations. First, the
REM sleep proportion to total sleep in our study appears
to be lower than that in natural sleep in rabbits,
although previous studies showed wide variations in
REM percentage during natural sleep that vary from
2.6% to 8.0%.17,20 In the present study, the identification
of REM was somewhat less reliable due to the effects of
phasic twitches on the amplitude of the integrated EMG
signal. Although the needle electrodes provided adequate
signals, they were difficult to insert into awake rabbits
and difficult to keep in place when an animal shook its
trunk. Furthermore, sustained EMG inhibition, which is
a common feature of REM in the rabbit, and extreme
sensitivity to environmental stimuli and vulnerability to
stress could be reasons for the low REM percentage.20
Further evaluation of the differences in sleep disordered
breathing between REM and non-REM in the rabbit
model is warranted. Another problem in our study was
the difficulty in maintaining a continuous oximetry sig-
nal. Perhaps newer, more sensitive oximetry probes will
eliminate this difficulty. Other studies have indicated
that pulse oximetry can accurately detect changes in
SaO2 in pigs.21–23 Finally, the ideal animal model of
OSA should involve an animal that is freely behaving
Laryngoscope 124: March 2014
794
Fig. 5. Example of a polysomnogra-
phy recording during sleep 1 month
after injection. Animals in the sili-
cone group showed hypopnea and
apnea. There were no significant
changes in breathing events in the
saline group. Airflow 5 nasal pres-
sure transducer; Effort 5 abdominal
strain gauges; EMG 5 electromyo-
gram; F3/Pz, F4/Pz, P3/Pz, P4/
Pz 5 electroencephalography leads;
LOC and ROC 5 left and right elec-
trooculogram; SaO2 5 oxygen satu-
ration. [Color figure can be viewed
in the online issue, which is avail-
able at wileyonlinelibrary.com.]
and unrestrained. In this respect, our model has a limi-
tation in that the experiments were performed with ani-
mals under restraint. Nevertheless, the restraint was
unavoidable in order to achieve high sensitivity and sta-
bility of sleep parameter recordings, especially airflow
status, which is necessary in order to detect abnormal
breathing during sleep. Also, the ventilation face mask
for recording nasal and oral airflow was difficult to keep
in place under freely behaving conditions.
At present, no single treatment exists for all OSA
patients. The most effective and commonly used treat-
ment for OSA is nasal continuous positive airway pres-
sure, which requires patients to wear a mask through
which pressurized air is delivered to the nose during
sleep. Many patients, however, are unable to tolerate
this therapy.24 There are no medications that are effec-
tive against OSA. Although surgical procedures such as
tracheostomy and mandibular advancement are effective
in most patients, they are either deforming or require a
long surgical procedure with a painful postoperative
course.25 Therefore, better treatments are clearly
needed. Animal models for sleep apnea may allow inves-
tigators to perform pharmacological and surgical inter-
ventions that are not possible in humans. These
interventions can be directed at understanding the
mechanisms by which upper airway obstruction contrib-
utes to sleep apnea as well as to the development of bet-
ter and more widely available treatments.
Yu et al.: Rabbit Model of Obstructive Sleep Apnea
Fig. 6. Microscopic view of the tongue base 3 months after silicone (upper) and saline (lower) injection. Liquid silicone (S) occupied the sub-
epithelial space and intramuscular space after injection. There was no evidence of inflammation or fibrosis in either group. Hematoxylin-
eosin stain, 310 (left), 3100 (right). E 5 stratified squamous epithelium; M 5 skeletal muscle fiber. [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]

CONCLUSION acted as a guarantor of the article. Ms. N. R. Jung contrib-

In the present study, an animal model for OSA was
developed by injecting silicone into the tongue base of
rabbits. This model may enable clinicians to evaluate
the progressive consequences of OSA and may lead to
the development of better treatments for OSA. However,
our experimental models could be useful for investigat-
ing isolated mechanisms such as upper airway obstruc-
tion. Therefore, more complex and realistic models
combining the various injurious challenges characteriz-
ing OSA will be needed to allow a more accurate transla-
tion from animal researches to patients.
Acknowledgements
The authors would like to thank Mr. C. S. Kim at the AMC
Cranial Nerve Examination Laboratory for technical sup-
port in polysomnography. Author contributions include the
following: Dr. M. S. Yu contributed to the conception of the
study design, the execution of the study, the discussion of
the findings and results, the preparation of the article, and
uted to the execution of the study and the discussion of find-
ings. Dr. K. H. Choi contributed to conception of the study
design and the discussion of results. Dr. K. Choi contributed
to conception of the study design and the discussion of
results. Dr. B. J. Lee contributed to conception of the study
design and the discussion of results. Dr. Y. S. Chung contrib-
uted to conception of the study design, the execution of the
study, the discussion of findings and results, the prepara-
tion of the article, and acted as a guarantor of the article.
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