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J Appl Physiol 107: 13, 2009;


Invited Editorial

Intermittent hypoxia: keeping it real

Barbara J. Morgan
Department of Orthopedics and Rehabilitation, School of Medicine and Public Health, University of Wisconsin,
Madison, Wisconsin
Submitted 20 March 2009; accepted in final form 23 March 2009
IN THIS ISSUE of the Journal of Applied Physiology, Tamisier and
colleagues (20) describe a novel method for studying the
effects of chronic intermittent hypoxia (CIH) in healthy human
subjects. To investigate the effects of CIH on sleep, ventilatory
control, and blood pressure, the authors make clever use of
commercially available altitude tents to mimic the cyclical
arterial oxygen desaturations-resaturations of sleep apnea.
Young healthy men and women slept in the tents with a
fraction of inspired oxygen (FIO2) of 13% for either 14
(Grenoble, France) or 28 (Boston, MA) consecutive nights. At
2-min intervals throughout the night, supplemental oxygen was
administered for 15 s via a nasal cannula. The oxygen flow rate
was adjusted for each subject so that the difference in nadir and
peak arterial oxygen saturation (SaO2) was 10% (mean values:
8595%). These procedures resulted in central hypopneas
(35 events/h) that were synchronous with reoxygenations
and accompanied by arousals. The authors found that CIH
administered in this manner for 14 days augmented hypoxic
and hypercpanic ventilatory responses, increased hematocrit
and hemoglobin concentration, and raised daytime blood
This new model produces clinically relevant fluctuations in
SaO2. Nevertheless, as the authors point out, there are several
ways (e.g., poikilocapnia and no negative intrathoracic pressure development) in which their model does not mimic sleep
apnea. We would add that the cardiovascular and respiratory
consequences of this CIH paradigm also differ in several ways
from the known effects of sleep apnea. For example, the
percentage of sleep time at 90% SaO2 (80%) greatly exceeded that of most patients with sleep apnea, and the exposure
caused increases in hematocrit and hemoglobin concentration
and increases in the slopes of the ventilatory response to
hypoxia and hypercapnia. The latter findings are not consistently seen in patients with sleep apnea (3, 16, 22). In these
aspects, the model of Tamisier et al. more closely resembles
the hypoxia of high-altitude exposure. Nevertheless, this innovative model can no doubt be refined to bring the pattern of
intermittent hypoxia more in line with the disease it is intended
to mimic. The model developed by Tamisier and colleagues
represents an important step forward in the quest for methods
that are realistic yet applicable to nonapneic human subjects
who are free from cardiovascular, respiratory, or metabolic
The report by Lee and colleagues (10), also in this issue of
the Journal of Applied Physiology, reports on blood gas
changes produced by an established mouse model of sleep
apnea. Through rapid sampling of arterial blood in conscious

Address for reprint requests and other correspondence: B. J. Morgan, Dept.

of Orthopedics and Rehabilitation, School of Medicine and Public Health,
Univ. of Wisconsin, 1300 Univ. Ave., 5173 Medical Sciences Center, Madison, WI 53706-1532 (e-mail:

mice, the authors defined the deoxygenation-reoxygenation

profile associated with a CIH paradigm designed to resemble
moderate to severe sleep apnea (60 events/h). In their model,
FIO2 (measured at the nose) was reduced to 5 6% over 30 s
followed by rapid reoxygenation to room air levels within the
succeeding 30 s. This paradigm resulted in clinically relevant
cyclical decreases in arterial PO2 (to 47 2 mmHg) and SaO2
(to 85 2%). The authors have previously demonstrated that
most desaturations caused by this CIH paradigm are accompanied by arousals from sleep; however, this model does not
mimic the fluctuations in intrathoracic pressure and arterial
PCO2 that occur during episodes of sleep apnea. Nevertheless,
this protocol, with its carefully quantified arterial oxygenation
profiles, represents an important advance in the development of
animal models of sleep apnea.
In the past, a rather wide variety of animal models has
been used to study the cardiovascular consequences of CIH
(1, 2, 4, 5, 7, 9, 11, 12, 19, 21) (see Table 1). The
groundbreaking study of Fletcher and colleagues (4) that
first demonstrated the hypertensive effect of CIH employed
exposures that were severe with regard to the frequency of
events (120 events/h) and level of FIO2 (25%). The episodes
of hypoxemia in these experiments were accompanied by
hypocapnia, not hypercapnia, and there were no large fluctuations in intrathoracic pressure secondary to airway obstruction. In what must be considered an experimental tour
de force, Brooks and colleagues (2) developed a dog model
that mimics all aspects of human sleep apnea. Using a
computer-controlled tracheal occluder that was activated by
EEG evidence of sleep and deactivated by arousal, they
demonstrated substantial increases in daytime arterial pressure caused by the equivalent of severe sleep apnea
(50 60 events/h for 14 16 h/day). This group of investigators also showed that arousals triggered by auditory stimuli, which were delivered at the same frequency and which
caused comparable acute pressor responses as the tracheal
occlusions, did not affect daytime blood pressure. More
recently, CIH protocols that model mild or moderate
sleep apnea in terms of desaturation frequencies have also
produced increases in normoxic blood pressure (1, 5, 7, 12,
21). In most cases, the depth of desaturation produced by
these protocols is not known; however, when data from
these separate laboratories are viewed together, there seems
to be a rough dose-response relationship between the frequency of CIH events and magnitude of blood pressure rise.
The greatest increases in blood pressure were observed in
studies in which hypocapnia was prevented by CO2 supplementation (1, 7, 21).
The validity of such a comparison is, of course, questionable. Each laboratory applied its own unique CIH paradigm;
the frequency of events was only one of many differences in
experimental conditions. These discrepancies make generali-

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Invited Editorial


Table 1. Animal models of sleep apnea and their effects on normoxic MAP
Author (Ref.)

Species (Gender)

Hypoxia Duty Cycle, Nadir FIO2, and Duration

Effect on MAP, mmHg

Severe CIH (50120 events/h)

Fletcher et al. (4)
Lesske et al. (11)

Rat (male)
Rat (male)

6 s:24 s, 35%, 68 h/day, 35 days total

6 s:24 s, 24%, 68 h/day, 35 days total, hypo-CO2, eu-CO2, or
6 s:24 s, 23%, 68 h/day, 35 days total
5060 EEG-triggered tracheal occlusions/h, 1416 h/day, 35 days

Tahawi et al. (19)

Brooks et al. (2)

Rat (unknown)
Dog (male and female)

Hinojosa-Laborde et al. (5)

Rat (male and female)

3 min:3 min, 10%, 8 h/day, 7 days total

Marcus et al. (12)

Kraiczi et al. (9)

Rat (male)
Rat (unknown)

1 min:3 min, 10%, 12 h/day, 14 days total

90 s:90 s, 6%, 8 h/day, 70 days total

Kanagy et al. (7)

Troncoso et al. (21)
Allahdadi et al. (1)

Rat (male)
Rat (male)
Rat (male)

90 s:90 s, 5% 5% CO2, 7 h/day, 11 days total

90 s:90 s, 5% 5% CO2, 7 h/day, 14 days total
90 s:90 s, 5% 5% CO2, 7 h/day, 14 days total


Mild CIH (10 events/h)

15 (males) and12 (females)

Moderate CIH (1520 events/h)

No difference from controls

Moderate CIH (20 events/h) eucapnia


MAP, mean arterial pressure; CIH, chronic intermittent hypoxia; 1, increase.

zations difficult, and, in our opinion, they hinder efforts to

understand the cardiovascular, respiratory, metabolic, and cognitive effects of sleep apnea. To maximize progress in this field
of inquiry, we believe that investigators should make a concerted effort to standardize their methods and employ the most
realistic models available. Such an effort would require knowledge of the deoxygenation-reoxygenation profile, the arousal
status, and changes in PCO2 associated with each protocol.
Hypercapnia and abrupt changes in sleep state are likely to be
important accompaniments of intermittent hypoxia in models
of sleep apnea, because they would be expected to augment the
amount of sympathetic activation evoked by each event (6, 13,
14). In contrast, negative intrathoracic pressure, because of its
sympathoinhibitory effect (8, 15), is probably not critical for
modeling the prohypertensive effects of sleep apnea. Second,
humans and animals of both genders must be studied, given
that there is some evidence that males and females respond
differently to CIH (5). Finally, the cardiovascular consequences of CIH paradigms that model mild and moderate
sleep-disordered breathing in terms of event frequency and
depth of desaturations must be determined. Mild to moderate
sleep-disordered breathing, consisting mainly of hypopneas
with modest desaturations, is highly prevalent in the general
population (23). Two prospective correlational studies (17, 18)
have reached disparate conclusions about the effect of mild to
moderate sleep-disordered breathing on the development of
hypertension, indicating that cardiovascular risks associated
with this amount of sleep-disordered breathing are as yet
uncertain. Experimental evidence from animal and human
models is required to elucidate such risks and inform clinical
decisions about whom to treat.
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