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crossover study of 15 patients with treated, stable systolic
heart failure, oral theophylline at therapeutic plasma con-
centration (11 µg/mL, range 7 to 15 µg/mL) decreased the
AHI by about 50% and improved arterial oxyhemoglobin
saturation. 123
Mechanisms of action of theophylline in improving
central apnea remain unclear. 123 At therapeutic serum con-
centrations, theophylline competes with adenosine at some
of its receptor sites. In the central nervous system, adenos-
ine is a respiratory depressant and theophylline stimulates
respiration by competing with adenosine. Conceivably,
therefore, an increase in ventilation by theophylline could
decrease central apnea during sleep. Theophylline does
not increase ventilatory response to CO 2 .
Potential arrhythmogenic effects and phosphodiesterase
inhibition are common concerns with long-term use of
theophylline in patients with heart failure. Therefore,
further controlled studies are necessary to ensure its safety.
If theophylline is used to treat CSA, frequent and careful
follow-ups are necessary.
80
Room air
Oxygen
Means ± SD
P < .0001
70
60
P < .01
P < .001
P < .05
50
P < .01
P = .02
40
30
20
10
0
n = 9
Hanly
n = 7
Walsh
n = 11
Staniforth
n = 7
Franklin
n = 22
Andreas
n = 29
Javaheri
Figure 122-12 Effects of supplemental nasal oxygen on
apnea-hypopnea index in patients with systolic heart failure.
A CETAZOLAMIDE
By inhibiting carbonic anhydrase in red blood cells, kidney,
and choroid plexus, acetazolamide causes acidosis in the
blood and cerebrospinal fluid124-126 124-126 and stimulates breath-
ing. By doing so, acetazolamide increases the PCO 2 reserve,
decreasing the likelihood of the development of central
apnea during sleep. 127
Acetazolamide has been used to treat idiopathic central
sleep apnea 128 - 129 and periodic breathing at high altitude.
In a double-blind placebo-controlled crossover study 130 of
12 patients with heart failure, acetazolamide, administered
at about 3 mg/kg one-half hour before bedtime, decreased
the central apnea-hypopnea index significantly from about
57/hr (in the placebo arm) to 34/hr. Acetazolamide
improved arterial oxyhemoglobin desaturation signifi-
cantly. Furthermore, patients reported improved subjec-
tive perceptions of the following: overall sleep quality,
feeling rested on awakening, falling asleep unintentionally
during daytime, and fatigue. Acetazolamide, therefore,
could have other advantageous effects when used in
patients with heart failure and CSA, including acting as a
mild diuretic and also normalizing the alkalemia (caused
by loop diuretics) commonly present in patients with heart
failure. In our patients, arterial blood pH decreased from
7.43 to 7.37. 130
MEDICATIONS
N ASAL N OCTURNAL O XYGEN
Systematic studies in patients with systolic heart
failure 114-119 have shown that nocturnal therapy with sup-
plemental nasal oxygen improves central sleep apnea
( Fig. 122-12 ). Oxygen therapy may also decrease arousals
and improve the hypnogram by shifting sleep structure
to deep sleep stages. In addition, randomized placebo-
controlled double-blind studies have shown that short-
term (1 to 4 weeks) administration of nocturnal
supplemental nasal oxygen improves maximal exercise
capacity 116 and decreases overnight urinary norepineph-
rine excretion. 117
Three randomized clinical trials of nocturnal nasal
oxygen therapy 120-122 for 9-, 12-, and 52-week periods,
reported that, when compared with the control group,
oxygen therapy improved CSA and desaturation and sig-
nificantly increased left ventricular ejection fraction and
quality of life of patients with heart failure. In the oxygen-
treated group, left ventricular ejection fraction increased
5% (versus 1% in the control group) in the 12-week
study, 122 and 5.5% (versus 1.3% in the control group) in
the 52-week study. 121
Supplemental administration of nasal oxygen may
decrease periodic breathing by several mechanisms. 119
These include an increase in the difference between the
prevailing PCO 2 and the PCO 2 at the apneic threshold; a
reduction in the ventilatory response to CO 2 and perhaps
to hypoxemia; and an increase in body stores (e.g., lung
contents) of oxygen, which increases damping. Prospective
placebo-controlled long-term studies, however, are neces-
sary to determine if nocturnal oxygen therapy has the
potential to decrease mortality of patients with systolic
heart failure.
B ENZODIAZEPINES
Benzodiazepines, by decreasing arousals, may decrease
central sleep apnea. However, a placebo-controlled dou-
ble-blind study 131 showed a reduction in arousals but failed
to show any improvement in CSA in patients with systolic
heart failure. Although benzodiazepines do not increase
the number of central apneas, their use may increase the
likelihood of developing obstructive apneas in some heart
failure patients.
I NHALED CO 2 AND A DDITION OF E XTERNAL D EAD S PACE
Several studies have shown that low-level inhalation of
CO 2 and addition of external dead space (by increasing
PCO 2 ) improve CSA. 132-136 However, studies 106,133,134 show
that CO 2 inhalation increases spontaneous arousals, which
T HEOPHYLLINE
Open and blind studies 7 , 123 have shown the efficacy of the-
ophylline in the treatment of central sleep apnea in heart
failure. In a double-blind randomized placebo-controlled
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