Editorials
only explanation can be that nosocomial transmission occurred
during these years in these hospitals. And finally, we must con-
clude that nosocomial transmission, not community exposure,
still represents a substantial and inexplicably underappreciated
risk for hospital workers throughout North America.
Finally, and perhaps most impressive and important of all,
this article and the work that the group has done before it show
the potent benefit of collaborative studies. It is somewhat em-
barrassing that these Canadian investigators, miles and miles
away from the multidrug-resistant TB outbreaks that nearly par-
alyzed several urban areas in the U.S. a decade ago, were able to
calmly and soberly develop a program to answer the fundamen-
tal questions that the U.S. outbreaks urgently posed: How does
TB spread in hospitals? What is the role of ventilation? What is
the contribution of a childhood BCG vaccination? Does clinical
experience matter? It is a puzzle why no group in the U.S.
stepped forward to confront these same questions. One suspects
that many good ideas were left stranded at the planning stage,
victims of posturing and egos and the entire nasty sideshow that
characterizes so many initially honorably academic pursuits. In
the meantime, our Canadian colleagues have executed a pro-
gram that is a model of simplicity, flexibility, and productivity.
Perhaps in addition to learning our lessons about the conse-
quences of delayed TB diagnosis, we would be well-served to
learn the benefits of real collaborative work from the Canadian
Collaborative Group in Nosocomial Transmission of TB.
Sleep Apneas
An Oxidative Stress?
Sleep apneas (obstructive or central) are one of the most com-
monly encountered respiratory disorders in humans. More im-
portantly, epidemiologic, retrospective, and cross-sectional
studies on sleep apnea patients have identified strong associa-
tions between apneas and serious cardiovascular disturbances.
For example, there is a strong linkage between the develop-
ment of hypertension and the severity of sleep apneas (num-
ber of apneas or near apneas/hour) (1). Sleep apnea patients
are also prone to myocardial infarctions, pulmonary hyperten-
sion, and stroke (2). In a large population of patients (Sleep
Heart Health study), sleep-disordered breathing is more
strongly associated with heart failure and stroke than coro-
nary heart disease (3). Treatment with continuous positive air-
way pressure reverses hypertension in sleep apnea patients (4).
Apneas are associated not only with periodic decreases in
arterial oxygen (hypoxia) but also simultaneous increases in
arterial carbon dioxide (hypercapnia). Therefore, one funda-
mental question that often surfaces is whether hypoxia or hy-
percapnia underlies the pathophysiology of sleep apneas. This
question has been recently addressed in animal models of epi-
sodic hypoxia. Fletcher (5) exposed rats to episodic hypoxia
(using a paradigm of intermittent hypoxia without hypercap-
nia) and found development of hypertension and increased
sympathetic activity after 30 days. Moreover, when hypoxia
was combined with hypercapnia using a similar paradigm, the
magnitude of hypertension was nearly the same, suggesting
that episodic hypoxia contributes more to the cardiovascular
abnormalities than hypercapnia.
Development of animal models of intermittent hypoxia has
greatly facilitated our understanding of the mechanisms associ-
ated with recurrent apneas. Hypertension caused by intermit-
tent hypoxia is due to enhanced reflex drive from peripheral
chemoreceptors, especially the carotid bodies (see Ref. 6 for
859
KENT A. SEPKOWITZ, M.D.
Memorial Sloan-Kettering Cancer Center
New York, New York
References
1. Greenaway C, Menzies D, Fanning A, Grewal R, FitzGerald M, and The Ca-
nadian Collaborative Group in Nosocomial Transmission of Tuberculosis.
Delay in diagnosis among hospitalized patients with active tuberculosis
predictors and outcomes. Am J Respir Crit Care Med 2002;165:927933.
2. Menzies D, Fanning A, Yuan L, FitzGerald JM. Tuberculosis in health
care workers: a multicentre Canadian prevalence survey: preliminary
results. Canadian Collaborative Group in Nosocomial Transmission of
Tuberculosis. Int J Tuberc Lung Dis 1998;2(9 Suppl 1):S98S102.
3. Menzies D, Fanning A, Yuan L, FitzGerald JM. Hospital ventilation and
risk for tuberculous infection in Canadian health care workers. Cana-
dian Collaborative Group in Nosocomial Transmission of TB. Ann In-
tern Med 2000;133:779789.
4. Begg CB, Cramer LD, Hoskins WJ, Brennan MF. Impact of hospital volume
on operative mortality for major cancer surgery. JAMA 1998;280:17471751.
5. Thiemann DR, Coresh J, Oetgen WJ, Powe NR. N Engl J Med 1999;340:
16401648.
6. Blumberg HW, Watkins DL, Berschling JD, Antle A, Moore P, White N,
Hunter M, Green B, Ray SM, McGowan JE Jr. Preventing the nosoco-
mial transmission of tuberculosis. Ann Intern Med 1995;122:658663.
7. Snider DE Jr, Cauthen GM. Tuberculin skin testing of hospital employ-
ees: infection, boosting, and two-step testing. Am J Infect Control
1984;12:305311.
DOI: 10.1164/rccm.2201073
references). Recent studies on a rat model of intermittent hy-
poxia suggest that enhanced peripheral chemoreceptor drive as
well as the development of hypertension critically depends on
the pattern of hypoxia (6). Thus, exposing rats to 10 days of in-
termittent hypoxia (15 seconds 5% O2 followed by 21% O2 for
5 minutes; 8 hours/day) resulted in marked enhancement of pe-
ripheral chemoreceptor activity, increased blood pressure, and
sympathetic activity. In sharp contrast, such cardiovascular
changes were not elicited by exposing animals to cumulative
comparable duration of sustained hypoxia. Similarly, exposing
cell cultures to intermittent hypoxia using the protocols similar
to experimental animals increased c-fos protooncogene expres-
sion, whereas the cumulative comparable duration of sustained
hypoxia had little effect (6). These studies suggest that inter-
mittent hypoxia is a more potent stimulus than sustained hy-
poxia and also emphasize that the pattern of hypoxia, i.e., re-
petitive or continuous, have profoundly different effects.
The major difference between intermittent and continuous
hypoxia is the episodic re-oxygenation in the former but not
the latter. In this respect, intermittent hypoxia seems to re-
semble ischemia-reperfusion. Several lines of evidence suggest
that ischemia-reperfusion represents an oxidative stress caus-
ing increased generation of reactive oxygen species, especially
superoxide anions (O2 ). Therefore, the cardiorespiratory al-
terations evoked by intermittent hypoxia are likely due to in-
creased generation of O2 . Such a possibility is supported by
the finding that administration of manganese (III) tetrakis
(1-methyl-4-pyridyl) porphyrin pentachloride (5 mg/kg/day in
animal studies; 50 M in cell studies), a potent scavenger of
O2 , prevented intermittent hypoxia-evoked changes in the
cardiorespiratory system as well as gene expression (6).
Based on the findings from experimental studies, it has been
proposed that intermittent hypoxia, such as that seen in sleep
860 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
apneas, represents a form of oxidative stress leading to in-
creased generation of reactive oxygen species. Such an idea
seems to be supported by a recent study by Shultz and co-
workers (7), who reported increased O2 generation from
neutrophils in patients with obstructive sleep apnea, and treat-
ment with continuous positive airway pressure led to rapid de-
crease in O2 generation. Circulating nitric oxide levels, mea-
sured by serum nitrite/nitrate, are decreased in patients with
sleep apnea and the levels were restored after treatment with
continuous positive airway pressure (8). These studies suggest
that intermittent hypoxia represents a form of oxidative stress.
However, the association between increased generation of re-
active oxygen species and pathogenesis in patients with sleep
apnea has not been explored. In this issue of the AJRCCM,
Dyugovskaya and colleagues (pp. 934939) examined genera-
tion of reactive oxygen species and adhesion molecule expres-
sion in neutrophils from patients with sleep apnea (9). Their
results showed increased expression of CD15 and CD11c in
monocytes from the patients, which were correlated with in-
creased intracellular production of reactive oxygen species.
Furthermore, alterations in adhesion molecule expression and
levels of reactive oxygen species were associated with in-
creased adherence of monocytes to human endothelial cells in
cell cultures. More importantly, treatment with continuous
positive airway pressure down-regulated the adhesion mole-
cule expression and decreased basal production of reactive ox-
ygen species in CD11c monocytes. Because increased expres-
sion of adhesion molecules contributes to atherogenesis, the
findings of Dyugovskaya and associates (9) are important in
that they link the oxidative stress caused by recurrent apneas
to the pathogenesis of the vascular disease.
Several mechanisms contribute to endogenous generation
of reactive oxygen species. For instance, NADPH oxidases
produce O2 via protein kinase C (PKC)-dependent mecha-
nism. The data presented by Dyugovskaya and colleagues (9)
suggest that increased generation of reactive oxygen species
involves PKC-dependent NADPH oxidase activation because
they observed a marked enhancement of O2 generation with
phorbol ester, a potent activator of PKC. However, it remains
to be determined whether increased reactive oxygen species in
patients with obstructive sleep apnea is due to upregulation of
NADPH-oxidases and/or PKC-dependent phosphorylation.
Reactive oxygen species could also be generated when mito-
chondrial oxidative metabolism is perturbed at the level of
VOL 165 2002
complexes I or III. Hopefully, future studies will provide fur-
ther insight as to the effects of intermittent hypoxia on
NADPH oxidases and/or mitochondrial function and their re-
spective contributions to oxidative stress in recurrent apneas.
Thus, both experimental and human studies seem to be con-
sistent with the idea that intermittent hypoxia, associated with
recurrent apneas, represents a form of oxidative stress. More
importantly, whatever the source of reactive oxygen species,
these studies beg the question of whether scavengers can be
used as an effective therapeutic intervention in alleviating the
cardiovascular disturbances associated with recurrent apneas.
NANDURI R. PRABHAKAR, PH.D.
Department of Physiology and Biophysics
Case Western Reserve University
Cleveland, Ohio
References
1. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, DAgostino
RB, Newman AB, Lebowitz MD, Pickering TG. Association of sleep-dis-
ordered breathing, sleep apnea, and hypertension in a large community-
based study. Sleep Heart Health Study. JAMA 2000;283:18291836.
2. Cherniack NS. New mechanisms for the cardiovascular effects of sleep
apnea. Am J Med 2000;109:592594.
3. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto J, OCon-
nor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing
and cardiovascular disease. Am J Respir Crit Care Med 2001;163:1925.
4. Wright J, Johns R, Watt I, Melville A, Sheldon T. Health effects of ob-
structive sleep apnea and the effectiveness of continuous positive air-
ways pressure: a systematic review of the research evidence. BMJ 1997;
314:851860.
5. Fletcher EC. Effect of episodic hypoxia on sympathetic activity and blood
pressure. Respir Physiol 2000;119:189197.
6. Prabhakar NR. Oxygen sensing during intermittent hypoxia: cellular and
molecular mechanisms. J Appl Physiol 2001;90:19861994.
7. Schultz R, Mahmoudi S, Hattar K, Sibelius U, Olschewski H, Mayer K,
Seeger W, Grimminger F. Enhanced release of superoxide from poly-
morphonuclear neutrophils in obstructive sleep apnea. Am J Respir
Crit Care Med 2000;162:566570.
8. Ip MSM, Lam B, Chan LY, Zheng L, Tsang KWT, Fung PC, Lam WK.
Circulating nitric oxide is suppressed in obstructive sleep apnea and is
reversed by nasal continuous positive airway pressure. Am J Respir Crit
Care Med 2000;162:21662171.
9. Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expres-
sion and production of reactive oxygen species in leukocytes of sleep
apnea patients. Am J Respir Crit Care Med 2002;165:934939.
DOI: 10.1164/rccm.2202024