Redolfi et al , 2015 Attenuation of obstructive sleep apnea and overnight rostral fluid shift by physical activity

Prévia do material em texto

Gustavo Pacheco-Rodriguez, Ph.D.
Joel Moss, M.D., Ph.D.
National Institutes of Health
Bethesda, Maryland
*Current address: Institute of TCM Diagnostics, Hunan University of Chinese
Medicine, 113 Shaoshan Avenue, Yuhua District, Changsha, Hunan 410007,
China.
References
1. Henske EP, McCormack FX. Lymphangioleiomyomatosis - a wolf in
sheep’s clothing. J Clin Invest 2012;122:3807–3816.
2. Smolarek TA, Wessner LL, McCormack FX, Mylet JC, Menon AG, Henske
EP. Evidence that lymphangiomyomatosis is caused by TSC2 mutations:
chromosome 16p13 loss of heterozygosity in angiomyolipomas and
lymph nodes from women with lymphangiomyomatosis. Am J Hum
Genet 1998;62:810–815.
3. Yu J, Astrinidis A, Henske EP. Chromosome 16 loss of heterozygosity in
tuberous sclerosis and sporadic lymphangiomyomatosis. Am J Respir
Crit Care Med 2001;164:1537–1540.
4. Sato T, Seyama K, Fujii H, Maruyama H, Setoguchi Y, Iwakami S,
Fukuchi Y, Hino O. Mutation analysis of the TSC1 and TSC2 genes
in Japanese patients with pulmonary lymphangioleiomyomatosis.
J Hum Genet 2002;47:20–28.
5. Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous
sclerosis complex gene TSC2 are a cause of sporadic pulmonary
lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000;97:
6085–6090.
6. Karbowniczek M, Astrinidis A, Balsara BR, Testa JR, Lium JH, Colby TV,
McCormack FX, Henske EP. Recurrent lymphangiomyomatosis after
transplantation: genetic analyses reveal a metastatic mechanism.
Am J Respir Crit Care Med 2003;167:976–982.
7. Crooks DM, Pacheco-Rodriguez G, DeCastro RM, McCoy JP Jr, Wang
JA, Kumaki F, Darling T, Moss J. Molecular and genetic analysis of
disseminated neoplastic cells in lymphangioleiomyomatosis.
Proc Natl Acad Sci USA 2004;101:17462–17467.
8. Cai X, Pacheco-Rodriguez G, Fan Q-Y, Haughey M, Samsel L, El-
Chemaly S, Wu H-P, McCoy JP, Steagall WK, Lin J-P, et al.
Phenotypic characterization of disseminated cells with TSC2 loss
of heterozygosity in patients with lymphangioleiomyomatosis.
Am J Respir Crit Care Med 2010;182:1410–1418.
9. Cai X, Pacheco-Rodriguez G, Haughey M, Samsel L, Xu S, Wu HP,
McCoy JP, Stylianou M, Darling TN, Moss J. Sirolimus decreases
circulating lymphangioleiomyomatosis cells in patients with
lymphangioleiomyomatosis. Chest 2014;145:108–112.
10. Páez D, Labonte MJ, Bohanes P, Zhang W, Benhanim L, Ning Y,
Wakatsuki T, Loupakis F, Lenz H-J. Cancer dormancy: a model of
early dissemination and late cancer recurrence. Clin Cancer Res
2012;18:645–653.
11. Ikeda Y, Taveira-DaSilva AM, Pacheco-Rodriguez G, Steagall WK,
El-Chemaly S, Gochuico BR, May RM, Hathaway OM, Li S, Wang JA,
et al. Erythropoietin-driven proliferation of cells with mutations in the
tumor suppressor gene TSC2. Am J Physiol Lung Cell Mol Physiol
2011;300:L64–L72.
12. Steagall WK, Pacheco-Rodriguez G, Glasgow CG, Ikeda Y, Lin JP,
Zheng G, Moss J. Osteoprotegerin contributes to the metastatic
potential of cells with a dysfunctional TSC2 tumor-suppressor gene.
Am J Pathol 2013;183:938–950.
13. Pacheco-Rodriguez G, Kumaki F, Steagall WK, Zhang Y,
Ikeda Y, Lin J-P, Billings EM, Moss J. Chemokine-enhanced
chemotaxis of lymphangioleiomyomatosis cells with mutations
in the tumor suppressor TSC2 gene. J Immunol 2009;182:
1270–1277.
14. Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences.
Biochim Biophys Acta 2010;1805:105–117.
15. McCormack FX, Travis WD, Colby TV, Henske EP, Moss J.
Lymphangioleiomyomatosis: calling it what it is: a low-grade,
destructive, metastasizing neoplasm. Am J Respir Crit Care Med
2012;186:1210–1212.
Copyright © 2015 by the American Thoracic Society
Attenuation of Obstructive Sleep Apnea
and Overnight Rostral Fluid Shift by
Physical Activity
To the Editor:
Physical activity attenuates obstructive sleep apnea (OSA) severity,
as assessed by the frequency of apneas and hypopneas per hour of
sleep (i.e., the apnea/hypopnea index [AHI]), even in absence of
weight loss, but the underlying mechanisms remain unknown (1–3).
Overnight fluid shift from the legs into the neck has been indicated
as a contributor to OSA (4). We have previously shown that
prevention of fluid accumulation in the legs, obtained by wearing
compression stockings during the day, reduces the AHI by
attenuating overnight fluid shift (5, 6). Moreover, intensified
diuretic therapy reduced the AHI in proportion to the decrease
in overnight fluid shift (7). Fluid accumulation in the legs is
promoted by sedentary living (8, 9) and is counteracted by physical
activity, which activates the musculovenous pumps (8–10). We
hypothesized that 1 week of two periods a day of 45 minutes of
moderate-speed walking will reduce the AHI in non–severely obese
sedentary subjects with moderate to severe OSA by decreasing
overnight fluid shift around the pharynx. Some of the results of this
study have been previously reported in the form of an abstract (11).
We consecutively selected subjects having a new diagnosis of
moderate to severe OSA, defined as an AHI greater than 15, and
a sedentary lifestyle, defined as not practicing physical activity
regularly. Subjects were excluded if they were severely obese (body
mass index [BMI], .35 kg/m2) and if they had a current history of
smoking or alcohol abuse, history of nasal or pharyngeal disease
or other chronic disease, use of prescribed medications, and
previously treated OSA. Seven men and one woman, middle-aged
(age, 566 11 years) and overweight (BMI, 28.96 3.9 kg/m2), were
randomly assigned to either a 1-week walking period (consisting
of walking at a rate at which they were able to keep up a full
conversation, which roughly corresponds to a speed of 5 km per
hour, 45 minutes twice a day, late in the morning and late in the
afternoon, for 7 days, while maintaining usual activities for the rest
of the time) or to a 1-week control period, after which they crossed
over to the other group. Physical activity was measured over the
walk and control periods using ActiGraph GT3X1 (ActiGraph
LLC, Fort Walton Beach, FL) in terms of the mean number of
steps taken a day during the week with and without physical
activity, respectively, which reflects the daily amount of
walking and is a marker of musculovenous pump activation.
Polysomnography and measurement of overnight changes
in legs fluid volume by bioelectrical impedance (4), in neck
circumference (4), and in air volume of the pharynx from the
hard palate level to the upper border of the hyoid bone by
magnetic resonance imaging were performed at the end of
the walk and control periods.
Author Contributions: S.R., M.B., I.A., T.S., and C.T. contributed to
conception, hypothesis delineation, and design; S.R., M.B., N.V., M.R., L.P.,
L.T.-M., I.A., T.S., and C.T. contributed to acquisition, analysis, and
interpretation; S.R., M.B., I.A., T.S., and C.T. contributed to drafting the
manuscript for important intellectual content.
This letter has an online supplement, which is accessible from this issue’s
table of contents at www.atsjournals.org
CORRESPONDENCE
856 American Journal of Respiratory and Critical Care Medicine Volume 191 Number 7 | April 1 2015
http://www.atsjournals.org
At the end of the control period, a substantial reduction
in leg fluid volume (Figure 1) and a pronounced increase of
neck circumference (Table 1) did occur overnight, indicating
a significant shift of fluid from the legs into the neck. This
overnight rostral fluid shift was accompanied by a 12% reduction in
pharyngeal air volume, attributable to the accumulation of fluid
in the pharyngeal walls (Figure 1 and Figure E2 in the online
supplement). The average AHI values at the end of the control
period indicate severe OSA (Figure 1). Compared with the end of
the control period, at the end of the walk period, there was an 80%
increase in the mean number of steps taken a day (Table 1),
accompanied by a significant reduction in the overnight fluid shift
by 40% (Figure 1) and in nocturnal neck enlargement by 64%
(Table 1), and concomitant suppression of the nocturnal change in
the pharyngealair volume (Figure 1), in association with 30%
reduction in the AHI (Figure 1), without weight and neck
circumference change (Table 1). We found significant linear
correlations (r = 0.796; P = 0.018) between the reduction in overnight
rostral fluid shift and reduction in AHI obtained after the walk
period compared with the control period, such that the greater the
reduction in the amount of fluid displaced from the legs overnight,
the greater the reduction in the AHI (Figure E3). There were
no differences in body position during sleep, sleep quality, and
architecture, except for a small increase in proportion of time spent
in stage N3 (Table 1), which was not correlated (r = 0.290; P = 0.486)
with the decrease in AHI, demonstrating that this is not attributable
to changes in this variable.
This randomized, controlled crossover study shows that
increasing the physical activity level of sedentary subjects with OSA is
associated with a reduction in AHI without change in body weight.
This occurs concomitantly with a reduction in the amount of fluid
shifting from the legs to the pharynx overnight. In addition, this
reduction in the rostral fluid shift was significantly correlated to the
reduction in the AHI and accounted for 63% of its variability among
subjects. These observations thus shed light on a previously not
considered mechanism by which physical activity may attenuate
–800
–700
–600
–500
–400
–300
–200
–100
0
Control
C
ha
ng
es
 in
 L
eg
s 
F
lu
id
 V
ol
um
e 
(m
l)
Walk period
–343 + 171 –206 + 197
p=0.001
20
18
16
14
12
10
8
6
4
P
ha
ry
ng
ea
l A
ir 
V
ol
um
e 
(c
m
3 )
13.1 11.5
p=0.005
14.2 14.5
NS
Control Walk period
Before
sleep
After
sleep
Before
sleep
After
sleep
140
120
100
80
60
50
40
30
20
Control
A
H
I
Walk period
58.0 + 28.6 40.6 + 21.8
p=0.003
Figure 1. Influence of 1 week of 45 minutes of walking twice a day (walk period) on overnight changes in leg fluid volume, pharyngeal air volume, and apnea–
hypopnea index in the seven men and one woman. Leg fluid volume is the mean of the volumes of the two legs. AHI = apnea/hypopnea index; NS=not significant.
Table 1. Number of Steps per Day, Body Weight, and Neck Circumference before Sleep and Their Overnight Changes, Overnight
Water Balance, and Polysomnographic Measures for Control and Walk Periods
Control Period Walk Period P
Steps, n/d 5,9156 2,362 10,6586 3,797 0.010
Body weight before sleep, kg 89.86 13.6 89.16 13.7 0.917
Neck circumference before sleep, cm* 42.76 2.8 42.86 3.1 0.921
Change in body weight overnight, kg 20.86 0.3 20.86 0.5 0.709
Change in neck circumference overnight, cm 1.16 0.7 0.46 0.5 0.011
Overnight water balance, ml 24356 209 22946 201 0.190
Water intake, ml 1156 149 986 116 0.797
Urine volume, ml 5506 283 3916 210 0.223
Total sleep time, min 3686 60 3866 57 0.259
Sleep time in supine position, % of total sleep time 516 41 546 41 0.114
Sleep efficiency, % 716 12 766 13 0.103
Stage N1–N2, % of total sleep time 806 13 746 13 0.083
Stage N3, % of total sleep time 116 10 146 13 0.039
Rapid eye movement sleep, % of total sleep time 106 7 126 4 0.367
Arousal index, events/h 466 12 356 19 0.144
Periodic legs movement index, events/h 126 20 146 20 0.129
Values are expressed as mean6 SD.
*Measured in supine position. Overnight water balance is the difference between water intake and urine volume during the night.
CORRESPONDENCE
Correspondence 857
OSA. In particular, physical activity may attenuate the severity of
OSA, even in the absence of weight loss, by activating themusculovenous
pump, which counteracts fluid accumulation in the legs during
daytime, as well as its redistribution overnight around the pharynx.
It has been previously shown that excess fluid accumulated in the
legs while upright during the day, because of gravity, and redistributed
rostrally overnight on lying down, again because of gravity, may
reach the neck, predisposing to OSA (4). In previous studies, the
increase in neck fluid volume consequent to overnight rostral fluid
shift was not directly measured, but the overnight changes in neck
circumference were used as a surrogate measurement. For the first
time in the present study, we showed, using magnetic resonance
imaging performed before and after sleep, that the fluid displacement
from the legs into the neck occurring spontaneously overnight during
sleep was accompanied by an evident reduction in pharyngeal caliber,
attributable to the accumulation of fluid in the pharyngeal walls.
Other mechanisms by which physical activity may reduce
OSA severity have been previously proposed and only partially
tested. They include sleep quality improvement with consequent
respiratory stabilization, increase in strength of pharyngeal
dilator muscles, decrease in nasal resistance, and enhancement
of chemoreceptor sensitivity. Experimental research in
individuals with OSA has produced conflicting results about
changes in objective sleep quality from physical activity (1–3).
We found a small statistically but not clinically significant
increase in the amount of stage N3 sleep after the walk period,
but the improvement in AHI was not found to be significantly
correlated with the increase in stage N3 sleep. Even if we did not
consider the other possible factors, our results strongly suggest
the attenuation of overnight rostral fluid shift as a major factor
responsible for the AHI reduction in the current study,
accounting for 63% of its variability.
The number of subjects was small, mainly because of the
complexity and the cost of the protocol. Nevertheless, because
the study was performed according to a stringent clinical trial
design and because the effects of physical activity on both overnight
rostral fluid shift and AHI were very consistent (Figure E3), we
can conclude that one of the most important implications of
our observations is that physical activity can specifically act on
a mechanism of disease for OSA, which is the redistribution
of fluid in the pharynx walls during the night. Future studies
involving more subjects over longer periods are needed, and
are now justified. n
Author disclosures are available with the text of this letter at
www.atsjournals.org.
Stefania Redolfi, M.D., Ph.D.
University of Brescia
Brescia, Italy
AP-HP–Groupe Hospitalier Pitié-Salpêtrière Charles Foix
Paris, France
and
Sorbonne Universités–UPMC Univ Paris 06–INSERM
Paris, France
Michela Bettinzoli, M.D.
Nicola Venturoli, M.D.
Marco Ravanelli, M.D.
Leonardo Pedroni
University of Brescia
Brescia, Italy
Luigi Taranto-Montemurro, M.D.
A. O. M. Mellini
Chiari (BS), Italy
Isabelle Arnulf, M.D., Ph.D.
AP-HP–Groupe Hospitalier Pitié-Salpêtrière Charles Foix
Paris, France
Thomas Similowski, M.D., Ph.D.*
AP-HP–Groupe Hospitalier Pitié-Salpêtrière Charles Foix
Paris, France
and
Sorbonne Universités–UPMC Univ Paris 06–INSERM
Paris, France
Claudio Tantucci, M.D., Ph.D.*
University of Brescia
Brescia, Italy
*T.S. and C.T. are co–last authors.
References
1. Giebelhaus V, Strohl KP, Lormes W, Lehmann M, Netzer N. Physical
exercise as an adjunct therapy in sleep apnea-an open trial. Sleep
Breath 2000;4:173–176.
2. Sengul YS, Ozalevli S, Oztura I, Itil O, Baklan B. The effect of exercise on
obstructive sleep apnea: a randomized and controlled trial. Sleep
Breath 2011;15:49–56.
3. Kline CE, Crowley EP, Ewing GB, Burch JB, Blair SN, Durstine JL, Davis JM,
Youngstedt SD. The effect of exercise training on obstructive sleep apnea
and sleep quality: a randomized controlled trial. Sleep 2011;34:1631–1640.
4. White LH, Bradley TD. Role of nocturnal rostral fluid shift in the
pathogenesis of obstructive and central sleep apnoea. J Physiol 2013;
591:1179–1193.
5. Redolfi S, Arnulf I, Pottier M, Bradley TD, Similowski T. Effects of venous
compression of the legs on overnight rostral fluid shift and obstructive
sleep apnea. Respir Physiol Neurobiol 2011;175:390–393.
6. Redolfi S, Arnulf I, Pottier M, Lajou J, Koskas I, Bradley TD, Similowski T.
Attenuationof obstructive sleep apnea by compression stockings in
subjects with venous insufficiency. Am J Respir Crit Care Med 2011;
184:1062–1066.
7. Kasai T, Bradley TD, Friedman O, Logan AG. Effect of intensified diuretic
therapy on overnight rostral fluid shift and obstructive sleep apnoea in
patients with uncontrolled hypertension. J Hypertens 2014;32:673–680.
8. Winkel J, Jørgensen K. Evaluation of foot swelling and lower-limb
temperatures in relation to leg activity during long-term seated office
work. Ergonomics 1986;29:313–328.
9. Stick C, Grau H, Witzleb E. On the edema-preventing effect of the calf
muscle pump. Eur J Appl Physiol Occup Physiol 1989;59:39–47.
10. Stranden E. Dynamic leg volume changes when sitting in a locked and
free floating tilt office chair. Ergonomics 2000;43:421–433.
11. Redolfi S, Venturoli N, Ravanelli M, Taranto-Montemurro L, Bettinzoli
M, Corda L, Pedroni L, Similowski T, Tantucci C. Physical activity
attenuates fluid shift and obstructive sleep apnea [abstract].
Eur Respir J 2013;42:A4619.
Copyright © 2015 by the American Thoracic Society
No Significant Reduction in Antibiotic
Treatment Using a Procalcitonin Algorithm
with Low Cutoff Value in the Intensive
Care Unit?
To the Editor:
Early administration of antibiotics is lifesaving in critically ill
patients with severe sepsis. However, overuse of antibiotics in
nonseptic patients may result from strategies to enhance early
CORRESPONDENCE
858 American Journal of Respiratory and Critical Care Medicine Volume 191 Number 7 | April 1 2015
http://www.atsjournals.org/doi/suppl/10.1164/rccm.201412-2192LE/suppl_file/disclosures.pdf
http://www.atsjournals.org