(Chest. 2000;117:48S-53S.)
© 2000
American College of Chest Physicians
Impact of Sleep in COPD*
Walter T. McNicholas, MD, FCCP
*
From the Department of Respiratory Medicine, St. Vincent’s University Hospital, Dublin, Ireland.
Correspondence to: Walter T. McNicholas, MD, FCCP, Department of Respiratory, Medicine, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland
 |
Abstract
|
|---|
Sleep has well-recognized effects on breathing, including changes
in central respiratory control, airways resistance, and muscular
contractility, which do not have an adverse effect in healthy
individuals but may cause problems in patients with COPD. Sleep-related
hypoxemia and hypercapnia are well recognized in COPD and are most
pronounced in rapid eye movement sleep. However, sleep studies are
usually only indicated in patients with COPD when there is a
possibility of sleep apnea or when cor pulmonale and/or polycythemia
are not explained by the awake PaO2 level.
Management options for patients with sleep-related respiratory failure
include general measures such as optimizing therapy of the underlying
condition; physiotherapy and prompt treatment of infective
exacerbations; supplemental oxygen; pharmacologic treatments such as
bronchodilators, particularly ipratropium bromide, theophylline, and
almitrine; and noninvasive positive pressure
ventilation.
Key Words: COPD • sleep
|
Introduction
|
|---|
Sleep
has well-recognized effects on breathing, which in normal individuals
have no adverse impact. These effects include a mild degree of
hypoventilation with consequent hypercapnia, and a diminished
responsiveness to respiratory stimuli. However, in patients with
chronic lung disease, these physiologic changes during sleep may have a
profound effect on gas exchange, and episodes of profound hypoxemia may
develop, particularly during rapid eye movement (REM)
sleep.1
|
Effects of Sleep on Respiration
|
|---|
The effects of sleep on respiration include changes in central
respiratory control, airways resistance, and muscular contractility. A
schematic outline of the effects of sleep on respiration is given in
Figure 1 .
|
Central Respiratory Effect
|
|---|
Sleep is associated with a diminished responsiveness of the
respiratory center to chemical, mechanical, and cortical
inputs,2
3
particularly during REM sleep. Furthermore, the
responsiveness of the respiratory muscles to respiratory center outputs
are also diminished during sleep, particularly during REM, although the
diaphragm is less affected than the accessory muscles in this
regard.2
There is a decrease in minute ventilation during
non-REM sleep and more so during REM sleep,4
5
6
predominantly because of a reduction in tidal volume, which is
associated with a rise in end-tidal
PCO2. During REM sleep, both tidal
volume and respiratory frequency are much more variable than in non-REM
sleep,4
5
6
7
particularly during phasic REM. These
physiologic changes are not associated with any clinically significant
deterioration in gas exchange among normal subjects, but may produce
profound hypoxemia in patients with respiratory
insufficiency.1
|
Airway Resistance
|
|---|
Most normal subjects have circadian changes in airway caliber with
mild nocturnal bronchoconstriction.8
9
Such
bronchoconstriction may be exaggerated in patients with asthma, who can
demonstrate falls in peak flow rate of 
50%, compared with an
average of 8% in normal subjects.9
|
Ribcage and Abdominal Contribution to Breathing
|
|---|
A reduction in ribcage contribution to breathing has been reported
during REM sleep compared with wakefulness and non-REM sleep because of
a marked reduction in intercostal muscle activity,10
whereas diaphragmatic contraction is little affected. This fall in
intercostal muscle activity assumes particular clinical significance in
patients who are particularly dependent on accessory muscle activity to
maintain ventilation, such as those with COPD where lung hyperinflation
reduces the efficacy of diaphragmatic contraction.11
|
Functional Residual Capacity
|
|---|
A modest fall in functional residual capacity (FRC) has been noted
in both non-REM and REM sleep,12
13
which does not cause
significant ventilation to perfusion mismatching in healthy subjects,
but can do so, with resulting hypoxemia, in patients with chronic lung
disease.12
Possible mechanisms responsible for this
reduction in FRC include respiratory muscle hypotonia, cephalad
displacement of the diaphragm, and a decrease in lung
compliance.4
|
Sleep in COPD
|
|---|
Sleep-related hypoxemia and hypercapnia are well recognized in
COPD, particularly during REM sleep, and may contribute to the
development of cor pulmonale14
and nocturnal
death.15
These abnormalities are most common in
"blue–bloater"-type patients, who also have a greater degree of
awake hypoxemia and hypercapnia than "pink–puffer"-type
patients.3
14
However, many patients with awake
PaO2 levels in the mildly hypoxemic
range can also develop substantial nocturnal oxygen desaturation, which
appears to predispose to the development of pulmonary
hypertension.16
|
Mechanisms of Nocturnal Oxygen Desaturation in COPD
|
|---|
1. Hypoventilation
Studies using noninvasive methods of quantifying respiration have
shown clear evidence of hypoventilation, particularly during REM sleep,
associated with periods of hypoxemia in patients with
COPD,17
18
19
20
but the semiquantitative nature of these
measurements makes it difficult to determine if this is the sole
mechanism of oxygen desaturation, or whether other factors are
involved.
2. Impact of the Oxyhemoglobin Dissociation Curve
There is a close relationship between awake
PaO2 and nocturnal arterial oxygen
saturation (SaO2) levels, and it has
been proposed that nocturnal oxygen desaturation in patients with COPD
is largely the consequence of the combined effects of physiologic
hypoventilation during sleep and the fact that hypoxemic patients show
a proportionately greater fall in
SaO2 with hypoventilation than
normoxemic, because of the effects of the oxyhemoglobin dissociation
curve.17
18
However,
PaO2 has also been shown to fall more
during sleep in major desaturators as compared with minor
desaturators,19
which indicates that other factors must
also play a part in nocturnal oxygen desaturation in patients with
COPD.
3. Altered Ventilation/Perfusion Relationships
The reduction in accessory muscle contribution to breathing
particularly during REM sleep result in a decreased FRC, and contribute
to worsening ventilation/perfusion (
/
) relationships
during sleep, which also aggravate hypoxemia in COPD.17
18
We have found that transcutaneous
PCO2 levels rise to a similar extent
in those patients who developed major nocturnal oxygen desaturation as
those who developed only a minor degree of desaturation,19
which suggests a similar degree of hypoventilation in both groups,
despite the different degrees of nocturnal oxygen desaturation. The
much larger fall in PaO2 among the
major desaturators as compared with the minor desaturators, in
conjunction with the similar rise in transcutaneous
PCO2 in both patient groups, suggests
that in addition to a degree of hypoventilation operating in all
patients, other factors such as / mismatching must also
play a part in the excess desaturation of some COPD patients.
4. Coexisting Sleep Apnea (the Overlap Syndrome)
The incidence of sleep apnea in patients with COPD is about 10 to
15%,21
22
which is higher than would be expected in a
normal population of similar age. Factors that may predispose to sleep
apnea in patients with COPD include impaired respiratory drive,
particularly in blue–bloater-type COPD patients. Patients with
coexisting COPD and sleep apnea typically develop more severe hypoxemia
during sleep because such patients may be hypoxemic at the commencement
of each apnea, whereas patients with pure sleep apnea tend to
resaturate to normal SaO2 levels
between apneas. Therefore, they are particularly prone to the
complications of chronic hypoxemia, such as cor pulmonale and
polycythemia.21
|
Investigation of Sleep-Related Breathing Disturbances in COPD
|
|---|
The serious and potentially life-threatening disturbances in
ventilation and gas exchange that may develop during sleep in patients
with COPD raise the question of appropriate investigation of these
patients. However, it is widely accepted that sleep studies are not
routinely indicated in patients with COPD associated with respiratory
insufficiency, particularly since the awake
PaO2 level provides a good indicator
of the likelihood of nocturnal oxygen desaturation.23
24
Sleep studies are only indicated when there is a clinical suspicion of
an associated sleep apnea syndrome or manifestations of hypoxemia not
explained by the awake PaO2 level,
such as cor pulmonale or polycythemia.
Management of Respiratory Insufficiency During Sleep
A summary of management options for patients with respiratory
insufficiency during sleep is given in Table 1
.
These options can be viewed as a stepwise approach, and in many
instances, careful attention to detail with the earlier options such as
optimizing the patient’s general condition, in addition to appropriate
use of supplemental oxygen and pharmacologic therapy, can obviate the
need for assisted ventilation.
General Principles
The first principle of management of sleep-related breathing
disturbance in COPD should be to optimize the underlying condition,
since this will almost invariably have beneficial effects on breathing.
For example, optimizing bronchodilator therapy has been shown to
improve gas exchange during sleep.25
26
Respiratory
infections in these patients should be treated promptly and vigorously.
Oxygen Therapy
The most serious consequence of hypoventilation, particularly
during sleep, is hypoxemia, and appropriate oxygen therapy plays an
important part in the management of any disorder associated with
respiratory insufficiency. Care must be taken that correction of
hypoxemia is not complicated by hypercapnia in patients with
respiratory insufficiency due to hypoventilation from any cause, since
respiratory drive in such patients is partly dependent on the stimulant
effect of hypoxemia. Therefore, the concentration of added oxygen
should be carefully titrated to bring the
PaO2 up into the mildly hypoxemic
range in order to minimize the tendency to carbon dioxide retention,
particularly during sleep.27
However, the risk of carbon dioxide retention with supplemental oxygen
therapy in such patients may have been overstated in the past, and some
reports have found that carbon dioxide retention with oxygen
supplementation is often modest, and usually
nonprogressive.20
SaO2 levels do not need to be measured
routinely during sleep in patients with COPD complicated by hypoxemia
unless there is a concern that nocturnal ventilatory support may be
required, or in patients without significant awake hypoxemia who have
complications suggestive of chronic hypoxemia such as cor pulmonale or
polycythemia, since unrecognized nocturnal hypoxemia may be an
important factor in the pathogenesis of these
complications.28
|
Pharmacologic Therapy
|
|---|
1. Anticholinergics
Cholinergic tone is increased at night, and it has been proposed
that this contributes to airflow obstruction and deterioration in gas
exchange during sleep in patients with obstructive airways disease.
There is recent evidence that ipratropium improves
SaO2 in addition to sleep quality in patients
with COPD,29
although other studies have shown conflicting
results on the ability of ipratropium to block nocturnal
bronchoconstriction in asthma.30
31
2. Theophylline
In addition to being a bronchodilator, theophylline has important
effects on respiration that may be particularly beneficial in patients
with chronic hypoventilation, including central respiratory
stimulation32
and improved diaphragmatic
contractility,33
and improves gas exchange during sleep in
COPD.25
In COPD, the benefits appear to be more likely
caused by a reduction in trapped gas volume than by
bronchodilation.25
However, theophyllines have an adverse
effect on sleep quality25
in contrast with
ipratropium bromide,29
and also have a relatively high
incidence of GI intolerance.
3. ß2-Agonists
There are only limited data on the efficacy of
ß2-agonists on the management of sleep-related
breathing abnormalities in COPD. One report found a long-acting
theophylline superior to salbutamol in terms of nocturnal gas exchange
and overnight fall in spirometry.34
However, there are no
studies of the impact of long-acting
ß2-agonists on sleep and breathing in COPD.
4. Almitrine
This agent is a powerful carotid body agonist that stimulates
ventilation.35
Almitrine also improves /
relationships within the lung,36
probably by an
enhancement of hypoxic pulmonary vasoconstriction.37
The
overall effect is to lessen hypoxemia awake and asleep, and is
beneficial in hypoxemic patients with COPD.38
Important
side effects include pulmonary hypertension, dyspnea, and peripheral
neuropathy.39
5. Noninvasive Ventilation
In the past decade, increasing attention has been directed toward
noninvasive methods of ventilatory support of COPD patients with
chronic respiratory insufficiency, particularly during
sleep.40
41
42
Beneficial effects on gas exchange during
wakefulness have been widely reported in patients treated with
nocturnal ventilatory support in addition to improvements in
respiratory muscle strength and endurance.43
44
45
An
example of the beneficial effect of noninvasive positive pressure
ventilation (NIPPV) on oxygenation during sleep in a patient
with chronic respiratory failure caused by an old thoracoplasty and
COPD is given in Figure 2
.
View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2. SaO2 during sleep before
and after NIPPV in a 65-year-old man with chronic respiratory failure
due to COPD and an old thoracoplasty for tuberculosis. Each section
represents a 20-min continuous record of SaO2
in each of wakefulness, non-REM, and REM sleep. The lower tracings in
each panel represent SaO2 levels before NIPPV
while the patient was receiving 28% supplemental oxygen by Ventimask.
The upper tracings represent the values while on NIPPV in addition to 4
L/min supplemental oxygen through the nasal mask.
|
|
The mechanism by which NIPPV produces improvements in daytime blood
gases likely involve a number of factors, including resting of the
respiratory muscles41
46
47
; resetting of respiratory
drive, particularly at the chemoreceptor level; and a reduction in
residual volume and in the degree of gas trapping.45
Short-term withdrawal of NIPPV for periods of up to 2 weeks may be
associated with persistence of the improvement in daytime blood gases,
but not in nighttime gas exchange.48
Recently, NIPPV has been successfully used in the management of acute
exacerbations of COPD associated with respiratory failure, and has been
shown to reduce the need for intubation and mechanical ventilation in
such patients.49
The findings from studies of NIPPV in
COPD offer exciting new prospects for the management of patients with
advanced disease who are in chronic respiratory failure. However, the
health care resource implications of this therapy are potentially very
great because of the high prevalence of COPD. While it is clear from
the literature that NIPPV will play an increasing role in the
management of patients with advanced COPD over coming years, it is
likely that only a subset of patients with advanced COPD will benefit
from this therapy. These considerations emphasize the importance of
outcome studies that evaluate the efficacy of this therapy in different
patient populations.
|
Footnotes
|
|---|
Abbreviations: FRC = functional residual capacity;
NIPPV = noninvasive positive pressure ventilation;
REM = rapid eye movement sleep;
SaO2 = arterial oxygen saturation;
/ = ventilation/perfusion
|
References
|
|---|
-
Douglas, NJ, Calverley, PMA, Leggett, RJE, et al (1979) Transient hypoxaemia during sleep in chronic bronchitis and emphysema. Lancet 1,1-4[Medline]
-
Phillipson, EA (1978) Control of breathing during sleep. Am Rev Respir Dis 118,909-939[ISI][Medline]
-
Gothe, B, Altose, MD, Goldman, MD, et al (1981) Effect of quiet sleep on resting and CO2-stimulated breathing in humans. J Appl Physiol 50,724-730[Abstract/Free Full Text]
-
Douglas, NJ, White, DP, Pickett, CK, et al (1982) Respiration during sleep in normal man. Thorax 37,840-844[Abstract]
-
Krieger, J, Turlot, J-C, Mangin, P, et al (1983) Breathing during sleep in normal young and elderly subjects: hypopneas, apneas and correlated factors. Sleep 6,108-120[ISI][Medline]
-
Gothe, B, Goldman, MD, Cherniack, NS, et al (1982) Effect of progressive hypoxia on breathing during sleep. Am Rev Respir Dis 126,97-102[ISI][Medline]
-
Stradling, JR, Chadwick, GA, Frew, AJ (1985) Changes in ventilation and its components in normal subjects during sleep. Thorax 40,364-370[Abstract]
-
Kerr, HD (1973) Diurnal variation of respiratory function independent of air quality. Arch Environ Health 26,144-153[Medline]
-
Hetzel, MR, Clark, TJH (1980) Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate. Thorax 35,732-738[Abstract]
-
Tusiewicz, K, Moldofsky, H, Bryan, AC, et al (1977) Mechanics of the ribcage and diaphragm during sleep. J Appl Physiol 43,600-602[Abstract/Free Full Text]
-
Johnson, MW, Remmers, JE (1984) Accessory muscle activity during sleep in chronic obstructive pulmonary disease. J Appl Physiol 57,1011-1017[Abstract/Free Full Text]
-
Ballard, RD, Irvin, CG, Martin, RJ, et al (1990) Influence of sleep on lung volume in asthmatic patients and normal subjects. J Appl Physiol 68,2034-2041[Abstract/Free Full Text]
-
Hudgel, DW, Devadetta, P (1984) Decrease in functional residual capacity during sleep in normal humans. J Appl Physiol 57,1319-1322[Abstract/Free Full Text]
-
DeMarco, FJ, Jr, Wynne, JW, Block, AJ, et al (1981) Oxygen desaturation during sleep as a determinant of the "blue and bloated" syndrome. Chest 79,621-625[Abstract/Free Full Text]
-
McNicholas, WT, FitzGerald, MX (1984) Nocturnal death among patients with chronic bronchitis and emphysema. Br Med J 289,878
-
Fletcher, EC, Luckett, RA, Miller, T, et al (1989) Pulmonary vascular hemodynamics in chronic lung disease patients with and without oxyhemoglobin desaturation during sleep. Chest 95,757-766[Abstract/Free Full Text]
-
Caterall, JR, Calverley, PMA, McNee, W, et al (1985) Mechanism of transient nocturnal hypoxemia in hypoxic chronic bronchitis and emphysema. J Appl Physiol 59,1698-1703[Abstract/Free Full Text]
-
Fletcher, EC, Gray, BA, Levin, DC (1983) Nonapneic mechanisms of arterial oxygen desaturation during rapid-eye-movement sleep. J Appl Physiol 54,632-639[Free Full Text]
-
Mulloy, E, McNicholas, WT (1996) Ventilation and gas exchange during sleep and exercise in patients with severe COPD. Chest 109,387-394[Abstract/Free Full Text]
-
Goldstein, RS, Ramcharan, V, Bowes, G, et al (1984) Effects of supplemental oxygen on gas exchange during sleep in patients with severe obstructive lung disease. N Engl J Med 310,425-429[Abstract]
-
Chaouat, A, Weitzenbum, E, Krieger, J, et al (1995) Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am J Respir Crit Care Med 151,82-86[Abstract]
-
Bradley, TD, Rutherford, R, Lue, F, et al (1986) Role of diffuse airway obstruction in the hypercapnia of obstructive apnea. Am Rev Respir Dis 134,920-924[ISI][Medline]
-
Stradling, JR, Lane, DJ (1983) Nocturnal hypoxaemia in chronic obstructive pulmonary disease. Clin Sci 64,213-222[Medline]
-
Connaughton, JJ, Caterall, JR, Elton, RA, et al (1988) Do sleep studies contribute to the management of patients with severe chronic obstructive pulmonary disease? Am Rev Respir Dis 138,341-344[ISI][Medline]
-
Mulloy, E, McNicholas, WT (1993) Theophylline improves gas exchange during rest, exercise and sleep in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 148,1030-1036[ISI][Medline]
-
Fitzpatrick, MF, Mackay, T, Driver, H, et al (1990) Salmeterol in nocturnal asthma: a double blind placebo controlled trial of a long acting ß2-agonist. Br Med J 301,1365-1368
-
West, JB (1977) Oxygen therapy. Pulmonary pathophysiology ,169-183 Williams & Wilkins Baltimore, MD.
-
Fletcher, EC, Luckett, RA, Miller, T, et al (1989) Pulmonary vascular hemodynamics in chronic lung disease patients with and without oxyhemoglobin desaturation during sleep. Chest 95,757-766
-
Martin, RJ, Bartelson, BL, Smith, P, et al (1999) Effect of ipratropium bromide on oxygen saturation and sleep quality in COPD. Chest 115,1338-1345[Abstract/Free Full Text]
-
Catterall, JR, Rhind, GB, Whyte, KF, et al (1988) Is nocturnal asthma caused by changes in airway cholinergic activity? Thorax 43,720-724[Abstract]
-
Gaultier, C, Reinberg, A, Girard, F (1980) Circadian rhythms in lung resistance and dynamic lung compliance in healthy children. Adv Biosci 28,41-53
-
Eldrige, FL, Millhorn, DE, Waldrop, TG, et al (1983) Mechanism of respiratory effects of methylxanthines. Respir Physiol 53,239-261[CrossRef][ISI][Medline]
-
Murciano, D, Aubier, M, Lecocguic, Y, et al (1984) Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. N Engl J Med 311,349-353[Abstract]
-
Man, GC, Chapman, KR, Ali, SH, et al (1996) Sleep quality and nocturnal respiratory function with once-daily theophylline (Uniphil) and inhaled salbutamol in patients with COPD. Chest 110,648-653[Abstract/Free Full Text]
-
Laubie, M, Schmitt, H (1980) Long-lasting hyperventilation induced by almitrine: evidence for a specific effect on carotid and thoracic chemoreceptors. Eur J Pharmacol 61,125-136[CrossRef][ISI][Medline]
-
Reyes, A, Roca, J, Rodriguez-Roisin, R, et al (1988) Effect of almitrine on ventilation-perfusion distribution in adult respiratory distress syndrome. Am Rev Respir Dis 137,1062-1067[ISI][Medline]
-
Naeije, R, Lejeune, P, Vachiery, JL, et al (1990) Restored hypoxic pulmonary vasoconstriction by peripheral chemoreceptor antagonists in dogs. Am Rev Respir Dis 142,789-795[Medline]
-
Bell, RC, Mullins, RC, West, LG, et al (1986) The effect of almitrine bismesylate on hypoxemia in chronic obstructive pulmonary disease. Ann Intern Med 105,342-346
-
Howard, P (1989) Hypoxia, almitrine, and peripheral neuropathy. Thorax 44,247-250[Medline]
-
Elliott, MW, Simonds, AK, Carroll, MP, et al (1992) Domiciliary nocturnal nasal intermittent positive pressure ventilation in hypercapnic respiratory failure due to chronic obstructive lung disease: effects on sleep and quality of life. Thorax 47,342-348[Abstract]
-
Meecham Jones, DJ, Paul, EA, Jones, PW, et al (1995) Nasal pressure support ventilation plus oxygen compared with oxygen therapy alone in hypercapnic COPD. Am J Respir Crit Care Med 152,538-544[Abstract]
-
Strumpf, DA, Millman, RP, Carlisle, CC, et al (1991) Nocturnal positive pressure ventilation by nasal mask in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 144,1234-1239[ISI][Medline]
-
Goldstein, RS, Molotiu, N, Skrastins, R, et al (1987) Reversal of sleep-induced hypoventilation and chronic respiratory failure by nocturnal negative pressure ventilation in patients with restrictive ventilatory impairment. Am Rev Respir Dis 135,1049-1055[ISI][Medline]
-
Goldstein, RS, De Rosie, JA, Avendano, MA, et al (1991) Influence of noninvasive positive pressure ventilation on inspiratory muscles. Chest 99,408-415[Abstract/Free Full Text]
-
Elliott, MW, Mulvey, DA, Moxham, J, et al (1991) Domiciliary nocturnal nasal intermittent positive pressure ventilation in COPD: mechanisms underlying changes in arterial blood gas tensions. Eur Respir J 4,1044-1052[Abstract]
-
Ambrosino, N, Nava, S, Bertone, P, et al (1992) Physiologic evaluation of pressure support ventilation by nasal mask in patients with stable COPD. Chest 101,385-391[Abstract/Free Full Text]
-
Renston, JP, DiMarco, AF, Supinski, GS (1994) Respiratory muscle rest using nasal BiPAP ventilation in patients with stable severe COPD. Chest 105,1053-1060[Abstract/Free Full Text]
-
Masa Jimenez, JF, Sanchez de Cos Escuin, J, Disdier Vicente, C, et al (1995) Nasal intermittent positive pressure ventilation: analysis of its withdrawal. Chest 107,382-388[Abstract/Free Full Text]
-
Brochard, L, Mancebo, J, Wysocki, M, et al (1995) Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 333,817-822[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
T. L. Croxton, G. G. Weinmann, R. M. Senior, R. A. Wise, J. D. Crapo, and A. S. Buist
Clinical Research in Chronic Obstructive Pulmonary Disease: Needs and Opportunities
Am. J. Respir. Crit. Care Med.,
April 15, 2003;
167(8):
1142 - 1149.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Zoccali, F. Mallamaci, and G. Tripepi
Nocturnal Hypoxemia Predicts Incident Cardiovascular Complications in Dialysis Patients
J. Am. Soc. Nephrol.,
March 1, 2002;
13(3):
729 - 733.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
Abstract
Introduction
