Weaning Failure, Muscle Injury, and Fatigue

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Correspondence
Modafinil and Sleepiness
To the Editor:
I enjoyed the Pro/Con Debate of Drs. Black (1) and Pollak (2)
and the associated Essay by Dr. Pack (3). Like Pollak and Pack, I
have significant concerns about the widespread use of modafinil.
Dr. Black is economical with the truth when considering
fears that patients with obstructive sleep apnea (OSA) taking
modafinil might lose their incentive to use continuous positive
airway pressure (CPAP). He states “All evidence thus far, how-
ever, suggests otherwise—CPAP-compliant patients taking mo-
dafinil do not reduce CPAP use.” This was not the finding in a
double-blind study we performed and published in this journal
(4). Modafinil decreased CPAP use significantly, albeit by a small
amount (3%) in a short-term study. Furthermore, this study was
analyzed entirely independently, and there is an urgent need for
more independent studies to clarify the conflicting data.
Dr. Black (1) also states “It is well established that approxi-
mately 30 to 50% of patients with diagnosed OSA are CPAP
noncompliant.” This figure is highly dependent on patient selec-
tion (5) and the support provided to them, and must be seen in
the context that noncompliance with all long-term medication
is 30 to 50% (6). Given the cardiovascular benefits of CPAP
(7), the first-line treatment of CPAP noncompliers must be to try
to improve CPAP use; if this fails, provide patients with alterna-
tive effective treatment for their apneas. This must supersede
any temptation to give them a medication that has no effect on
cardiovascular risk and little effect on symptoms; the benefits
in terms of Epworth Sleepiness Score range from (a nonsignifi-
cant) 2 to 3 for modafinil over placebo in the studies cited by
Black (1) in comparison with 3 to 7 for CPAP over placebo in
the studies cited by Pack (3).
I share Dr. Pack’s concerns about the Food and Drug Admin-
istration (FDA) considering a broad indication for modafinil
use in excessive sleepiness. Subjective sleepiness is frequently a
response to inadequate sleep, shift work, or psychological fac-
tors. To provide a medication with poorly documented long-
term side effects to such individuals is not good medicine. Even if
use was limited to patients with “sleep disorders” with continued
sleepiness, I share Dr. Pack’s concern that this would prejudice
accurate diagnosis and specific therapy. Furthermore, some al-
leged “sleep disorders” such as periodic limb movement disor-
der, are so prevalent that most of the elderly would still be in
line for modafinil treatment.
Modafinil is useful in the treatment of narcolepsy. The FDA
would be well advised to limit its use to areas where there is a
sound evidence base.
Neil J. Douglas
Department of Medicine
University of Edinburgh
Edinburgh, Scotland
References
1. Black J. Pro: Modafinil has a role in management of sleep apnea. Am J
Respir Crit Care Med 2003;167:105–108.
2. Pollak CP. Con: Modafinil has no role in management of sleep apnea.
Am J Respir Crit Care Med 2003;167:106–108.
3. Pack AI. Should a pharmaceutical be approved for the broad indication
of excessive sleepiness? Am J Respir Crit Care Med 2003;167:109–111.
4. Kingshott RN, Vennelle M, Coleman EL, Engleman HM, Mackay TW,
Douglas NJ. Randomized, double-blind, placebo-controlled crossover
trial of modafinil in the treatment of residual excessive daytime sleepi-
ness in the sleep apnea/hypopnea syndrome. Am J Respir Crit Care
Med 2001;163:918–923.
5. McArdle N, Devereux G, Heidarnejad H, Engleman HM, Mackay TW,
Douglas NJ. Long-term use of CPAP therapy for sleep apnea/hypopnea
syndrome. Am J Respir Crit Care Med 1999;159:1108–1114.
6. Rudd P. Clinicians and patients with hypertension: unsettled issues about
compliance. Am Heart J 1995;130:572–579.
7. Becker HF, Jerrentrup A, Ploch T, Grote L, Penzel T, Sullivan CE, Peter
JH. Effect of nasal continuous positive airway pressure treatment on
blood pressure in patients with obstructive sleep apnea. Circulation 2003;
107:68–73.
Dr. Charles Pollak and Dr. Allan Pack were given the opportunity to respond
to this letter but declined to do so.
From the Author:
Dr. Douglas refers to the Pro/Con debate, which ultimately proved
to be without great contrast in perspectives (1, 2). Concern exists
on both sides that some patients may reduce or eliminate contin-
uous positive airway pressure (CPAP) use in response to improved
daytime alertness with modafinil. Treating physicians must moni-
tor CPAP compliance when adding modafinil for residual sleepi-
ness. Prudent management mandates that modafinil prescrip-
tions be discontinued in patients with reduced compliance in
response to modafinil treatment, when and if this may occur.
Moreover, inadequate management of sleep-related airway
obstruction before modafinil initiation is untenable. All appro-
priate measures must be used to ensure optimal use of and bene-
fit from CPAP or from alternative treatments when CPAP fails.
Adequate sleep-related airway management is essential as pri-
mary treatment to ameliorate obstructive sleep apnea (OSA)-
related cardiovascular risks (3, 4). With CPAP as primary OSA
management, treatment optimization frequently requires multi-
ple interventions that can include mask refitting, humidification,
and retitration with esophageal pressure monitoring, among
many others. In addition, long-term follow up is critical.
When patients continue to experience daytime sleepiness de-
spite optimal airway management, compassionate care dictates
the pursuit of secondary treatments to temper the residual sleepi-
ness. Well conducted, controlled treatment trials exist suggesting
that patients with OSA with residual sleepiness may experience
improved alertness with the addition of modafinil to primary
treatment (nasal CPAP) without evidence of reductions in CPAP
use for up to 12 weeks (5, 6). In many areas of medicine, when
primary treatment fails to eliminate condition-associated symp-
toms, secondary measures are used, if available, to provide fur-
ther symptom relief. Again, this is the compassionate approach.
If, however, secondary treatment of symptoms yields reduced
compliance with primary treatment, the ultimate value of the
secondary treatment is called into question.
I maintain my original claim that modafinil has a role in the
treatment of residual sleepiness in patients with OSA, after the
institution of proper primary upper airway management of sleep-
related obstruction. As is always the case in medicine, judicious
prescribing is imperative.
In addition, the potential role of modafinil in the treatment
of primary OSA-related sleepiness when the patient is unable
to adequately tolerate CPAP and other treatments fail, has not
been studied, and is entirely a separate matter, but one that may
be worthy of further evaluation.
Jed Black
Stanford University
Stanford, California

Correspondence 1539
References
1. Black JE. Pro: Modafinil has a role in management of sleep apnea. Am
J Respir Crit Care Med 2003;167:105–108.
2. Pollak CP. Con: Modafinil has no role in management of sleep apnea.
Am J Respir Crit Care Med 2003;167:106–108.
3. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto
F, O’Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered
breathing and cardiovascular disease: cross-sectional results of the Sleep
Heart Health Study. Am J Respir Crit Care Med 2001;163:19–25.
4. Sanner BM, Tepel M, Markmann A, Zidek W. Effect of continuous posi-
tive airway pressure therapy on 24-hour blood pressure in patients with
obstructive sleep apnea syndrome. Am J Hypertens 2002;15:251–257.
5. Pack AI, Black JE, Schwartz JR, Matheson JK. Modafinil as adjunct
therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir
Crit Care Med 2001;164:1675–1681.
6. Black JE, Douglas NJ, Earl CQ, Modafinil OSA Study Group: Effi-
cacy and safety of modafinil as adjunctive therapy for excessive sleepi-
ness associated with obstructive sleep apnea [abstract]. Sleep 2002:25
(S-1):A22.
Weaning Failure, Muscle Injury, and Fatigue
To the Editor:
Dr. Laghi (1) and colleagues have made some interesting mea-
surements in patients undergoing weaning trials in the intensive
care unit. They have attempted to avoid any of the inherent
problems with measuring twitch pressure including twitch poten-
tiation (2) and changes in geometry of the chest wall. The subjects
who failed the weaning trial did not show a drop in twitch pres-
sure, which suggested to the authors that low frequency fatigue,
which the authors equate with injury of the diaphragm, is not
responsible for the subjects’ weaning failure. These subjects did
reach a pressure–time index where the diaphragm would be
anticipated to be contracting at fatiguing levels—i.e., pressure–
time index of 0.17 to 0.22. This pressure–time index was maintained
for 44 minutes. The weaning trials were stopped because the pa-
tients developed signs of distress, which, according to the authors’
calculations, may have occurred before fatigue developed.
Although these patients may have been put back on mechani-
cal ventilation before developing fatigue, fatigue as evidenced
by reduced force immediately after exertion should not be taken
as an indication to exclude muscle injury. Injured muscles do
not develop immediate evidence of force loss (3). Indeed, the
injurious contraction initiates a process of inflammation and re-
pair that takes place over days to weeks. The force loss with mus-
cle injury can be detected with both high and low frequency
electrical stimulation. After injurious muscle contraction, the
maximum force loss occurs at a time when muscle enzyme release
peaks, as does the symptom of muscle soreness, usually three
days after the injury (3–6). Indeed, we have found negligible drops
in transdiaphragmatic pressure generation (force–frequency
curves) in an animal model of diaphragmatic injury immediately
after the inspiratory loading protocol (3). However, three days
later, there is quite marked force loss at both high and low fre-
quencies that approximates 40%, but we found no difference in
twitch force until after the second IRL on Day 3 (3). These val-
ues are obtained during supramaximal epiphrenic stimulation.
Muscle biopsies in this animal model reveal muscle fiber necrosis
and inflammation. Recovery from muscle injury takes at least
two weeks, is well documented in human limb muscles (4, 5), and
has been shown to occur in the diaphragm (6). Thus, although
diaphragm function as measured by twitch Pdi is not reduced
after weaning failure in these patients, this does not exclude the
possibility of diaphragm injury.
Jeremy Road
Tian-Xi Jiang
Department of Medicine
University of British Columbia
Vancouver, British Columbia, Canada
W. Darlene Reid
School of Rehabilitation Sciences
University of British Columbia
Vancouver, British Columbia, Canada
References
1. Laghi F, Cattapan SE, Jubran A, Parthasarathy S, Warshawsky P, Choi
YS, Tobin MJ. Is weaning failure caused by low-frequency fatigue of
the diaphragm? Am J Respir Crit Care Med 2003;167:120–127.
2. Wragg S, Hamnegard C, Road J, Kyroussis D, Moran J, Green M, Moxham
J. Potentiation of diaphragmatic twitch after voluntary contraction in
normal subjects. Thorax 1994;49:1234–1237.
3. Jiang TX, Reid WD, Road JD. Delayed diaphragm injury and diaphragm
force production. Am J Respir Crit Care Med 1998;157:736–742.
4. Friden J, Lieber RL. Structural and mechanical basis of exercise-induced
muscle injury. Med Sci Sports Exerc 1992;24:521–530.
5. Jones DA, Newham DJ, Round JM, Tolfree SE. Experimental human
muscle damage: morphological changes in relation to other indices of
damage. J Physiol 1986;375:435–448.
6. Reid WD, Huang J, Bryson S, Walker DC, Belcastro AN. Diaphragm
injury and myofibrillar structure induced by resistive loading. J Appl
Physiol 1994;76:176–184.
From the Authors:
Dr. Road and colleagues ask a critical question about the patho-
physiology of weaning failure: Is the load on the respiratory mus-
cles sufficient to cause respiratory muscle damage? Their ques-
tion is of fundamental importance. Were patients to develop
respiratory muscle injury during a failed weaning trial, this new
injury could become the ultimate determinant of whether the
ventilator is discontinued.
Excessive mechanical load on muscles can cause short-lasting,
high-frequency fatigue, long-lasting, low-frequency fatigue (1),
and early (2) and delayed muscle injury (3). An inspiratory load
that induces visible injury on light microscopy of the diaphragm
has to be extremely large (3). Even loads sufficient to cause acute
hypercapnic respiratory failure (arterial carbon dioxide tension
of 95 mm Hg and pH of 7.14) did not cause visible diaphragmatic
injury in the study of Jiang and collaborators (3). None of our
weaning failure patients (4) developed that degree of respiratory
acidosis (3). It is thus unlikely, and perhaps impossible, that a
failed weaning trial can in itself cause sufficient stress to inflict
diaphragmatic damage (4).
If low-frequency fatigue and muscle damage are not responsi-
ble for weaning failure, what is? We can only speculate. The mas-
sive recruitment of ribcage and expiratory muscles in weaning
failure patients (4) probably represents an integrated response
by the respiratory centers to prevent the type of muscle damage
to which Dr. Road and colleagues are referring. Another vital
aspect, often overlooked in research on respiratory muscle fail-
ure, is the presence of an intensivist who reinstitutes mechanical
ventilation before a patient reaches respiratory extremis. That
fundamental intervention is not replicated in most (if not all)
animal studies of severe respiratory loading, which often con-
tinue to respiratory arrest.
What is the direction for future research on respiratory muscles
in weaning? At least three aspects need to be addressed. First,
could insults to the respiratory muscles before the first weaning
trial—such as sepsis (5) or ventilator-associated muscle injury (6)—
influence weaning outcome? Second, does high-frequency fatigue
play a role in causing weaning failure? Third, can we identify
treatments that improve respiratory muscle function and therefore
improve outcome in the difficult-to-wean patient?
Conflict of Interest Statement :F.L. has no declared conflict of interest; M.J.T. has
no declared conflict of interest.

1540 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 168 2003
Franco Laghi
Martin J. Tobin
Division of Pulmonary and Critical Care
Medicine
Edward Hines Jr. Veterans Administration
Hospital
Loyola University of Chicago
Stritch School of Medicine
Hines, Illinois
References
1. Laghi F, Topeli A, Tobin MJ. Does resistive loading decrease diaphrag-
matic contractility before task failure? J Appl Physiol 1998;85:1103–
1112.
2. Zhu E, Comtois AS, Fang L, Comtois NR, Grassino AE. Influence of
tension time on muscle fiber sarcolemmal injury in rat diaphragm. J
Appl Physiol 2000;88:135–141.
3. Jiang TX, Reid WD, Road JD. Delayed diaphragm injury and diaphragm
force production. Am J Respir Crit Care Med 1998;157:736–742.
4. Laghi F, Cattapan SE, Jubran A, Parthasarathy S, Warshawsky P, Choi
YS, Tobin MJ. Is weaning failure caused by low-frequency fatigue of
the diaphragm? Am J Respir Crit Care Med 2003;167:120–127.
5. Ebihara S, Hussain SN, Danialou G, Cho WK, Gottfried SB, Petrof BJ.
Mechanical ventilation protects against diaphragm injury in sepsis: in-
teraction of oxidative and mechanical stresses. Am J Respir Crit Care
Med 2002;165:221–228.
6. Sassoon CS, Ciaozzo VJ, Manka A, Sieck GC. Altered diaphragm contrac-
tile properties with controlled mechanical ventilation. J Appl Physiol
2002;92:2585–2595.
Obstructive Hypopneas in Children and Adolescents:
Normal Values
To the Editor:
Despite the widespread use of the apnea–hypopnea index to
determine the presence of obstructive sleep apnea, there are
virtually no normative data for obstructive hypopneas in chil-
dren. Marcus and colleagues (1) had originally published normal
values for obstructive apneas in children and adolescents in the
American Review of Respiratory Diseases (now American Jour-
nal of Respiratory and Critical Care Medicine), but obstructive
hypopneas were not included because no standard definition for
hypopneas existed at the time.
The American Academy of Sleep Medicine has subsequently
published consensus definitions for scoring obstructive hypo-
pneas in adults (2–4), which include (1) an abnormal respiratory
event lasting more than 10 seconds with a 50% decrease in
baseline airflow amplitude, or (2) an abnormal respiratory event
lasting more than 10 seconds with a smaller reduction in airflow
amplitude, but with an associated desaturation/arousal.
We therefore reviewed the original overnight polysomno-
graphic data of 41 children (data for 9 were no longer available)
from the original 50 children in the study by Marcus and col-
leagues (1) for obstructive hypopneas. The interested reader is
referred to the original article for patient characteristics (1).
Direct extrapolation of adult parameters to children may not be
appropriate, because children have a faster respiratory rate and
different breathing characteristics during sleep than adults (5, 6).
We therefore modified the Academy of Sleep Medicine defini-
tion and defined an obstructive hypopnea as a decrease in air-
flow to less than 50% baseline amplitude for a minimum of
two respiratory cycles. Desaturations (⭓3%) and arousals were
scored if present, but they were not required to identify the
obstructive hypopnea.
Our data showed that obstructive hypopneas are uncommon
in normal children. Only six children had any hypopneas. The
mean duration of obstructive hypopnea was 12.8 (range 3.5–40)
seconds. One child had arousals associated with hypopneas, and
two children had desaturation of 3%. None of the children had
carbon dioxide retention with hypopneas. The mean obstructive
hypopnea index was 0.1 ⫾0.1 (range 0.0–0.7) events per hour.
The combined apnea/hypopnea index was 0.2 ⫾0.6 (0.0–3.4)
events per hour. The normative values did not vary with age.
The results did not change when using the standard scoring
criteria used by the American Academy of Sleep Medicine.
Based on our data, the statistically significant apnea hypopnea
index in healthy children is 1.5 events per hour (i.e., the
mean ⫾2 SD). We conclude that obstructive hypopneas are
uncommon in older healthy children, similar to results by Acebo
and colleagues (7). Our data are limited in that they are based on
older technology. New normative data are needed using newer
technology, such as nasal pressure monitoring (7, 8). In the
interim, these data will contribute to our understanding of what
is normal. Without normative data, interpretation of obstructive
hypopneas can be subjective or arbitrary, leading to inappropri-
ate diagnosis and potentially worse morbidity.
Conflict of Interest Statement :M.B.W. has no declared conflict of interest; T.G.K.
has no declared conflict of interest; S.L.D.W. has no declared conflict of interest;
C.L.M. has no declared conflict of interest.
Manisha B. Witmans
Thomas G. Keens
Sally L. Davidson Ward
Childrens Hospital of Los Angeles
Los Angeles, California
Carole L. Marcus
Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania
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WS, Keens TG, Davidson Ward SL. Normal polysomnographic values
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