23 Gardner ID. Suppression of antibacterial immunity by infec¬
tion with influenza virus. J Infect Dis 1981; 144:225-31
24 Walsh TJ, Hiemenz JW, Seibel N, et al. Amphotericin B lipid
complex in the treatment of 228 cases of invasive mycosis.
Abstract. In: Program and abstracts of the 34th Interscience
Conference
on
Antimicrobial
(Orlando, FL). Washington,
crobiology,
Agents
and
DC: American
1994
Chemotherapy
Society for Mi¬
25 Petrikkos G, Sambatakou H, Korantzis J, et al. Amphotericin
B lipid complex for the management of systemic mycosis in
patients with nephrotoxicity and/or failure of previous
anti¬
fungal treatment. Abstract 089. In: The 13th Congress of the
International Society for Human and Animal Mycology,
Parma, Italy, 1997
26 Kitahara M, Seth VK, Medoff G, et al. Activity of amphoter¬
icin B, 5-fluorocytosine, and rifampin against six clinical
isolates of aspergillus. Antimicrob Agents Chemother 1976;
9:915
27 Lauer BA, Reller LB, Schroter GPJ. Susceptibility of as¬
pergillus to 5-fluorocytosine and amphotericin B alone and in
combination. J Antimicrob Chemother 1978; 4:375
28 Hughes CE, Harris C, Moody JA, et al. In vitro activities of
amphotericin B in combination with four antifungal agents
and rifampin against Aspergillus spp. Antimicrob Agents
Chemother 1984; 25:560
29 Arroyo J, Medoff G, Kobayashi GS. Therapy of murine
aspergillosis with amphotericin B in combination with ri¬
or 5-fluorocytosine. Antimicrob Ag Chemother 1977;
fampin
11:21
30 Polak A. Pharmacokinetics of amphotericin B and flucytosine.
Postgrad Med J 1979; 55:667
31 Carrizosa J, Levinson ME, Lawrence T, et al. Cure of
Aspergillus ustus endocarditis on a prosthetic valve. Arch
Intern Med 1974; 133:486
32 Denning DW, Stevens DA. Antifungal and surgical treatment
of invasive aspergillosis: review of 2,121 published cases. Rev
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Denning DW, Tucker RM, Hanson LH, et al. Treatment of
invasive aspergillosis with itraconazole. Am J Med 1989;
86:791-800
Denning DW, Lee JY, Hostetler JS, et al. NIAID mycoses
study group multicenter trial of oral itraconazole therapy for
invasive aspergillosis. Am J Med 1994; 97:135-44
Sugar AM. Use of amphotericin B with azole antifungal
drugs: what are we doing? Antimicrob Agents Chemother
1995; 39:1907-12
Denning DW, del Favero A, Gluckman E, et al. The efficacy
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of invasive aspergillosis (IA). Abstract P552. The 13th Con¬
gress of the International Society for Human and Animal
Mycology, Parma, Italy, 1997
37 Caillot D, Casasnovas O, Bernard A, et al. Improved man¬
agement of invasive pulmonary aspergillosis in neutropenic
patients using early thoracic computed tomographic scan and
surgery. J Clin Oncol 1997; 15:139-47
38 Roilides E, Holmes A, Blake C, et al. Antifungal activity of
elutriated human monocytes against Aspergillus fumigatus
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stimulating factor and interferon-gamma. J Infect Dis 1994;
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39 Roilides E, Uhlig K, Venzon D, et al. Enhancement of
oxidative response and damage caused by human neutrophils
to Aspergillus fumigatus hyphae by granulocyte colony stim¬
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Enuresis and Obstructive
Apnea in Adults*
Naomi R. Kramer, MD; Alice E. Bonitati,
Richard P. Millman, MD, FCCP
Sleep
MD, FCCP; and
Adult enuresis is an unusual symptom of obstructive
sleep apnea (OSA). Although it is described as a
classic symptom of childhood OSA, enuresis is en¬
countered infrequently in adult sleep medicine. Five
adults with enuresis associated with sleep apnea
presented to our Sleep Disorders Center. In all five
cases, the onset of enuresis was associated with the
progression of sleep apnea symptoms. In each case,
the enuresis resolved with treatment with nasal con¬
tinuous positive airway pressure. Current medical
literature on the postulated mechanisms of nocturia
and enuresis in sleep apnea is reviewed. Based on
the experience of the authors and review of the
medical literature, one may conclude that severe
OSA may lead to new-onset enuresis in adults and
that effective treatment of OSA is associated with
resolution of enuresis.
(CHEST 1998; 114:634-637)
Key words: adults; enuresis; obstructive sleep apnea
Abbreviations: ANP=atrial naturetic peptide; CPAP=continuous
positive airway pressure; OSA= obstructive sleep apnea
*From the Division of
Pulmonary, Sleep,
and Critical Care
Medicine, Rhode Island Hospital and Brown University School
of Medicine, Providence, RL
Manuscript received July 17, 1997; revision accepted December
to: Naomi R. Kramer, MD, Sleep Disorders
Correspondence
Center, Rhode Island Hospital, 593 Eddy Street, Providence, Rl
02903
26, 1997.
Selected
Reports
A dult enuresis is an unusual symptom of obstructive
-^*- sleep apnea (OSA). Although it is described as a classic
symptom of childhood OSA,15 enuresis is encountered
of adult sleep medi¬
infrequently in the clinical practice
cine. Five adults with enuresis associated with sleep apnea
to the Sleep Disorders Center during 1 year.
presented
The purpose of this study is to review the key clinical
features and polysomnogram data of these patients in
order to better define who is likely to develop this
troubling symptom.
Case Series
Clinical Data
All five patients were referred for evaluation of snoring with
witnessed apneas and excessive sleepiness. All five patients were
male. The mean age at time of presentation was 38 ±9 years. All
the patients were obese, with mean (± SEM) body mass index of
38.6±2.1 kg/m2 and neck size of 17.5±0.3 cm. Comorbid
illnesses included hypertension (2 patients), moderate COPD
(FEVjl of 1.69 in 1 patient), moderate alcohol use (3 to 6 alcoholic
and diabetes mellitus (1
beveragesNoper night inwere2 patients),diuretics.
Caffeine use was
taking
patient). patients
quite extensive in most patients and ranged from 16 oz of soda to
32 oz of coffee plus 12 oz of soda per day. However, no patient
used caffeine in the evening after dinner.
Although all of these patients snored for many years, there had
been a significant increase in snoring, witnessed apnea, and
sleepiness associated with weight gain in the months prior to
presentation. In all five patients, enuresis developed during this
time period of progressive sleep apnea symptoms. Only one of
these patients had a prior history of enuresis. The enuresis had
previously resolved at age 19 and then recurred at age 29 when
he developed symptoms of sleep apnea. In one other patient,
enuresis occurred transiently 1 year prior to presentation and
then recurred in the 2 to 3 months prior to presentation. He
to five
multiple episodes per night requiring threesheets.
experienced
In
changes of underwear per night and the use of plastic
contrast, 2 other patients each experienced only 4 episodes of
enuresis occurring over 4 to 5 months of increasing snoring and
sleep apnea symptoms prior to presentation. In the fifth patient,
the enuresis occurred intermittently. He would experience en¬
uresis on a nightly basis for three to four nights and then it would
abate for several nights. This patient also started sleep walking
(not in association with enuresis per se), which he had not done
in childhood. The patient with the most severe enuresis (multiple
episodes per night) did not have a higher apnea/hypopnea index,
lower oxygen saturation, or longer duration of respiratory events.
He did, however, have the highest body mass index.
Table 1.Clinical Features
Age
kg/m2
AHI,
Baseline
46
29
35
42
33
37.0±3.1
46.7
35.2
36.9
38.5
35.7
38.6±2.1
80
109
117
105
126
107.4±7.7
BMI,
Testing
In the laboratory, split-night polysomnograms were recorded
for all five patients. Monitoring was accomplished using two EEG
leads, two electro-oculogram leads, a submental electromyogram,
a snoring microphone, an airflow thermistor, chest and abdomi¬
nal Piezo electrode bands, pulse oximetry, an ECG, and bilateral
anterior tibialis electromyogram. All 5 patients had severe sleep
apnea during a baseline period of a minimum 2 h of sleep. The
events per
apnea/hypopnea index was 107.4±7.7 (mean±SEM)
hour of sleep with a nadir 02 saturation of 75.2±2.7%. The apnea
duration ranged from 10 to 45 s. The mean duration of the
longest event of each record was 35 s. Mean sleep efficiencyofwas
84%, with a range of 60 to 98% during the baseline portion the
record. In three of the five studies, rapid eye movement sleep was
not seen during the baseline portion of the record; thus, the
degree of sleep apnea may have been underestimated in these
patients. Nasal continuous positive airway pressure (CPAP) was
titrated during the second half of the study. The optimal pressure
ranged from 12.5 to 20 cm H20. The apnea/hypopnea index at
the optimal CPAP pressure was 10.6±2.7 with a nadir 02
saturation of 91.2±1.2% (Table 1).
Results of Treatment
The patients were seen 1 to 2 weeks after the sleep study and
nasal CPAP was started at home. They were again seen for
reported
follow-up examination in 1 to 4 months. All the patients
complete resolution of snoring, daytime sleepiness, and enuresis
with use of CPAP.
DISCUSSION
To date, there are a maximum of 17 cases of enuresis
associated with sleep apnea reported in adults.511 The
general
early reports of enuresis are included in severalfrom
the
reviews and case series about sleep apnea
same institution. Therefore, it is possible that some
patients may have been included in more than one
report. It is not clear, however, who experiences enure¬
sis and why. This study presents five men with OSA and
enuresis who presented to the sleep center over a
the closest calendar year,
period of 12 months. During
1,561 polysomnograms were recorded. Of these, 775
studies were initial studies establishing a diagnosis of
OSA in an adult patient. Although a positive history of
enuresis unrelated to other medical disorders was doc¬
umented in only five patients, the absence of this
symptom was not always documented in other patients.
Therefore, the true incidence of this symptom cannot
of Enuresis and Obstructive Sleep Apnea
Nadir 02 %,
Baseline
AHI With
CPAP*
Nadir 02 %,
With CPAP*
82
74
74
66
70
10
10
2
19
12
92
89
93
88
94
73.2±2.7
10.6±2.7
91.2±1.2
*p<0.005 compared to baseline. Data is expressed as Mean±SEM. BMI=body mass index; AHI=apnea/hypopnea index
CHEST/114/2/AUGUST, 1998
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635
be established. However, it is clearly an infrequently
offered complaint The patients were all obese with very
severe disease. The enuresis developed in conjunction
with weight gain and worsening symptoms of OSA. The
onset of enuresis with the onset of sleep apnea symp¬
toms and the resolution of enuresis with CPAP treat¬
ment of OSA suggests that the sleep apnea may be the
cause of the enuresis in these patients.
The mechanism of enuresis in patients with sleep apnea
is probably multifactorial. Patients with massive obesity
have an increased glomerular filtration rate.12 Krieger et
al13 demonstrated higher fractional urinary flows, higher
fractional sodium and chloride excretion, and a lower
percentage of filtered sodium reabsorption in patients
with sleep apnea compared with those values in normal
subjects. Treatment with nasal CPAP tended to normalize
the renal function in the patients with OSA. Furthermore,
the use of CPAP was associated with reduced urinaiy
output and increased Na+ resorption. Although this study
is limited because patients and normal subjects were not
age- and weight-matched, other research has shown sim¬
ilar results.1416
articles by these and other authors sug¬
Subsequent
a
role
for
atrial naturetic peptide (ANP) in these
gest
in
renal
function.1520 Negative intrathoracic
changes
pressure swings associated with respiratory effort
against a closed airway are associated with increased
venous return. In addition, the hypoxia associated with
an apneic event may induce pulmonary vasoconstriction, which can cause right ventricular overload and
right atrial distention. The subsequent atrial dilatation
may lead to ANP release, and this increase in ANP
levels enhances urinary excretion. In support of this, the
work by Krieger and his colleagues17 suggested that the
ANP levels correlated with the degree of hypoxemia as
well as the degree of negative intrathoracic pressure
associated with apneas.
Although several articles have demonstrated in¬
creased ANP levels in patients with sleep apnea and a
decrease in ANP levels with treatment with nasal
CPAP,1618 not all studies have been consistent in their
findings. In a study by Warley et al,21 ANP levels were
not elevated in normal subjects when OSA was simu¬
lated in normal subjects with an inspiratory threshold
load. The degree of negative inspiratory pressure swings
and the degree of hypoxemia were not as severe as those
seen in actual patients with OSA in the other studies.
Bodenstein et al22 found changes in diuresis and natriuresis in patients with sleep apnea before and after
treatment, similar to those documented by other au¬
thors. However, they were not able to demonstrate a
change in ANP levels with CPAP. Some of their patients
did have left ventricular dysfunction, which can raise
ANP levels. This rise in ANP would not be expected
necessarily to improve with CPAP. In addition, the
blood samples these authors collected were peripheral
venous samples drawn in the morning, after the patients
were awake. Although Krieger et al18 found a trend
towards lower ANP levels in OSA patients receiving
CPAP treatment, the difference in ANP level before
and after CPAP therapy only reached statistical signif¬
636
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pulmonary artery samples rather than
peripheral
samples were analyzed. ANP levels
are higher in the pulmonary artery than in peripheral
venous blood even in normal subjects. In addition, ANP
has a very short half-life (2 to 3 min). Therefore, some
discrepancy in results between studies may reflect time
and site of ANP sampling.
Typically, patients with sleep apnea complain of
frequent awakenings to urinate.23'24 The fact that a
small subset of patients do not fully awaken to urinate,
but rather have enuresis, suggests that there may be
something abnormal with their arousal response. Per¬
haps the inordinately high number of arousals that these
patients experienced may have blunted their ability to
fully wake up. Data from Berry et al25 suggest that OSA
itself (perhaps due to sleep fragmentation) decreases
the arousal response to airway occlusion. The apnea
duration in patients in this study was not as long as that
seen by Berry et al.25 (Berry et al found apnea duration
increased as arousal threshold increased.) However, this
study did not measure esophageal pressure swings or
responses to other stimuli, so data on arousal threshold
per se cannot be provided. To determine if an altered
arousal threshold is really the key factor in causing
enuresis rather than nocturia, a prospective study ex¬
amining the duration of apnea, changes in esophageal
and arousal
to other
icance when
venous
stimuli, among
pressure,
response
other variables, is necessary. It has been shown, how¬
ever, that sleep fragmentation alone (not associated
with respiratory disturbance) impairs the arousal re¬
sponse to acoustic and respiratory stimuli in humans
and animals.26'27 The patients presented in this study all
had very severe OSA with frequent arousals.
In summary, severe OSA may lead to new-onset enure¬
sis in adults. The enuresis resolves with successful treat¬
ment of the sleep apnea. Further research in human
subjects is necessary to fully elucidate the pathophysio¬
logic features of this disorder.
1
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guanosine 3':5'-cyclic monophosphate during sleep in ob¬
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16
17
Warley ARH, Stradling JR. Abnormal diurnal variation in salt
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27
Edward P. Gerstenfeld, MD; Yogarajah Balarajan, MD;
Robert Cooke, PAC; and Robert S. Mittleman, MD
36-year-old man with a history of hypertrophic
obstructive cardiomyopathy presented to the emer¬
gency room with "stabbing" chest pain. He had
undergone dual-chamber pacemaker implantation
in 1993 using an atrial lead (Accufix; Telectronics;
Englewood, Colo) and a myomeetomy in 1996 during
which the distal portion of the atrial lead was re¬
moved. Digital fluoroscopy revealed that the reten¬
tion wire had migrated out of the remaining atrial
lead and perforated the right atrium. The retention
wire was successfully removed percutaneously. The
need for complete removal of the retention wire in
the Accufix lead at the time of open-heart surgery is
A
emphasized.
(CHEST 1998; 114:637-639)
Key words: atrial lead; hypertrophic obstructive cardiomyopa¬
thy; lead extraction; pacemaker
patient who had implantation of a dual chamber
****pacemaker experienced "stabbing" pain that resulted
from migration of the retention wire out of the atrial lead
and perforation of the right atrium. This report recounts
the clinical data pertinent to the patient.
A
Case Report
A 36-year-old man with a history of hypertrophic obstructive
cardiomyopathy presented to the emergency department com¬
plaining of severe, pleuritic chest pain radiating to his back. A
diagnosis of hypertrophic obstructive cardiomyopathy had
been made when the patient was a child. Because of symptoms
of exertional dyspnea and chest pain refractory to medical
therapy, he underwent implantation of a dual-chamber pace¬
maker in 1993 with the use of an atrial lead (Accufix;
Telectronics; Englewood, CO). The atrial lead is now known to
be susceptible to fracture of the retention wire, leading to
cardiac perforation or embolization (J. W. Dennis; Telectron¬
ics; written communication; November 3, 1994). His symp¬
toms persisted, and he was referred to an outside institution
in 1996.
time of
At the
where he underwent a myomeetomy
at
of
atrial
lead
was
cut
the
the
surgery,
junction the superior
vena cava and right atrium as recommended, with the inten¬
tion of removing the retention wire. The rest of the lead was
109:
1490-96
26
Migration and Right Atrial
Perforation of an Accufix Atrial
Lead Retention Wire Following
Partial Lead Removal During
Myomeetomy*
Downey B, Bonnet MH. Performance during frequent sleep
disruption. Sleep 1987; 10:354-63
Phillipson EA, Bowes G, Sullivan CE, et al. The influence of
sleep fragmentation on arousal and ventilatory responses to
respiratory stimuli. Sleep 1980; 3:281-88
and Pacing,
Electrophysiology
of Medicine, University of
Department
Massachusetts Medical Center, Worcester.
received November 21, 1997; accepted December
Manuscript
17, 1997.
Correspondence to: Edward Gerstenfeld, MD, UMMC, Division
of Cardiology, 55 Lake Avenue Noi~th, Worcester, MA 01655
*From the Section of Cardiac
Division of Cardiology,
CHEST/114/2/AUGUST, 1998
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637