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Jornal de Pediatria - Vol. 77, Supl.1 , 2001 S97
0021-7557/01/77-Supl.1/S97
Jornal de Pediatria
Copyright © 2001 by Sociedade Brasileira de Pediatria
REVIEW ARTICLE
Neonatal apnea
José Maria de Andrade Lopes*
Abstract
Objective: to review medical literature related to apnea of prematurity.
Sources: extensive literature search and clinical practice-oriented concepts.
Summary of the findings: apnea is one of the most common respiratory disorders in the neonatal
period. Immaturity of the central nervous system is associated with instability of respiration. Therefore,
apnea manifests itself in other systems, causing problems such as hypoglycemia, hypothermia, infection,
or patent ductus arteriosus. Apnea may be central, obstructive or mixed depending on the presence of air
flow through the upper airways. Diagnosis should involve careful observation by unit personnel and the
monitoring of heart rate, respiratory frequency or arterial oxygen saturation. Initially, the treatment consists
of xanthines (caffeine and aminophylline). If respiratory failure occurs, then continuous positive airway
pressure (CPAP), and mechanical ventilation should be used.
Conclusions: preterm newborns are susceptible to respiratory problems, having apnea as a clinical
manifestation of disorders in many organs and systems.
J Pediatr (Rio J) 2001; 77 (Supl.1): S97-S103:apnea, prematurity, respiration.
Introduction
Apnea is the most frequent type of breathing disorder in
the neonatal period.1 During the past few years, the use of
artificial surfactants, of new technologies, and the progress
in neonatal care have allowed for a considerable increase in
the survival of newborn infants with less than 1,500 grams
and, consequently, in the population at risk for apnea. 2
Most of the times, apnea is an isolated event, but that can put
the newborn’s life at risk if not promptly diagnosed and
adequately treated. Exceptionally, severe apnea affects
term newborn infants, but it is common in newborns with
less than 2,500 grams.
In this paper, we will discuss basic concepts and practical
aspects of the treatment of apnea in newborn infants.
Definition and concepts
The definition of apnea has been changing in the past
years due to new findings on its physiopathology. Initially,
apnea was defined in terms of respiratory movements.
Cessation of respiratory movements of 5, 10, 20, or 30
seconds’ duration have been used to define apnea. Most
authors agree that episodes of any duration followed by
bradycardia and/or cyanosis are considered pathological.3,4
It is important to underscore that the more immature the
newborn, the greater the irregularity of respiration and the
* Chief, Department of Neonatology, Instituto Fernandes Figueira,
FIOCRUZ. Member, Perinatology Committee, Brazilian Society of
Pediatrics (SBP).
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S98 Jornal de Pediatria - Vol. 77, Supl.1, 2001
number of episodes of apnea without bradycardia and
cyanosis, and with spontaneous recovery. Particularly during
REM (Rapid Eye Movement) sleep, apneic spells with 10 to
15 seconds’ duration are very frequent.5 Alternately with
episodes of periodic respiration, others have also reported
apneic spells lasting 5 to 10 seconds without physiological
consequences (see next section).
The definition of apnea based on respiratory movements
is incomplete, and that is because even during active
respiratory movements there may be an obstruction of the
upper airways and a cessation of gas exchange. This condition
is known as obstructive apnea (Figure 1).
Central apnea -
total cessation of respiratory
movements, and consequent
cessation of airflow in the upper
airways.
Obstructive apnea - cessation of airflow in the upper
airways in the presence of active
respiratory movements.
Mixed apnea episode of central apnea
followed by obstructive episode
(respiratory movements without
airflow in the airways) or
obstructive episode followed by
central apnea.
Figure 1 - Classification of neonatal apneas
In this sense, apnea is currently defined as the cessation
of airflow longer than 5 seconds in the upper airways.
Apnea is pathological and, independently of its duration, it
is followed by bradycardia and cyanosis.
It is interesting to underscore that as a general rule,
obstructive apneas lead to earlier bradycardia. Central
apnea rarely presents hemodynamic consequences if it lasts
less than 20 seconds.
Predisposing factors
We will discuss two of these factors, firstly, respiration
control and, secondly, sleep and alterations of thoracic
cavity.
Respiration Control
Respiration control in newborn infants is the focus of
extensive research projects carried out worldwide due to
the differences in relation to adult patients.
Neonatal apnea - Lopes JMA
The response to hypoxia is paradoxal.6 While in adults
patients hypoxemia stimulates breathing, in newborn patients
the response is diphasic, initially with hyperventilation and
followed by ventilatory depression. One of the possible
causes of post-hypoxia depression in newborns is the release
of adenosine to the central nervous system. Adenosine is a
nitrogen base produced with breakdown of adenosine
triphosphate (ATP) during hypoxia. Its effects can be
blocked by xanthines (caffeine and teophylline). Xanthines
are adenosine receptor antagonists. Lopes et al. 7 studied the
role of adenosine in newborn piglets. The authors concluded
that pretreatment with xanthine abolished the ventilatory
depression associated with hypoxia.7
The diphasic response to hypoxia can deteriorate cases
of neonatal apnea because patients will enter an endless
cycle of apnea-hypoxia-apnea, which leads to worsening of
ventilatory depression.6
The response to hypercapnia is still controversial. Some
authors consider that the response is similar to that of the
adult; whereas others insist that, at least during the first days
of life, the response is depressed. In very low birth weight
newborns (less than 1,500 g), studies have reported a
reduced sensitivity to CO2, which improved with increase
in gestational age.8
The most important aspect of respiration control is that
there is a poor neuronal organization. The more immature
the newborn infant, the more immature the central nervous
system, with reduced synapses and dendritic branches.9
Physiologists tend to define the respiration of the newborn
as a sensory and motor experience extremely dependent on
the quantity and quality of sensory afferent stimulation.
This concept is based on the facts that simple alterations of
room temperature (hypo and hyperthermia) can, sometimes,
cause apnea; physical or sensory stimulation are capable or
reverting clinical status of apnea; hypoglycemia is frequently
associated with apnea; and apnea itself is, at times, the most
common symptom in the presence of infection, anemia, or
metabolic disorders.10
Consequently, if, on the one hand, there are more
exciting stimuli than grating stimuli, breathing will continue.
If, on the other hand, there are more grating stimuli, apnea
will occur.
Sleep and alterations of the thoracic cavity
Sleep will determine important changes in the respiration
of the newborn infant. There are basically two types of
sleep, non-rapid eye movement (NREM) and rapid eye
movement (REM). As soon as we fall asleep we enter the
NREM stage. This stage is characterized by regular
breathing, broadband waves, low-frequency EEG, and no
REM for a duration of 15 to 20 minutes (EEG indicating
rapid, low-voltage waves). These two stages are repeated
Neonatal apnea - Lopes JMA
Jornal de Pediatria - Vol. 77, Supl.1 , 2001 S99
during sleep in the NREM-REM sequence. Adults will have
approximately 80% of their sleep in NREM. Conversely,
premature newborn infants with less than 32 weeks will
have approximately 80%of their sleep in REM.4,11
Table 1 -
Factor
Possible mechanism
During sleep, the REM stage is characterized by irregular
breathing with intermittent respiratory pauses and apneas.
During this period of sleep, there is a central inhibition of all
postural muscles inducing a generalized muscle hypotonia.
Among the muscles affected there are the inspiratory
intercostal muscles, which keep the thoracic cavity together.
Near atonia of these muscles will lead, consequently, to
distortion of the rib cage during inspiration causing what is
called paradoxical inspiratory motion of the abdomen
(abdominal paradox). This distortion will result in an increase
in the work done by the diaphragm, which will have to
contract more in order to maintain adequate levels of
ventilation (see below fatigue of the diaphragm).12,13
PDA
Hypoxia and/or muscle fatigue
Anemia
Hypoxia
Hypoglycemia
Central, lack of substrate to
respiratory muscles
Hypocalcemia
Central, lack of substrate to
respiratory muscles
Infection
Hypoxemia? Increased metabolic
rate, central inhibition
Prematurity
CNS immaturity, muscle fatigue
Thermal instability
Inhibitory afferent stimulation
Intracranial pathology
Direct effect on respiratory centers
The lung volume at rest (functional residual capacity =
residual volume + expiratory reserve volume) is 30% lower
in REM sleep in relation to that of NREM sleep.24 According
to some authors, this fact, in addition to the alterations to the
thoracic cavity, is responsible for the fall of approximately
10 mmHg in TcPO2 (transcutaneous PO2) during REM
sleep.14 It is a known fact that a small grade of hypoxia can
be the cause of apnea; in this sense, this condition can be
easily reverted with the newborn being administered oxygen
at 25%.
Gastroesophageal reflux
Inhibitory reflex concerning
upper airways
Drugs
CNS depression
Another important aspect related to sleep is muscle
tonus. It is understood that muscle tonus is reduced during
sleep and there is a near state of atonia in REM sleep. This
hypotonia also affects the upper airway muscles, and it is
responsible for a significant increase in lung resistance and
in respiratory work.15
Currently, it is understood that maintaining airways
permeable depends on a perfect respiratory, pharynx and
larynx muscles coordination. These muscle groups contract
in synchrony during inspiration. The generation of negative
airway pressure by the respiratory muscles, in normal
situations, should be counteracted by contraction of upper
airway muscles. One of these muscles, which is widely
studied even in newborn patients, is the genioglossus (GG).
Contraction of the GG will set the tongue in the anterior
position, avoiding contact with the posterior wall of the
pharynx. Lack of contraction of this muscle, consequently,
will almost always result in obstructive apnea. In 1987,
Carlo et al. detected obstructive episodes related to
unsynchronized GG and diaphragm.17
Etiology
The mechanisms through which different factors are
related to the occurrence of apnea are not entirely established.
Table 1 presents a relationship between some of the possible
physiological mechanisms involved.
Factors related to the occurrence of apnea, and some
possible physiological mechanisms involved
For a long time neonatologists and physiologist have
been in search for an explanation for occurrence of apnea.
It is neither understood why newborns stop breathing nor
why once it has stopped most of these babies do not resume
regular breathing. These are classical factors reported in the
literature as to the occurrence of apnea. Often, when the
related pathologies are treated, apnea will improve or
disappear completely. However, there are many cases of
newborn infants whose apnea does not present a related
cause; these cases are called idiopathic apnea. 1,10
Recently, at the Instituto Fernandes Figueiras, a study
was carried out on the risk factors for neonatal apnea in
newborns with less than 1,500 g. Out of a total 63 newborns
who survived until 1 year of age, 32 presented apnea at some
point and that required treatment, and 10 presented severe
and recurring apnea. The average weight of newborns with
apnea was of 1,124 g, whereas in those without apnea it was
of 1,270 g. The incidence of apnea was inversely proportional
to gestational age/weight. Results indicated an incidence of
90% in patients with less than 1,000 g and of 43% in those
between 1,000 and 1,500 g. The relative risk for apnea did
not differ for type of delivery, sex, sepsis, intracranial
hemorrhage, and bronchopulmonary dysplasia. However,
results also indicated that the relative risk for apnea was of
1.73 (1.13 - 2.66) in patients with weight appropriate for
gestational age as compared to those small for gestational
age; and of 2.58 (1.16 - 5.74) in patients with hyaline
membrane disease as compared to those without hyaline
membrane. These data corroborate the international literature
in the sense that risk for apnea is greater in small, appropriate
for gestational age newborns and in situations of posthyaline membrane disease.18
S100 Jornal de Pediatria - Vol. 77, Supl.1, 2001
In a different study carried out in Canada, we indicated
that approximately 30% of the so-called idiopathic apneas
may actually be a consequence of respiratory muscle
failure.12 The increase in respiratory work associated with
increased rib cage compliance will put the premature
newborn infant at risk for muscular fatigue. Moreover, the
respiratory muscles (especially the diaphragm) of these
babies are not well-developed, and present poor
differentiation and low enzymatic capacity. Keens et al.
showed that the percentage of muscle fibers with great
oxidizing capacity (type 1 fibers) in the diaphragm is
reduced at 32 weeks. Adult percentage levels are attained
only at approximately one year of age.19
During the 1980s, studies with adult patients provided
information on the possible occurrence of diaphragm fatigue
in premature newborns. Chronic alcoholic, phosphorusdepleted patients with serum levels below 40 mg% were
removed from the ventilator as soon as plasmatic phosphorus
was corrected.20 In this sense, it is known that hypophosphatemia is common in premature newborns, especially in
those with birth weight less than 1,500 g and with history of
respiratory disease and parenteral nutrition. Human milk
lacks adequate phosphorus (P) content. Parenteral feeding
of P usually follows a fixed calcium:P ratio which affects
the intake of P. Currently, at various centers worldwide, the
administered intake of calcium and phosphorus is much
higher than that provided by human milk. The
supplementation with calcium and P is aimed at preventing
rickets of prematurity. The increased intake of these minerals
will certainly bring benefits to the respiratory muscle function
if normal levels of P are delivered to the patient.
Another mechanism of apnea - which is not widelydiscussed in the literature but is frequent in very low birth
weight newborns - is the reduction of functional residual
capacity. Newborns with birth weight less than 1,000 grams,
and who do not present severe pulmonary disease on the
first days of life can frequently maintain a regular respiratory
rhythm in the first few days of life. In this case, apnea
appears, in general, after the third day of life. Based on
indirect evidence only, it is believed that functional residual
capacity decreases progressively with repetitive collapse
and reexpansion (this can be verified with chest X-rays).
This situation will lead the newborn patient to hypoventilation, increase in oxygen requirements, and apnea.
Usually, these cases of apnea are severe enough to require
intubation and assisted ventilation.
Diagnosis
Apnea can be diagnosed as obstructive, mixed, or central
and also according to the etiology. In order to correctly
diagnose the type of apnea, it is necessary to use a polygraph
to register movements of the thorax and abdomen, and to
register airflow in the upper airways. In turn, direct and
careful observation by doctors and nurses for periods of 15
to 20 minutes can allow for an approximate clinical diagnosis.
Neonatal apnea - Lopes JMA
In a different study with a population of 20 newborns
with apnea, we showed the predominance of central episodes
in newborn infants without intracranial hemorrhage. 13
As to what concerns the etiology of episodes of apnea,
it is necessary to be on the look for the related factors, as
described above. Figure 2 presents the general diagnostic
guidelines.
1. In-depth clinical examination(auscultation of the
heart, and pulse rate);
2. Environmental conditions(temperature, necessity of
oxygen therapy, and positioning of the newborn);
3. Dextrostix, Multistix, Hematocrit;
4. Sodium, potassium, calcium, magnesium;
5. Hemogram + mini VHS (Screening for sepsis, as
indicated);
6. Blood gas analysis;
7. Chest x-ray;
8. pHmetry of the esophagus or radiological screening
for reflux;
9. Transfontanelle ultrasonography.
Figure 2 - General guidelines for the diagnosis of apnea
Treatment
General guidelines
Most services adopt a criterion for the beginning of
treatment for apnea. We indicate intervention when three or
more episodes requiring resuscitation and bag-mask
ventilation occur within 24 hours. Mild apneas with slight
cardiovascular complications and that require only physical
stimulation are usually directly observable. In these cases,
the most important measure is to monitor the newborn and
adequately register the number, the duration, and the types
of episodes.
Before beginning the treatment it is important to try to
establish an etiologic factor according to the discussion
above. When an etiologic factor is not identified, the apnea
is idiopathic and there is no question whether treatment
should be started. But if the diagnosis of apnea is related to
neonatal infection, the anti-infection therapy will not bring,
as a rule, immediate results. The question that remains is
whether it would be best to start pharmacological treatment
even considering that it is a case of infection; or whether it
Neonatal apnea - Lopes JMA
would be best to submit the patient to mechanical ventilation
until the infection gets better. This question is still to be
answered. The routine procedure at the Instituto Fernandes
Figueira is to treat only non-idiopathic apneas if the clinical
status of the patient is suggestive of rapid reversal of the
symptomatology. Newborn infants with apnea following
intracranial hemorrhage or with apnea following severe
infection require, first and foremost, that the baseline disease
be treated.
Treatment - basic principles
a) correct metabolic disorders or other intercurrent
pathologies and check environmental conditions
b) eliminate neonatal infections
c) register episodes appropriately, indicating duration, type,
frequency, and physiological consequences
d) establish treatment criteria - 3 episodes in 24 hours that
require bag-mask ventilation
Metabolic disorders and environment
Considering what we presented in the above section, it
is important to note that careful screening should be carried
out in order to correct the most frequent metabolic disorders.
Control of temperature is also critical in these situations.
Hypo- and hyperthermia can be easily corrected with
adequate temperature adjustments of the newborn’s
surrounding environment. It is recommended to register the
thermal curve simultaneously with the temperature of the
newborn and of the incubator in order to check the efficacy
of these measures. Together with the assessment of
environmental conditions, it is also important to check the
position and the neck flexion of the newborn (cause of
obstructive apnea). Moreover, it is also important to check
for upper airway obstruction and to ensure patent airways.
Neonatal infection
Unfortunately, neonatal infection is still very common.
Hence, all efforts should also be directed towards eliminating
or treating this type of infection, if it is the case. Apneas are
frequent and difficult to revert in cases of severe infection,
thus compromising the overall clinical status of the newborn.
According to our experience, infection/sepsis has been the
most frequent cause for indication of mechanical ventilation
in premature newborn infants. At our services, mechanical
ventilation is indicated in these cases since we know that
clinical status of severe infections last 48 to 72 hours, and
that apneas rarely improve before 72 hours.
Apnea and gastroesophageal reflux
The occurrence of apnea related with gastroesophageal
reflux is still a focus of discussion in the literature. 21,22 In
some cases, there is a clear relation between administration
Jornal de Pediatria - Vol. 77, Supl.1 , 2001 S101
of diet and episodes of apnea, which can be verified with
continuous esophageal pH-metry. In other cases, the pHmetry will indicate the reflux and the newborn will have an
episode of apnea, but the two episodes are not time-related.
In cases of apnea provenly related to reflux, it is
recommended that specific treatment observing posture,
diet, and administration of prokynetic drugs be carried out.
Registering episodes of apnea
Following the indication of an episode of apnea, it is
important to characterize and register episodes adequately.
It is important to register the number of episodes that
occurred within a 24-hour period, the duration of each
episode, the complications (bradycardia or cyanosis) and if
they were related to any procedure (airway aspiration or
feeding) or to position of the baby, and the maneuvers
required to reverse the situation. Careful observation of the
newborn in the incubator may not indicate the type of apnea.
Bradycardia can be often observed in newborns who are
apparently breathing normally (active thoracic movements);
hence, this is clearly an obstructive episode. If the episodes
can be reverted with adequate positioning of the baby or
changing decubitus, this indicates that they may be related
to upper airway obstruction.
Criteria for beginning treatment
We apply the criterion of occurrence of 3 or more
episodes, within 24 hours, requiring resuscitation and bagmask ventilation for the indication of intervention. Usually,
patients with apneas with 20 seconds duration or less, that
revert spontaneously or with slight physical stimulation,
and with mild cardiovascular complications can be simply
indicated for observation. In these cases, the most important
measure is to monitor the newborn and register the number,
duration, and type of episodes.
Therapeutics
Physical stimulation
Physical stimulation or repeated stimulation (kinesthetic
stimulation) are recommended in cases of mild apnea.
Other services have reported the use of oscillating mattress
as a form of repeated stimulation. This method was carried
out placing a disposable glove under the mattress and
connecting the glove to a ventilator, which is set at a low
frequency (5 to 10 minutes) for slight and intermittent
stimulation. This method has been reported efficient in a
number of cases.23,24 For severe, frequent apnea, we present
3 alternatives to be considered:
– pharmacological treatment;
– continuous positive airway pressure - CPAP;
– mechanical ventilation.
S102 Jornal de Pediatria - Vol. 77, Supl.1, 2001
Pharmacological treatment
The drug of choice is the teophylline. An initial dosage
of 6 mg/kg followed by a maintenance dosage of 4 mg/kg/
day divided in three doses is indicated. Dosages can be
administered either orally or endovenously since the
absorption of the drug is excellent. Thirty minutes after
administration of the drug, adequate plasmatic levels can be
detected, which can produce a therapeutic response. It is
important to monitor plasmatic levels 2 or 3 days after
treatment because the half-life of teophylline in newborns
varies considerably.23 Collection of blood samples pre- and
postxanthine treatment (30 minutes before and after) will
provide good information on minimum and maximum
plasmatic levels in blood. Levels between 5.0 and 15 mg/l
are considered adequate.
One of the problems with teophylline is that treatment
levels are very near the toxic levels. Clinically, tachycardia
is an early sign of toxicity. If the newborn presents
tachycardia before administering a dose of the drug
(obviously excluding other possible reasons), the next dose
should not be given. Next, plasmatic dosage should be
carried out in order to adjust blood levels. The drug causes
other undesirable effects such as upper digestive hemorrhage,
increase in diuresis, hyperglycemia, and hypercalciuria. It
is recommended to test periodically for blood glucose and
occult blood in feces.25
In the late 1980s, studies described the efficacy of
doxapram in the treatment of apnea refractory to therapeutic
levels of aminophylline. The treatment required continuous
infusion of the drug due to its short half-life. The therapeutic
regimen did not become widely used due to its complications,
such as hypertension and even intestinal hypoperfusion
with increased risk for enterocolitis. Before indicating
doxapram, it is necessary to better understand the
pharmacokinetics of the drug in newborns, as well as the
possible short- and long-term side-effects.26-28
Still in relation to treatment, it is important to comment
on the use of caffeine, which is the drug of choice at other
centers.29 The advantage of caffeine over teophylline is its
longer half-life, which allows for timed 24-hour
administration of the drug with less side-effects. In Brazil,
the caffeine citrate is not available for endovenous
administration. In turn, caffeine citrate for oral administration
is commercially available. Different authors have
recommended administration of caffeine in newborns who
despite the use of teophylline still present apnea.
Use of CPAP
Newborn infants with recurring apnea require a more
aggressive treatment despite administration of
aminophylline, caffeine, or other drugs. Apneas followed
by bradycardia and cyanosis frequently require bag-mask
ventilation. CPAP is indicated in cases of long and/or
frequent episodes of apnea.
Neonatal apnea - Lopes JMA
A common endotracheal tube can be used for CPAP.
The tube is inserted through the nose and located at the
hypopharynx. Positive pressure can be administered
following Gregory’s classical circuit or with a mechanical
ventilator. The administration of nasal CPAP can prevent
tracheal intubation in many newborn infants with apnea.
The action of CPAP is still being discussed. It is known
that there is an increase in functional residual capacity,
especially in newborns with less than 1,500 g. However, it
is not established that this is the reason for the efficacy of
CPAP. In some newborn infants, the action of CPAP is
basically that of maintaining a patent airway, which is
probably a case of obstructive apnea.
Finally, it is still necessary to consider the action
described as afferent stimulation. Positive pressure in the
hypopharynx and distention of the airways (trachea and
bronchi) can lead to stimulation of peripheral receptors. In
turn, these receptors would support the activity of respiratory
centers, thus allowing for regular breathing.
Mechanical ventilation
Mechanical ventilation is indicated in the treatment for
apnea refractory to clinical and pharmacological treatment
or to CPAP. There are two major groups of patients who
usually require mechanical ventilation:
– newborns of all birth weights and gestational age with
severe infection;
– newborns with very low birth weight (less than 1,000 g).
In septic newborns, the metabolic requirements are
increased and situations of coma are not infrequent. In these
cases it is indicated that early mechanical ventilation be
administered with the objective of reducing respiratory
work and improving prognosis. In newborns with this
clinical status, especially in septic newborns,
pharmacological treatment is indicated. In cases of good
response to antibiotictherapy, ventilatory assistance is
usually carried out for shorter periods of time.
Mechanical ventilation is indicated for newborns with
less than 1,000 g when, as a result of apnea, the baby is
labile, incapable of maintaining adequate oral intake, and
incapable of maintaining good lung volume (functional
residual capacity).
When carrying out ventilatory assistance with very low
birth weight newborns, it is important to monitor minimal
ventilator settings. Usually, there are no pulmonary diseases
and mechanical ventilation is indicated due to insufficient
drive or muscle fatigue. FiO2 (concentration of oxygen in
inspired air) should be monitored with frequency. Oxygen
should be used in amounts as low as possible to maintain
arterial PO2 between 50 and 60 mmHg in order to minimize
risks for bronchopulmonary dysplasia and retrolental
Neonatal apnea - Lopes JMA
fibroplasia. Ventilator frequency settings should be as low
as possible in order not to inhibit spontaneous breathing of
the newborn and, thus, prevent atrophy of respiratory
muscles.
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Correspondence:
Dr. José Maria de Andrade Lopes
Fundação Oswaldo Cruz
Av. Rui Barbosa, 716 - Flamengo
CEP 22250-020 – Rio de Janeiro, RJ, Brazil
Phone: + 55 21 558.1434 – Fax: + 55 21 558.1780
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